LONDON and LAUPHEIM, Germany, Feb. 11, 2021 (GLOBE NEWSWIRE) -- The Cell and Gene Therapy Catapult (CGT Catapult), an independent centre of excellence in innovation advancing the UKs cell and gene therapy industry, and Rentschler Biopharma SE, a leading global contract development and manufacturing organisation (CDMO) for biopharmaceuticals, have announced today that Rentschler Biopharma will establish their manufacturing capability in Advanced Therapy Medicinal Products (ATMPs), including Adeno-Associated Virus (AAV) Vectors for clinical trial supply, at the CGT Catapult site in Stevenage.

Under the terms of the agreement, Rentschler Biopharma will make a significant investment at the site over the next five years to set up their manufacturing capabilities, benefitting from the expertise and unique collaborative model provided by the CGT Catapult. The companys investment is expected to make a major contribution to meeting the demand from UK and international researchers for suitable manufacturing capability. This development will further strengthen the UK ecosystem through the addition of Rentschler Biopharmas more than 40 years of experience and solid reputation in the development and manufacturing of biologics for both clinical and commercial supply. The company will leverage the CGT Catapults expertise in ATMP manufacturing setup and technology development, as well as the cell and gene therapy cluster and ecosystem that has developed around Stevenage and across the UK.

Dr. Frank Mathias, CEO of Rentschler Biopharma, said:We are excited to take this next big step in our evolution and address the growing industry demand for ATMP manufacturing capacity and viral vector supply. With the largest industry cluster for cell and gene therapies outside the US, the UK is an ideal location for us to establish our Center of Excellence for cell and gene therapy. We look forward to working with the CGT Catapult as we invest in this growing field. They are well established in this important market, enabling us to immediately tap into the organisations network and utilisethe UKs strong expertise and supply chain in cell and gene therapy manufacturing.

Matthew Durdy, CEO of the Cell and Gene Therapy Catapult, commented:We are very pleased that Rentschler Biopharma, a global CDMO, has chosen to build their ATMP capacity in the UK, bringing in their expertise and investment. This will build new capacity to benefit the international ATMP supply chain and meet growing academic and commercial demand across the industry. As more companies from around the globe come to the UK, it demonstrates and enhances the attractiveness of its cell and gene therapy ecosystem as a place to develop new technologies and capabilities.

The investment in the UK cell and gene therapy industry announced today is expected to further accelerate the development of the vital infrastructure and skilled jobs needed to meet the rising demand for manufacturing capacity in the UK and globally, as well as streamline the supply chain for these advanced therapies. Currently, 27% of European ATMP companies are operating in the UK, and there are more than 90 advanced therapy developers. The last year has also seen a 50% increase in the number of ATMP clinical trials being run in the UK, accounting for 12% of global ATMP clinical trials, and these numbers are predicted to increase further.

The CGT Catapult manufacturing centre has been backed by over 75m of funding, including investment from the UK Governments Industrial Strategy Challenge Fund, the Department for Business, Energy and Industrial Strategy, Innovate UK and from the European Regional Development Fund. Since it was announced, there has been over 1.1bn of investment in the ATMP industry in its vicinity.

About Rentschler Biopharma SE

Rentschler Biopharma is a leading contract development and manufacturing organization (CDMO), focused exclusively on client projects. The company offers process development and manufacturing of biopharmaceuticals as well as related consulting activities, including project management and regulatory support. Rentschler Biopharma's high quality is proven by its long-standing experience and excellence as a solution partner for its clients. A high-level quality management system, a well-established operational excellence philosophy and advanced technologies ensure product quality and productivity at each development and manufacturing step. In order to offer best-in-class formulation development along the biopharmaceutical value chain, the company has entered into a strategic alliance with Leukocare AG. Rentschler Biopharma is a family-owned company with about 1,000 employees, headquartered in Laupheim, Germany, with a second site in Milford, MA, USA. In Stevenage, UK, Rentschler Biopharma launched a company dedicated to cell and gene therapies, Rentschler ATMP Ltd.

For further information, please visit http://www.rentschler-biopharma.com. Follow Rentschler Biopharma on LinkedIn and Facebook.

About the Cell and Gene Therapy Catapult

The Cell and Gene Therapy Catapult was established as an independent centre of excellence to advance the growth of the UK cell and gene therapy industry, by bridging the gap between scientific research and full-scale commercialisation. With more than 330 employees focusing on cell and gene therapy technologies, it works with partners in academia and industry to ensure these life-changing therapies can be developed for use in health services throughout the world. It offers leading-edge capability, technology and innovation to enable companies to take products into clinical trials and provide clinical, process development, manufacturing, regulatory, health economics and market access expertise. Its aim is to make the UK the most compelling and logical choice for UK and international partners to develop and commercialise these advanced therapies. The Cell and Gene Therapy Catapult works with Innovate UK.

For more information please visit ct.catapult.org.uk or visit http://www.gov.uk/innovate-uk.

About the European Regional Development Fund

This project has received 3.36m of funding from the England European Regional Development Fund as part of the European Structural and Investment Funds Growth Programme 2014-2020. The Ministry of Housing, Communities and Local Government (and in London the intermediate body Greater London Authority) is the Managing Authority for European Regional Development Fund. Established by the European Union, the European Regional Development Fund helps local areas stimulate their economic development by investing in projects which will support innovation, businesses, create jobs and local community regenerations. For more information visit https://www.gov.uk/european-growth-funding.

About the Industrial Strategy Challenge Fund

This project has received 12m of funding from the Industrial Strategy Challenge Fund, part of the governments modern Industrial Strategy. The Industrial Strategy Challenge Fund is a four-year, 1 billion investment in cutting-edge technology designed to create jobs and improve living standards, built on guidance from business and the academic community. Healthcare and Medicine is one of three core areas for investment under the programme.

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Rentschler Biopharma to build new cell and gene therapy capabilities in the UK - BioSpace

Recommendation and review posted by Bethany Smith

Part of Aldevrons expansion is a fermentation suite that will allow the company to expand its projects scope and scale. Submitted photo

From February through June, we will highlight the ways that UWMadison powers the states economy through research and innovation, educates the next generation and reaches out to Wisconsinites to improve their lives. Februarys theme is Economic Prosperity. Watch for more at #CantStopABadger and #UWimpact on social media.Your supportcan help us continue this work.

February 10, Aldevron hosted a virtual celebration of its lab facility expansion in Madison.

Aldevron produces the raw materials that allow clients to make groundbreaking therapies, and its protein business unit has operated within University Research Park since 2009. The facilitys growth from 8,000 to nearly 30,000 square feet includes a new 3,500-square-foot fermentation suite and will allow the company to expand its projects scope and scale.

Aldevron founders John Ballantyne and Michael Chambers partnered with Tom Foti to establish the companys protein business unit in Madison in 2009 to expand Aldevrons offerings.

Madison is rightly known around the world as a biotech hotspot, and the fact that there was a team out there ready to hit the ground running made it sort of a no-brainer, said Ballantyne, who serves as Aldevrons Chief Science Officer.

Speakers at the celebration pointed out that Aldevrons partnerships with UWMadison in research and education benefit both the company and the university.

I watched Aldevron partner with researchers at the University of WisconsinMadison, with other companies at the Park, and with partners all over the globe, and its these partnerships that are at the very center of Aldevrons business model, said Aaron Olver, the Managing Director of University Research Park, a UWMadison-affiliated nonprofit that creates neighborhoods where innovation can flourish. So with the newly expanded capacity at the Park, I know Aldevrons going to be able to find new partnerships and new opportunities, to push the boundaries of science even further.

Ballantyne envisions the Madison team continuing their collaborations with researchers and also expanding into RNP capabilities for gene editing and IVT enzymes. He praised the teams reputation and ability to transition new products into a manufacturing environment, saying theres an art to that tech transfer.

A lot of rigor goes into building our systems, especially with the complexity of protein, he said. Its very exciting what their ramp-up is going to look like out there.

The University of Wisconsin has created a dynamic hub of biotech companies, based on its amazing research companies and abundance of trained talent, said Aldevron CEO Kevin Ballinger, citing Aldevrons partnership with UWMadison as a compelling reason the company has continued to invest in its Madison site.

We made the investment ten years ago and doubled down on this site because we see the incredible return and endless possibilities in the following areas: scientific collaboration around gene editing, a supply chain for cell therapy manufacturing, partnership on workforce development, and talent recruitment to help staff our growing team.

The University of Wisconsin has created a dynamic hub of biotech companies, based on its amazing research companies and abundance of trained talent. Aldevron CEO Kevin Ballinger

Aldevrons Madison team makes CRISPR proteins like Cas9 that are essential to the field of gene editing and its potential to treat thousands of previously untreatable medical conditions. Aldevron Madison also makes the IVT enzymes for research use that support mRNA technology. Later this year, Aldevron will be making GMP IVT enzymes for clinical applications, all of which will be supported by the companys pending ISO1345:2016 registration. The company is currently pursuing ISO 1345:2016, a standard for FDA compliance.

Aldevrons RNP services turn CRISPR reagents into therapies, and by the middle of this year, well be the only company to launch a RNP manufacturing service to provide GMP reagents to clients developing gene therapies, says Ballinger.

Tom Foti, President of Aldevrons protein business unit since its 2009 Madison launch, said he will likely increase his staff by about 40% with the facilities expansion.

Diversity is super important in high-performing teams, said Foti. We are investing in talent to build a strong culture centered around problem-solving and continuous improvement.

Both Foti and Katie Rogers, Aldevrons Senior Manager of Upstream Processing, described the expanded main lab area and vibrant communal spaces bathed in natural light.

More scientists and equipment mean Aldevron can serve more clients, said Rogers.

Local expansion partners include companies based in the Madison area: J.H. Findorff & Son Inc.; Strang, Inc.; M&M Office Interiors; Fearings Audio Video Security; Capitol Mechanical; Faith Technologies; Livesey Painting, Inc.; Lake City Glass; Monona Plumbing and Fire Protection; Sergenians Floor Coverings; and Badger Acoustics, Inc.; as well as Wausau-based Graphic House.

Dr. Richard Moss, Senior Associate Dean for Basic Research, Biotechnology and Graduate Studies at the University of WisconsinMadison School of Medicine and Public Health, emphasized the strength of Aldevrons collaboration with UWMadison.

Our relationship with Aldevron over time has evolved into a partnership that is not only collaborative but very effective, said Moss. Ongoing conversations between UW and Aldevron are really focused on expanding learning opportunities for students at the UW in the health professions.

Aldevron supports UWMadisons Masters program in biotechnology, offering real-world educational opportunities for students in the program and for graduate students and postdocs across campus. UWMadisons Department of Industrial Engineering has collaborated with Aldevrons quick response manufacturing team on biological manufacturing processes, and Aldevron has partnered with professor Kris Saha in the Department of Biomedical Engineering on gene editing approaches to genetic medicine.

We hope we will be able to expand our partnership in the near future to our program in advanced cellular therapies, with the idea of moving these new therapies to cell therapy manufacturing, said Moss. We see these partnerships as a win for translating discoveries from the bench to the bedside. Its a win for learners; its a win for researchers; and most importantly, its a win for advancing the health of the patients in the communities that all of us serve.

UW-Madison contributes $20.8 billion per year to the Wisconsin economy, and UWMadison related start-ups contribute an additional $10 billion. Read morehere.

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Aldevron expands manufacturing capabilities in Madison - University of Wisconsin-Madison

Recommendation and review posted by Bethany Smith

The global rare disease gene therapy is expected to witness a significant growth in the forecast period, 2020-2030 on account of the increasing cases of genetic diseases worldwide. Gene therapy is relevant to rare disease patients and has improved the wellbeing and personal satisfaction of more seasoned kids and youthful grown-ups with X-SCID. These kids are expected to experience complex clinical issues in the wake of getting live-sparing bone marrow transfers to treat the condition.

Impact of COVID-19 on the Healthcare Industry

The COVID-19 pandemic has caused severe impacts on the global economy at various levels and which can be seen on the Healthcare industry as well. The thriving market of health care research and development is expected to exhibit a steep decline in the sales during the lockdown period owing to the shutdown of the manufacturing units, acute shortage in the supply of raw materials and absence of potential manpower. It can be deduced from the current situations brought about by the pandemic that the production, and supply chain activities have experienced minor hurdles. However, the market is projected to gradually recover post-COVID-19, which will present attractive opportunities for sales across various regions of the world in the following years.

Future Market Insights (FMI) adopted a multidisciplinary approach during the pandemic-era to focus on the growth and development of theRare Disease Gene Therapy Market. The study features insights on the current growth dynamics and the major revenue reforms prevailing in the market as of 2019 along with the key takeaways over the forecast period 2020 to 2030.

The team of analysts at Future Business Insights are focussing on research and market study to produce different Rare Disease Gene Therapy Market forecasts and predictions at both national and international levels. They have considered several leads of information pertaining to the industry like market figures and merger estimations to assess and produce reliable and informative insights on the Rare Disease Gene Therapy Market.

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Key Players

The writer will create content on the general strategies of market players. And then will write the key players in the market are: Pfizer Inc., Amgen Inc., Bristol-Myers Squibb Company, AbbVie Inc., Novartis AG F. Hoffmann-La Roche Ltd., Teva Pharmaceutical Industries Ltd and Others

Segmentation

The report provides insights on the important highlights and current trends prevailing in the market. This helps the readers to gain a deeper understanding and form an unbiased opinion on the market. Numerous segmentations have been provided for this market based on:

Gene Therapy

Indication

Administration

Distribution Channel

Get Access to Research Methodology Prepared by Experts >>https://www.futuremarketinsights.com/askus/rep-gb-12563

Product Segmentation

The investigation offers a top to bottom evaluation of different clients journeys pertinent to the market and its segments.The study endeavours to assess the current and future development possibilities, undiscovered roads, factors that shapes their income potential in the global market by breaking it into di such as its types, applications, and region-wise assessment.

By Regional Analysis Covered

Full in-depth analysis of the parent market

The analysts at FMI are dedicated to provide insights after extensive research and study. The study also includes estimations, projections and evaluation of the market dynamics.

Important changes in market dynamics

The report has been created after detailed and exhaustive studies by the analysts at FMI taking several factors into consideration like monetary, ecological, social, mechanical, and political status of a particular demography. They study the key data to assess the revenue and production of manufacturers across various regions. The report also covers an in-depth analysis of the key changes in market dynamics in the recent past and the near future.

Segmentation details of the market

Queries Solved

To receive extensive list of important regions, ask for TOC here >>https://www.futuremarketinsights.com/toc/rep-gb-12563

Table of Content

Reasons to Buy the report

About FMI

Future Market Insights (FMI) is a leading provider of market intelligence and consulting services, serving clients in over 150 countries.FMIis headquartered in Dubai, the global financial capital, and has delivery centers in the U.S. and India. FMIs latestmarket research reportsand industry analysis help businesses navigate challenges and make critical decisions with confidence and clarity amidst breakneck competition. Our customized and syndicated market research reports deliver actionable insights that drive sustainable growth. A team of expert-led analysts at FMI continuously tracks emerging trends and events in a broad range of industries to ensure that our clients prepare for the evolving needs of their consumers.

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Rare Disease Gene Therapy Market: Increasing cases of genetic diseases to drive the market - PharmiWeb.com

Recommendation and review posted by Bethany Smith

Feb. 15, 2021 19:00 UTC

MONTPELLIER, France--(BUSINESS WIRE)-- Regulatory News:

Sensorion (Paris:ALSEN)(FR0012596468 ALSEN) a pioneering clinical-stage biotechnology company which specializes in the development of novel therapies to restore, treat and prevent within the field of hearing loss disorders, announces the addition of a new gene therapy target, GJB2 coding for the Connexin 26 protein, to its development portfolio. The target is the third candidate to emerge from Sensorions R&D collaboration with Institut Pasteur. The GJB2 program will focus on major new markets with an estimated patient population (prevalence) of 300,000 children and adults in Europe and in the United-States alone.

New research (Boucher et al., Proc Natl Acad Sci U S A. 2020;117(49):31278-3128) published by scientists at the Institut Pasteur shows that anomalies in GJB2 are not only the most common cause of congenital deafness (prevalence of around 200,000 individuals in the US and in Europe alone) but also occur in adult cases of severe age-related hearing loss (around 100,000 adults in the same geographies). Although the types of GJB2 mutations in children and adults may differ, gene therapy could potentially provide a solution to both.

Sensorion's GJB2 gene therapy program has the potential to target three pathologies related to GJB2 mutations: age-related hearing loss in adults, progressive forms of hearing loss in children, and pediatric congenital deafness. Initially, the focus will be on the first two populations with GJB2-associated hearing loss, making Sensorion the first company to address these important medical needs in adults and potentially large market opportunities.

Current scientific understanding suggests that mutations in GJB2 alter a gap junction protein widely expressed in the inner ear, disturbing intercellular exchanges of molecules and leading to hearing loss that is severe-to-profound in a majority of cases.

The emergence of a new gene therapy target candidate validates our conviction that long-term solutions for restoring hereditary hearing loss will arise from an in-depth analysis of the "genetic landscape" of hearing loss," said Nawal Ouzren, CEO of Sensorion. "It was clear that mutations in the GJB2 gene are important in severe to profound childhood hearing loss. However, the new discovery made by our collaborators at Institut Pasteur shows that alteration of this gene in adults offers new opportunities for Sensorion. It marks significant potential expansion of our pipeline and supports our goal of becoming a global leader in the field of gene therapies for hearing loss disorders.

"Until now, the genetics of late forms (age-related deafness or presbycusis) was considered to involve multiple variants in each individual," said Professor Christine Petit, Director of the French Hearing Institute, an Institut Pasteur Center. "We have shown that the same genes underlying congenital or childhood deafness are also involved in severe forms of early presbycusis. The presence of these very rare genetic variants makes these forms of presbycusis appear to be monogenic types of hearing loss which can therefore be potentially treated by gene therapy."

Sensorions collaboration with Institut Pasteur initiated in 2019 has already led to gene therapy candidate programs in two other indications - Otoferlin deficiency and Usher Syndrome Type 1. GJB2-GT is the third program under this collaboration and represents the largest gene therapy opportunity for Sensorion to date.

Considering its broad and rich pipeline, Sensorion may have to consider a reallocation of some resources in the future to focus on the most attractive development programs.

Sensorion will host a webcast on the expansion of its gene therapy pipeline on Tuesday, February 16 at 2:00pm CET (8:00am ET). Please register for the webcast here.

About Sensorion

Sensorion is a pioneering clinical-stage biotech company, which specializes in the development of novel therapies to restore, treat and prevent within the field of hearing loss disorders. Its clinical-stage portfolio includes one Phase 2 product: SENS401 (Arazasetron) for sudden sensorineural hearing loss (SSNHL). Sensorion has built a unique R&D technology platform to expand its understanding of the pathophysiology and etiology of inner ear related diseases enabling it to select the best targets and modalities for drug candidates. The Company is also working on the identification of biomarkers to improve diagnosis of these underserved illnesses. In the second half of 2019, Sensorion launched two preclinical gene therapy programs aimed at correcting hereditary monogenic forms of deafness including Usher Type 1 and deafness caused by a mutation of the gene encoding for Otoferlin. The Company is potentially uniquely placed, through its platforms and pipeline of potential therapeutics, to make a lasting positive impact on hundreds of thousands of people with inner ear related disorders, a significant global unmet medical need.

http://www.sensorion.com

Label: SENSORION ISIN: FR0012596468 Mnemonic: ALSEN

Disclaimer

This press release contains certain forward-looking statements concerning Sensorion and its business. Such forward looking statements are based on assumptions that Sensorion considers to be reasonable. However, there can be no assurance that such forward-looking statements will be verified, which statements are subject to numerous risks, including the risks set forth in the 2020 Half-Year financial report published on October 21, 2020 and available on our website and to the development of economic conditions, financial markets and the markets in which Sensorion operates. The forward-looking statements contained in this press release are also subject to risks not yet known to Sensorion or not currently considered material by Sensorion. The occurrence of all or part of such risks could cause actual results, financial conditions, performance or achievements of Sensorion to be materially different from such forward-looking statements. This press release and the information that it contains do not constitute an offer to sell or subscribe for, or a solicitation of an offer to purchase or subscribe for, Sensorion shares in any country. The communication of this press release in certain countries may constitute a violation of local laws and regulations. Any recipient of this press release must inform oneself of any such local restrictions and comply therewith.

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Sensorion Announces Third Gene Therapy Collaboration With Institut Pasteur Targeting Important Pediatric and Adult Deafness Segments - BioSpace

Recommendation and review posted by Bethany Smith

LEIDEN, Netherlands & CAMBRIDGE, Mass., Feb. 16, 2021 (GLOBE NEWSWIRE) -- ProQR Therapeutics N.V. (Nasdaq: PRQR) (the Company), a company dedicated to changing lives through the creation of transformative RNA therapies for inherited retinal diseases (IRDs), today announced that the Company will host an Expert Perspectives call on February 22, 2021 at 12:00pm EST. The call will feature a discussion between Aniz Girach, MD, Chief Medical Officer of ProQR Therapeutics and Paul Yang, MD, PhD about disease education and endpoints in Usher syndrome and non-syndromic Retinitis Pigmentosa (nsRP). Areas of focus for the session will include which vision measures are most informative in the context of this disease setting, the role of patient baseline and disease progression, and an overview of the objectives of the Phase 1/2 Stellar trial of QR-421a.

Event Details

Date/Time: February 22, 2021, 12:00pm EST

To register, please follow this link.

Following the discussion, a portion of the call will be dedicated to Q&A. The archived presentation will be available on the Companys website for approximately 30 days following the presentation date.

Paul Yang, MD, PhD, Casey Eye Institute, Oregon Health & Science University

Dr. Paul Yang received doctorates in medicine and neurophysiology at Dartmouth Medical School, which was funded by an MD/PhD pre-doctoral award from the National Institutes of Health. He completed residency and fellowship in ophthalmology at the Moran Eye Center in Salt Lake City, during which he first developed an interest in inflammatory eye diseases and degenerative retinal disorders. Thereafter, he pursued a fellowship in ocular immunology and uveitis at the Massachusetts Eye Research and Surgery Institution in Cambridge, Massachusetts, as well as a fellowship in ophthalmic genetics and inherited retinal degenerations at Casey Eye Institute in Portland, Oregon. He was funded by the Foundation Fighting Blindness (FFB) Clinical Research Fellowship Award, FFB Career Development Award, and NIH K08 to evaluate the effectiveness of mycophenolate as a neuroprotective agent in inherited retinal degenerations. For his pioneering work, he was awarded the 2015 ARVO/Alcon Early Career Clinician-Scientist Research Award. Dr. Yang is an assistant professor in ophthalmic genetics and immunology at the Casey Eye Institute (Oregon Health & Science University) where he specializes in patients with inherited retinal degenerations, autoimmune retinopathy, and gene therapy associated uveitis. He is a principal investigator and sub-investigator on numerous gene therapy and neuroprotection clinical trials for inherited retinal degenerations. Dr. Yang continues to conduct translational research in his lab with the goal of bringing new medical treatments to the clinic for patients with inherited retinal degenerations.

About Usher Syndrome Type 2a and Non-Syndromic Retinitis Pigmentosa

Usher syndrome is the leading cause of combined deafness and blindness. People with Usher syndrome type 2a are usually born with hearing loss and start to have progressive vision loss during adulthood. The vision loss can also occur without hearing loss in a disease called non-syndromic retinitis pigmentosa. Usher syndrome type 2a and non-syndromic retinitis pigmentosa can be caused by mutations in the USH2A gene. To date, there are no pharmaceutical treatments approved or in clinical development that treat the vision loss associated with mutations in USH2A.

About QR-421a

QR-421a is being evaluated in the Phase 1/2 Stellar trial and is a first-in-class investigational RNA therapy designed to address the underlying cause of vision loss in Usher syndrome type 2a and non-syndromic retinitis pigmentosa (RP) due to mutations in exon 13 of the USH2A gene. QR-421a is designed to restore functional usherin protein by using an exon skipping approach with the aim to stop or reverse vision loss in patients. QR-421a is intended to be administered through intravitreal injections in the eye and has been granted orphan drug designation in the US and the European Union and received fast-track and rare pediatric disease designations from the FDA.

About ProQR

ProQR Therapeutics is dedicated to changing lives through the creation of transformative RNA therapies for the treatment of severe genetic rare diseases such as Leber congenital amaurosis 10, Usher syndrome and retinitis pigmentosa. Based on our unique proprietary RNA repair platform technologies we are growing our pipeline with patients and loved ones in mind.

Learn more about ProQR at http://www.proqr.com.

FORWARD-LOOKING STATEMENTS

This press release contains forward-looking statements. All statements other than statements of historical fact are forward-looking statements, which are often indicated by terms such as "anticipate," "believe," "could," "estimate," "expect," "goal," "intend," "look forward to", "may," "plan," "potential," "predict," "project," "should," "will," "would" and similar expressions. Such forward-looking statements include, but are not limited to, statements regarding this Expert Perspectives event. Forward-looking statements are based on management's beliefs and assumptions and on information available to management only as of the date of this press release. Our actual results could differ materially from those anticipated in these forward-looking statements for many reasons, including, without limitation, the risks, uncertainties and other factors in our filings made with the Securities and Exchange Commission, including certain sections of our annual report filed on Form 20-F. Given these risks, uncertainties and other factors, you should not place undue reliance on these forward-looking statements, and we assume no obligation to update these forward-looking statements, even if new information becomes available in the future, except as required by law.

ProQR Therapeutics N.V.

Investor Contact:Sarah KielyProQR Therapeutics N.V.T: +1 617 599 6228skiely@proqr.comorHans VitzthumLifeSci AdvisorsT: +1 617 535 7743hans@lifesciadvisors.com

Media Contact:Cherilyn Cecchini, MDLifeSci CommunicationsT: +1 646 876 5196ccecchini@lifescicomms.com

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ProQR Announces Expert Perspectives Call on Disease Education and Endpoints in Usher Syndrome - GlobeNewswire

Recommendation and review posted by Bethany Smith

Videos showing for the first time how small circles of DNA adopt dance-like movements inside a cell have been developed by researchers in Yorkshire.

The footage, created by a team of scientists from the Universities of Leeds, Sheffield and York, is based on the highest resolution images of a single molecule of DNA ever captured.

They show in unprecedented detail how the stresses and strains that are placed on DNA when it is crammed inside cells can change its shape.

Previously scientists were only able to see DNA by using microscopes limited to taking static images. But now the Yorkshire team has combined advanced atomic force microscopy with supercomputer simulations to create videos of twisted molecules of DNA.

The images are so detailed it is possible to see the iconic double helical structure of DNA, but when combined with the simulations, the researchers were able to see the position of every single atom in the DNA and how it twists and writhes.

Credit: University of Sheffield

Dr Alice Pyne, Lecturer in Polymers & Soft Matter at the University of Sheffield, who captured the footage, said: "Seeing is believing, but with something as small as DNA, seeing the helical structure of the entire DNA molecule was extremely challenging.

"The videos we have developed enable us to observe DNA twisting in a level of detail that has never been seen before."

The study, Base-pair resolution analysis of the effect of supercoiling on DNA flexibility and major groove recognition by triplex-forming oligonucleotides, is published in Nature Communications.

Every human cell contains two metres of DNA. In order for this DNA to fit inside our cells, it has evolved to twist, turn and coil a process called supercoiling. That means that loopy DNA is everywhere in the genome, forming twisted structures which show more dynamic behaviour than their relaxed counterparts.

To investigate how this process works, the research team studied small "packets" of genetic information called DNA minicircles, engineered and isolated from bacteria. DNA minicircles are special becausethe molecule is joined at both ends to form a loop. This loop enabled the researchers to give the DNA minicircles an extra added twist, making the DNA "dance" more vigorously.

When the researchers imaged relaxed DNA, without any twists, they saw that it did very little. But when they gave the DNA an added twist, it suddenly became far more dynamic and could be seen to adopt some very exotic shapes.

These exotic "dance moves" were found to be the key to finding binding partners for the DNA.

Gene therapy is the use of nucleic acids such as DNA to repair, replace, or regulate genes to prevent or treat human disease. In the past few decades, hundreds of gene therapy candidate genes have been uncovered, yet very few of these have turned into target therapies because of the challenge of delivering the gene therapy.

Professor Lynn Zechiedrich from Baylor College of Medicine in Houston Texas, who made the minicircles used in this study, has found a way to design supercoiled minicircles or, minivectors for use in gene therapy by inserting short genetic messages.

Professor Zechiedrich said: "The research team in Yorkshire have developed a technique that reveals in remarkable detail how wrinkled, bubbled, kinked, denatured, and strangely shaped they are!

"We have to understand how supercoiling, which is so important for DNA activities in cells, affects DNA in hope that we can learn how to mimic or control it someday."

Dr Massa Shoura from Stanford University, who has detected DNA minicircles in human cells, said: "Very little is currently understood about the function of circular DNAs in cells, but there is a chance they could be used as markers for early detection of disease."

Dr Sarah Harris, Associate Professor in the School of Physics and Astronomy at the University of Leeds, who supervised the research, said: "The laws of physics apply just as well to the molecules that make up living systems as to sub-atomic particles and galaxies. The synergy between our experiments and computer models shows we are beginning to understand the physics underlying supercoiled DNA. This insight should help researchers such as Professor Zechiedrich design bespoke minicircles for future therapies."

Further information

Top image: A visualisation of a DNA minicircle

For media enquiries, please contact David Lewis in the University of Leeds press office: d.lewis@leeds.ac.uk

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News > Science > Visualisation of 'dancing DNA' - University of Leeds

Recommendation and review posted by Bethany Smith

Research from the Sheffield Institute for Translational Neuroscience (SITraN) suggests that routine genetic testing may be appropriate for all MND patients and could impact disease subclassification and clinical care.

Research from the Sheffield Institute for Translational Neuroscience (SITraN) suggests that routine genetic testing may be appropriate for all MND patients and could impact disease subclassification and clinical care.

The new study, published today (15 February 2021) in the Journal of Neurology, Neurosurgery and Psychiatry (JNNP), performed targeted genetic sequencing of MND-relevant genes on 100 patients.

Researchers found higher than expected genetic changes in the group of patients. The paper recommends that genetic testing could be appropriate for all MND patients whether or not they have a family history of the disease.

While the majority of MND cases are considered sporadic, five per cent to 10 per cent have been shown to be familial. Currently only patients with a family history of MND, dementia, or who experience disease onset at a young age are routinely offered genetic screenings in the UK. However, with the development of new therapies targeting specific genetic forms of the disease, researchers are recommending that all MND patients are offered a screening.

Prof Janine Kirby, Professor of Neurogenetics at the University of Sheffield, said Our study found that 42 per cent of patients involved in the screening showed variants in known MND-linked genes. This doesnt mean that 42 per cent of MND cases are familial - but shows that some familial and sporadic cases can share the same genetic cause of disease.

We found that 21 per cent of patients had a clinically reportable genetic alteration that has been proven to increase the likelihood of developing MND. Of these, 93 per cent had no family history of MND and 15 per cent met the inclusion criteria for a current MND gene therapy clinical trial.

As future studies expand the number of verified genetic causes of MND, we will continue to see if they are also found in cases without a family history.

Professor Dame Pamela Shaw, Director of SITraN and the NIHR Sheffield Biomedical Research Centre said Our study suggests that all patients with MND should, with careful counselling, be offered genetic testing.

We hope that by screening all MND patients for gene mutations that are a known factor in MND, we can further our knowledge on subclassification of the disease, but also ensure that patients have access to clinical trials that are relevant for them personally."

This is increasingly important in light of the new personalised medicine treatments in development for MND that target a specific gene mutation to ensure that patients have access to potential treatments that could be beneficial to them.

Dr Brian Dickie, Director of Research Development at the Motor Neurone Disease Association said MND is a complex disease involving a complex mix of genetic and environmental factors. This latest research sheds more light on the genetic component and will hopefully lead to greater availability of genetic testing to aid earlier diagnosis and more tailored treatments in the future.

This study was supported by funds raised through the Ice Bucket Challenge and will be widened to include analysis of additional samples from two other clinics collaborating on this MND Association funded project. This will provide an even clearer picture of the UK MND genetic landscape.

MND - also known as amyotrophic lateral sclerosis (ALS) - is an adult-onset neurodegenerative disease characterised by progressive injury and cell death of upper and lower motor neurons. This leads to progressive failure of the neuromuscular system with death, usually from respiratory failure, within 25 years of symptoms in most cases.

Currently, there is no cure for MND and no effective treatments to halt or reverse the progression of this devastating disease.

The National Institute for Health Research (NIHR) is the nations largest funder of health and care research. The NIHR:

The NIHR was established in 2006 to improve the health and wealth of the nation through research, and is funded by the Department of Health and Social Care. In addition to its national role, the NIHR commissions applied health research to benefit the poorest people in low- and middle-income countries, using Official Development Assistance funding.

This work uses data provided by patients and collected by the NHS as part of their care and support and would not have been possible without access to this data. The NIHR recognises and values the role of patient data, securely accessed and stored, both in underpinning and leading to improvements in research and care. http://www.nihr.ac.uk/patientdata

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New study suggests genetic testing could be appropriate for all motor neuron disease (MND) patients whether or not they have a family history of the...

Recommendation and review posted by Bethany Smith

LONDON--(BUSINESS WIRE)--Gyroscope Therapeutics Limited, a clinical-stage gene therapy company focused on diseases of the eye, today announced positive interim safety, protein expression and biomarker data from the ongoing open-label Phase I/II FOCUS clinical trial of its investigational gene therapy, GT005, in patients with geographic atrophy (GA) secondary to age-related macular degeneration (AMD). Interim results showed GT005 was well tolerated and resulted in sustained increases in vitreous Complement Factor I (CFI) levels in the majority of patients, as well as decreases in the downstream complement proteins associated with over-activation of the complement system. These results were observed both in GA patients who had rare variants in their CFI gene as well as those who did not. The data were presented today at the Angiogenesis, Exudation, and Degeneration 2021 virtual meeting by Nadia Waheed, M.D., MPH, Chief Medical Officer, Gyroscope Therapeutics.

Our investigational gene therapy, GT005, is designed to restore balance to an overactive complement system and reduce inflammation by increasing production of the CFI protein. We are excited by these early results from the FOCUS trial that showed GT005 has been well tolerated to date, increased CFI levels in a durable manner and caused down-regulation of an overactive complement system, said Dr. Waheed. These results give us confidence that a one-time treatment with GT005 may have the potential to slow progression of geographic atrophy, and this is being evaluated in our ongoing Phase II clinical trials.

There is strong evidence that an overactive complement system is a key driver of dry AMD, said Arshad Khanani, M.D., M.A., Director of Clinical Research at Sierra Eye Associates, Clinical Associate Professor at the University of Nevada, Reno School of Medicine, and an investigator in the FOCUS trial. The recently released data from the FOCUS trial suggest the potential of a one-time gene therapy with GT005 to regulate an overactive complement system. It is encouraging that GT005 generated sustained increases in CFI in a majority of the patients, even in some patients treated more than a year ago. We continue to look forward to learning more about GT005 as a potential treatment for GA in the ongoing Phase II clinical trial programme.

Interim Data from the Phase I/II FOCUS Trial

FOCUS [NCT03846193] is an open-label Phase I/II clinical trial evaluating the safety and dose response of three doses of GT005 given as a single subretinal injection to patients with GA secondary to AMD. The trial is divided into several cohorts, including dose escalation (Cohorts 1, 2, 3, 5 and 6) and dose expansion (Cohorts 4 and 7).

Interim results were reported today from patients in Cohorts 1 to 4. The three doses of GT005 evaluated were well tolerated and there were no signs of GT005-induced inflammation.

Interim results showed sustained increases in vitreous CFI levels in the majority of patients, as well as decreases in the vitreous levels of key proteins associated with complement over-activation (Ba and C3 breakdown proteins: C3b, iC3b and C3c).

Dr. Waheeds presentation will be made available on Gyroscopes website at https://www.gyroscopetx.com/publications/.

About GT005

GT005 is designed as an AAV2-based one-time investigational gene therapy for GA secondary to AMD that is delivered under the retina. GT005 aims to restore balance to an overactive complement system, a part of the immune system, by increasing production of the CFI protein. Complement overactivation has been strongly correlated with the development and progression of AMD. The CFI protein regulates the activity of the complement system. It is believed that increasing CFI production could dampen the systems overactivity and reduce inflammation, with the goal of preserving a persons eyesight.

As of December 2020, 22 patients had been dosed with GT005 in the FOCUS trial across Cohorts 1 to 5. Dosing in Cohorts 1, 2, 3 and 5 is complete. Patients continue to be enrolled in the dose expansion Cohort 4, which is planned to enrol up to 20 patients. GT005 is delivered to patients in Cohorts 1 to 4 using the standard transvitreal procedure and in Cohorts 5 to 7 using Gyroscopes proprietary Orbit subretinal delivery system.

Gyroscope is also evaluating GT005 in two Phase II clinical trials. EXPLORE [NCT04437368] and HORIZON [NCT04566445] are Phase II, multicentre, randomised, controlled trials evaluating the safety and effectiveness of GT005 administered as a single subretinal injection. The primary endpoint for both trials is progression of GA over 48 weeks. EXPLORE is enrolling people who have GA secondary to AMD who have rare variants in their CFI gene. HORIZON is enrolling a broader group of people who have GA secondary to AMD.

About Dry Age-Related Macular Degeneration (AMD) and Geographic Atrophy (GA)

Dry AMD is a leading cause of permanent vision loss in people over the age of 50 and is a devastating diagnosis.1 There are currently no approved treatments for dry AMD, which is the most common form, impacting approximately 85-90% of people with AMD.2 As dry AMD advances, it leads to GA, an irreversible degeneration of retinal cells, causing a gradual and permanent loss of central vision. This disease can severely impact a persons daily life as they lose the ability to drive, read and even see the faces of loved ones.

About Gyroscope: Vision for Life

Gyroscope Therapeutics is a clinical-stage gene therapy company developing gene therapy beyond rare disease to treat diseases of the eye that cause vision loss and blindness. Our lead investigational gene therapy, GT005, is currently being evaluated in Phase II clinical trials for the treatment of geographic atrophy (GA) secondary to age-related macular degeneration (AMD), a leading cause of blindness. GT005 has received Fast Track designation from the U.S. Food and Drug Administration for the treatment of people with GA.

Syncona Ltd., our lead investor, helped us create a leading gene therapy company combining discovery, research, drug development, a manufacturing platform and surgical delivery capabilities. Headquartered in London with locations in Philadelphia and San Francisco, our mission is to preserve sight and fight the devastating impact of blindness. For more information visit: http://www.gyroscopetx.com and follow us on Twitter (@GyroscopeTx) and on LinkedIn.

1 National Eye Institute. Age-Related Macular Degeneration. https://www.nei.nih.gov/learn-about-eye-health/eye-conditions-and-diseases/age-related-macular-degeneration. Page last reviewed August 17, 2020. Accessed July 16, 2020.

2 American Macular Degeneration Foundation. What is Macular Degeneration? https://www.macular.org/what-macular-degeneration. Page last reviewed December 20, 2017. Accessed February 11, 2021.

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Gyroscope Therapeutics Announces Positive Interim Data from Phase I/II FOCUS Trial of Investigational Gene Therapy GT005 - Business Wire

Recommendation and review posted by Bethany Smith

LAS VEGAS, Feb. 15, 2021 /PRNewswire/ -- DelveInsight's Hemophilia A Market Analysisreport offers an integrated view of epidemiological trends, treatment approaches, unmet needs present in the treatment market, and the pipeline therapies expected to have a tremendous impact in the Hemophilia A market in the coming next decade in the 7MM (the US, EU5 (the UK, Germany, Spain, Italy, and France), and Japan).

The Hemophilia A Market reportoffers a detailed mapping of the key companies at the forefront of the domain, major collaborations, deals, and tie-ups taking place, as well as clinical trials, and recent happenings ongoing in the Hemophilia A market landscape.

Some of the key highlights from the Hemophilia A Market Researchreport:

Request for Sample for more @ Hemophilia A Market Landscape

Hemophilia is a group of bleeding disorders. A congenital deficiency of certain clotting factors causes Hemophilia and the main form of Hemophilia is Hemophilia A and is due to the deficiency of factor VIII.

Hemophilia A Epidemiological Analysis

Over 80% of the total patient pool of Hemophilia has Hemophilia A. The total Hemophilia A prevalent population in the7MM in 2020 was 43,243. The prevalence is further expected to rise by 2030, during the study period (20182030). On the basis of severity, the Hemophilia A cases can be segmented in to mild, moderate and severe. Severe Hemophilia A cases are more prominent in comparison to mild and moderate. Additionally, moderate and severe accounts for 75% of the Hemophilia A patient pool.

The total Hemophilia A cases can be further bifurcated into with or without non-inhibitors, where the prevalent pool with non-inhibitors accounts for a higher number of Hemophilia A cases. In the 7MM, approximately 30% of severe Hemophilia A cases develop inhibitors; and the remaining 70% of the Hemophilia A cases were observed without inhibitors in 2020. The number of cases for both categories will increase during the study period.

The Hemophilia A Marketreport puts forward epidemiology division in the 7MM for the study period 2018-30 segmented into:

Hemophilia A Therapeutics Market Landscape

The Hemophilia A treatment landscape provides "On Demand" and "Prophylaxis" treatment options to the patients. However, the Prophylaxis treatment option has gained much absorption in the market as compared to the On-demand treatment option.

The treatment consists of replacing the missing clotting protein (factor VIII) and preventing the complications associated with the disorder. Replacement of this protein may be obtained through recombinant factor VIII, which is artificially created in a lab. Several recombinant forms of factor VIII are also approved for in the Hemophilia A treatment market.

The present Hemophilia A therapy market offers Factor Replacement Concentrates, and Bypassing agents as major treatment options. The market has several recombinant factor VIII (FVIII) products available with high specific activities. Plasma-derived clotting factors products are also present in the Hemophilia A treatment market. Furthermore, in adjunctive therapies, antifibrinolytic and supportive measures, which include icing, immobilization and others are also available. Besides, the market presence of approved treatment regimes, off-label products are also available for Hemophilia A.

However, the market is currently dominated by the recombinants of several generations (recombinant third-generation, and recombinant second generation).

Know more about the present market landscape @ Hemophilia A Drug Market Landscape

Hemophilia A Marketed Therapies

And others.

Undoubtedly, there are several safe and effective treatment options, such as replacement therapy, available in the Hemophilia A treatment market. However, the main goal of the present Hemophilia A treatment options is to reduce complications arising from blood accumulating in joint spaces and/or other tissues & organs; and not to cure the disease. Hemophilia A continues to form a huge burden on the healthcare domain. Patients continue to fight this progressive bleeding disease, with high chances of inhibitor development.

Further, the formation of inhibitors is associated to reduce FVIII efficacy in blood coagulation, which as a consequence hampers patients' health and quality of life, adding significantly to the Hemophilia A treatment costs.

Got queries? Reach out @ Hemophilia A Market Scenario in the Next Decade

Hemophilia A Market Forecast

To bridge the gap, and meet the unmet needs in the Hemophilia A market domain, the scientific community, academia, and pharmaceutical companies are actively, and collaboratively seeking novel approaches, taking advantage of advanced technologies, and developing new pipeline therapies.

Pharmaceutical companies like BioMarin Pharmaceutical, Novo Nordisk, Pfizer, Sangamo Therapeutics, Sanofi/Alnylam Pharmaceuticals, Catalyst Biosciences, Roche/Spark Therapeutics, Sigilon Therapeutics, Takeda, and others are busy investigating different candidates in Hemophilia A treatment market.

To accomplish and meet these unmet needs the future of Hemophilia treatment is continuing to incline toward extended half-life therapies as well as more novel approaches which include siRNA, bispecific antibodies, and gene therapy. The emerging therapies are expected to affirmatively challenge the presently Hemophilia A marketed therapies by snatching their market share. Although the Hemophilia A treatment market is already packed with many recombinant factor VIII therapy approaches, and upcoming treatment options based on similar MoA shall further cramp up space, it is going to affect the drug uptake without the strain of doubt.

Visit to get a picture of market forces @ Hemophila A Market Drivers and Barriers

In essence, an increasing observable trend of Hemophilia A prevalence is expected to soar the demand for effective treatment options that are curative in nature, which is lacking in the market at the moment. The advent of premium-priced agents shall dominate the Hemophilia A market in the upcoming years. However, it is not to lose sight of the fact that Hemophilia A gene therapies are heavier than expected on pockets. Thus, healthcare authorities will seek to restrict the pricing and usage of the high-cost agents. Further, the rarity of the disease facilitates accelerated approval, market exclusivity, clinical trials subsidies, and reduced regulatory fees, orphan drug designations, and several other leverages.

Visit for pictorial representation of Hemophilia A Market Outlook

Hemophilia A Pipeline Therapies

And others.

Rich insights @ Hemophila A Market Forecast and Pipeline Therapies

Scope of the Report

Table of Contents

1

Key Insights

2

Executive Summary of Hemophilia A

3

Competitive Intelligence Analysis for Hemophilia A

4

Hemophilia A: Market Overview at a Glance

5

Hemophilia A: Disease Background and Overview

6

Hemophilia A Patient Journey

7

Hemophilia A Epidemiology and Patient Population

8

Hemophilia A Treatment Algorithm, Current Treatment, and Medical Practices

9

Unmet Needs

10

Key Endpoints of Hemophilia A Treatment

11

Hemophilia A Marketed Products

12

Hemophilia A Emerging Therapies

13

Hemophilia A: Seven Major Market Analysis

14

Conjoint analysis

15

Hemophilia A 7MM: Market Outlook

16

Access and Reimbursement Overview of Hemophilia A

17

KOL Views

18

Hemophilia A Market Drivers

19

Hemophilia A Market Barriers

20

Appendix

21

DelveInsight Capabilities

22

Disclaimer

23

About DelveInsight

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Global Cancer Gene Therapy Market Research Report 2020-2028

COVID-19 can affect the global economy in three main ways: by directly affecting production and demand, by creating supply chain and market disruption, and by its financial impact on firms and financial markets. Global Cancer Gene Therapy Market size has covered and analyzed the potential of Worldwide market Industry and provides statistics and information on market dynamics, market analysis, growth factors, key challenges, major drivers & restraints, opportunities and forecast. This report presents a comprehensive overview, market shares, and growth opportunities of market 2028 by product type, application, key manufacturers and key regions and countries.

The recently released report byMarket Research Inctitled as Global Cancer Gene Therapy Market is a detailed analogy that gives the reader an insight into the intricacies of the various elements like the growth rate, and impact of the socio-economic conditions that affect the market space. An in-depth study of these numerous components is essential as all these aspects need to blend-in seamlessly for businesses to achieve success in this industry.

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The research report includes company Competitors top sellers profiles, their data, deals income, revenue share, deal volume, and purchaser volume are equally specified. The conclusions provided in this report are of great value for the leading industry players. Every organization partaking in the global production of the Cancer Gene Therapy products have been mentioned in this report, in order to study the insights on cost-effective manufacturing methods, competitive landscape, and new avenues for applications. The report is molded by tracking market performance since 2015 and is one of the most detailed reports.

List of Key Players in This Market:

Global Cancer Gene Therapy Market Segmentation:

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This report provides pin-point analysis for changing competitive dynamics

This research study examines the current market trends related to the demand, supply, and sales, in addition to the recent developments. Major drivers, restraints, and opportunities have been covered to provide an exhaustive picture of the market. The analysis presents in-depth information regarding the development, trends, and industry policies and regulations implemented in each of the geographical regions. Further, the overall regulatory framework of the market has been exhaustively covered to offer stakeholders a better understanding of the key factors affecting the overall market environment.

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Global Cancer Gene Therapy Market Is Projected to Grow at an Exponential Rate over 2020 to 2028 | Market Top Players Analysis, Revenue, Application,...

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DUBLIN, Feb. 16, 2021 /PRNewswire/ -- The "North America Virus Filtration Market 2020-2026 by Product (Consumables, Instruments, Services), Application, End User, and Country: COVID-19 Impact and Growth Opportunity" report has been added to ResearchAndMarkets.com's offering.

North America virus filtration market is expected to grow by 11.86% annually in the forecast period and reach $2,554.1 million by 2026 owing to rapid growth of pharmaceutical and biotechnology industry, increasing investments in R&D, surging need for virus removal and clearance amid COVID-19 pandemic.

Highlighted with 25 tables and 42 figures, this report is based on a holistic research of the entire North America virus filtration market and all its sub-segments through extensively detailed classifications. Profound analysis and assessment are generated from premium primary and secondary information sources with inputs derived from industry professionals across the value chain. The report is based on studies on 2016-2019 and provides forecast from 2020 till 2026 with 2019 as the base year.

The trend and outlook of North America market is forecast in optimistic, balanced, and conservative view by taking into account of COVID-19. The balanced (most likely) projection is used to quantify North America virus filtration market in every aspect of the classification from perspectives of Product, Application, End User, and Country.

The report also covers current competitive scenario and the predicted trend; and profiles key vendors including market leaders and important emerging players.

Specifically, potential risks associated with investing in North America virus filtration market are assayed quantitatively and qualitatively through a Risk Assessment System. According to the risk analysis and evaluation, Critical Success Factors (CSFs) are generated as a guidance to help investors & stockholders identify emerging opportunities, manage and minimize the risks, develop appropriate business models, and make wise strategies and decisions.

Key Players

Key Topics Covered:

1 Introduction1.1 Industry Definition and Research Scope1.2 Research Methodology1.3 Executive Summary

2 Market Overview and Dynamics2.1 Market Size and Forecast2.1.1 Impact of COVID-19 on World Economy2.1.2 Impact of COVID-19 on the Market2.2 Major Growth Drivers2.3 Market Restraints and Challenges2.4 Emerging Opportunities and Market Trends2.5 Porter's Five Forces Analysis

3 Segmentation of North America Market by Product3.1 Market Overview by Product3.2 Consumables3.3 Instruments3.3.1 Filtration Systems3.3.2 Chromatography systems3.4 Services

4 Segmentation of North America Market by Application4.1 Market Overview by Application4.2 Biological Applications4.2.1 Vaccines and Therapeutics4.2.2 Blood and Blood Products4.2.3 Cellular and Gene Therapy Products4.2.4 Tissue and Tissue Products4.2.5 Stem Cell Products4.3 Medical Devices4.4 Water Purification4.5 Air Purification4.6 Other Applications

5 Segmentation of North America Market by End User5.1 Market Overview by End User5.2 Pharmaceutical and Biotechnology Companies5.3 Contract Research Organisations (CROs)5.4 Academic & Research Institutes5.5 Medical Device Companies5.6 Other End Users

6 North America Market 2019-2026 by Country6.1 Overview of North America Market6.2 U.S.6.3 Canada6.4 Mexico

7 Competitive Landscape7.1 Overview of Key Vendors7.2 New Product Launch, Partnership, Investment, and M&A7.3 Company Profiles8 Investing in North America Market: Risk Assessment and Management8.1 Risk Evaluation of North America Market8.2 Critical Success Factors (CSFs)

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North America Virus Filtration Market 2020-2026: Surging Need for Virus Removal and Clearance amid COVID-19 Pandemic - PRNewswire

Recommendation and review posted by Bethany Smith

Janssen recently entered into an agreement with a company specialising in data analytics in the field of ophthalmology with the objective of advancing ocular treatments. Partnering with a company that specialises in data analytics is a definite win for Janssen in the long term.

By leveraging software technologies, Verana Health is able to draw insights that are useful to multiple stakeholders. These insights can be drawn rapidly and used across the breadth of product development from R&D to commercial positioning. While the ophthalmology indication of interest of this particular partnership focuses on diabetic macular edema, there is anticipation that a successful outcome from this collaboration can trigger expansion to other indications, particularly those of high unmet need. Verana Healths strategy can be attributed to two key features. First, the company partners with medical associations, in this case, the American Academy of Ophthalmology (AAO), with the objective of supporting the former as data curating and analytics partner. Data in this case refer to real-world clinical evidence of patient care. To bring the companys strategy into fruition, Verana Health utilises proprietary algorithms to clean and model data from electronic health records to derive clinical and business insights that can be critical for development of drugs and understanding current treatment paradigms.

Partnerships with digital healthcare companies have been on the rise in the ophthalmology space in the recent past. In 2020, Novartis entered into a number of agreements with stakeholders in the ophthalmology field who are engaged in the use of digital tools and technologies. These applications range from helping to remotely monitor patients with chronic eye diseases to utilising artificial tools to help assess disease activity in patients with neovascular age-related macular degeneration (nAMD).

Through the latest collaboration, Janssen will be hoping to further fortify its position in ophthalmology. In December 2020, the company bought a gene therapy for a severe form of age-related macular degeneration (AMD) from Hemera Biosciences. Besides providing pharmaceutical companies the advantage of pulling ahead of competitors in a broad spectrum of activities ranging from R&D to product positioning, use of digital technologies and tools can also be used to drive down costs and timelines associated with R&D in the pharmaceutical sector, as well as optimising patient selection for a particular treatment modality. Looking ahead, pharmaceutical companies are expected to increasingly look towards companies that specialise in digital tools and technologies, and while collaborations between such stakeholders are expected to rise in the pharmaceutical sector, it will also be crucial for these partners to ensure that the underlying patient data are treated with strict confidence and that these data are protected from possible threats of cyberattacks.

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Fourteen-month-old Fatima, who was afflicted with a killer muscular disorder, is now blessed with a new lease of life after she underwent a Rs 16 crore 'revolutionary' gene therapy at a Bengaluru hospital after winning a 'lottery'.

Fatima, daughter of Mohammed Basil and Khadija from Bhatkal town in Uttara Kannada district of Karnataka, is recovering after she was given 'Zolgensma' -- the gene therapy -- at Bangalore Baptist Hospital late last month, news agency PTI reported.

She emerged "a lucky winner of a lottery" through a compassionate access programme by drug major Novartis that helped her get the treatment which is affordable only by multi-millionaires, PTI quoted hospital authorities as saying.

"The cost of this medicine is about 2.1 million US dollars, which is roughly about Rs. 16 crore," hospital Director (CEO) Naveen Thomas said.

"There is gradual improvement. She is now able to move her leg. It will take time to become like a normal child," her father Basil told PTI.

The toddler was diagnosed with Spinal Muscular Atrophy or SMA, a disease caused by loss of nerve cells, which carry electrical signals from the brain to the muscles.

The protein needed for this signaling is coded by a gene for which everyone has two copies --- one from the mother and the other from the father, according to Thomas.

Thomas said a child develops this disorder only if both the copies were faulty and without treatment, this disease was ultimately fatal.

But the problem is that the treatment is out of reach of most people.

"Only multi-millionaires can afford it! Current treatment options range from medicines, which increase these proteins to replacing the faulty gene. Zolgensma, a gene therapy is a revolutionary treatment, which aims at curing the disease by replacing the faulty gene", he said.

"For the first time in Karnataka, Zolgensma was given at Bangalore Baptist hospital to a child who was the lucky winner of a lottery through a compassionate access programme by Novartis", Thomas said.

Incidentally, the couple had earlier lost a child, who was also suffering from SMA.

"On the 21st day of the 21st year of the 21st century, the baby was given the injection, which is a one-shot cure for this rare disease, said Dr Ann Agnes Mathew, Consultant Paediatric Neurologist and Neuromuscular Specialist.

At present there were about 200 children getting treatment in the Baptist Hospital which is specialised in genetic diseases, more specifically SMA and Duchenne muscular dystrophy (DMD), said the doctor.

She added that previous year alone, 38 children who were getting treatment in the hospital breathed their last in the absence of this expensive treatment.

In Fatima's case, Thomas said: It is a dream come true for doctors in this field. We hope more children receive this treatment and many such treatments will become affordable in the future."

(With inputs from PTI)

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14-month-old lottery winner with killer disease gets new life after expensive therapy in Bengaluru - India Today

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This article was originally published here

Front Immunol. 2021 Jan 21;11:594572. doi: 10.3389/fimmu.2020.594572. eCollection 2020.

ABSTRACT

Mycobacterium tuberculosis (Mtb), the causative organism of pulmonary tuberculosis (PTB) now infects more than half of the world population. The efficient transmission strategy of the pathogen includes first remaining dormant inside the infected host, next undergoing reactivation to cause post-primary tuberculosis of the lungs (PPTBL) and then transmit via aerosol to the community. In this review, we are exploring recent findings on the role of bone marrow (BM) stem cell niche in Mtb dormancy and reactivation that may underlie the mechanisms of PPTBL development. We suggest that pathogens interaction with the stem cell niche may be relevant in potential inflammation induced PPTBL reactivation, which need significant research attention for the future development of novel preventive and therapeutic strategies for PPTBL, especially in a post COVID-19 pandemic world. Finally, we put forward potential animal models to study the stem cell basis of Mtb dormancy and reactivation.

PMID:33584661 | PMC:PMC7873989 | DOI:10.3389/fimmu.2020.594572

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Initiation of Post-Primary Tuberculosis of the Lungs: Exploring the Secret Role of Bone Marrow Derived Stem Cells - DocWire News

Recommendation and review posted by Bethany Smith

Usama Gergis, MD, MBA Professor of Oncology Director, Bone Marrow Transplant and Immune Cellular Therapy Sidney Kimmel Cancer Center Thomas Jefferson University Hospital Philadelphia, PA, reviewed that difference in acute and chronic graft-versus-host disease (GVHD) and the treatment available for each.

Targeted OncologyTM: How would you treat a patient with GvHD in the second line?

GERGIS: If you [have a patient with] second-line acute GVHD, your answer should be ruxolitinib [Jakafi] because its the only drug that has been tried in phase 3 trials. If you get a [case of] chronic GVHD, your answer should be ibrutinib [Imbruvica].

What is the efficacy of peripheral blood stem cells (PBSC) versus bone marrow from unrelated donors in patients with acute and chronic GvHD?

[Results from] a phase 3 study of bone marrow versus stem cells for unrelated donors [showed] the acute GVHD population [cumulative incidence] was the same between both.1 For the chronic population, the bone marrow did better [PBSC 53% vs bone marrow 41%; P = .01]. This was published almost 8 years ago, [and it] was reported almost 10 years ago, but we still use stem cells.

This has not changed practices, and the reasons are, number 1, there was more primary graft failure on the bone marrow than the PBSC, and number 2, its pretty involved to do bone marrow harvest, although I have done it for 15 years, at least a few every month.

The benefit of bone marrow versus PBSCand this benefit was only studied in unrelated donors, not in matched related donorswas seen across all organs affected with chronic GVHD except lungs, [gut, and serosa].2 So, there was no real benefit in the lungs.

Can you explain the difference between acute and chronic GvHD?

Chronic GVHD is more complicated and involved than acute GVHD. In acute, you have the skin, gastrointestinal organs, and the liver [that may be affected]. Thats it. In chronic, all the patients other organs can be affected. The patients weight can be affected. [Chronic GVHD is] more debilitating over a long time and [can] go unrecognized for a while. [If a patient is] experiencing acute GVHD, you see them twice a week, whereas if the patient has chronic GVHD, you probably see them once a month. So you can see a very stark change in your patients within that month if they lose 10% of their body weight and they already lost a lot of weight in the period right after [transplantation], so that can be obvious to you.

[In my institution], we have the GVHD clinic where we [grade the patient based on] studying the degree of fibrosis, how many organs are affected, the patients range of motion, and the degrees in range of motion. We do frequent pulmonary function tests and various [other] testing. By looking at all the affected organs, you reach a grade, and that can be mild, moderate, or severe [chronic GVHD].

How do you treat moderate-to-severe chronic GVHD at initial presentation and in the second line?

First-line treatment for chronic GVHD are steroids. For second line, there are many agents [to consider]. Ive tried most of them. I like photopheresis because its not pharmacological, but its pretty involved. Your patient will need a permanent catheter, and they will need to come to the transplant center twice a week, and you see a response after a long time. It takes an average of 50 photopheresis sessions for a response. But the beauty of photopheresis [is that] you could try it with other agents, so its not mutually exclusive. You could use it with ruxolitinib, ibrutinib, or any other agents.

The answer will be ibrutinib [for chronic GVHD], and thats based on the [results of a] phase 2 clinical trial that treated 42 patients with steroid-refractory chronic GVHD, and the efficacy was 69% [best overall response rate], and 31% complete response rate.3

What do you think of these poll results?

Everybody agrees on giving ibrutinib. When I gave this talk a couple months ago, lenalidomide [Revlimid] was not included in the poll. I added it because [recently], a nice study in Blood came out from the National Institutes of Health where they tried lenalidomide at a small dose, 2 mg, in steroid-refractory chronic GVHD. Its a large trial; I think its about 100 patients. Theyve seen responses that are comparable with ibrutinib....I treated a patient for multiple myeloma; he received a transplant for multiple myeloma, and now, 6 months later, he has chronic GVHD and some clonal plasma cells. So for him, I was comforted to know the results of the lenalidomide trial.

How does ruxolitinib play a role in this setting?

Ruxolitinib was reported in the REACH3 trial [NCT03112603] with very good responses in chronic GVHD.4 I think it probably will get approved for that indication. Looking at this study about 2 years ago, nothing was studied well in this indication, and ibrutinib was approved.

REACH3 was a large trial, almost 300 patients, and everybody was randomized to ruxolitinib 10 mg twice a day versus best available treatment. They looked at everybody about 6 months later for response.

What should physicians keep in mind when treating?

Chronic GvHD is pretty involved. Your patients will need a multidisciplinary approach. You need to pay attention to their bones. In the first 100 days post transplant, the average bone aging is 17 years.

So although were trying to treat acute GVHD, viruses, and prevent relapses, [by putting] your patients on some steroids, you are aging your patients bones by 17 years only in the first 100 days. No matter what you do, give your patients vitamin D, calcium, and Fosamax [alendronate sodium].

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Gergis Explains the Differences Between Acute and Chronic GVHD - Targeted Oncology

Recommendation and review posted by Bethany Smith

Black patients in need of bone marrow or blood stem cell treatments have a decreased chance of matching with a donor. The Seattle branch hopes to change that.

Seattles Be The Match Collection Center opened up less than a year ago and is celebrating its 100th blood cell donation with an important message: More bone marrow donors of color are needed.

The nonprofit donation center is a part of the National Marrow Donor Program and increases the capacity to collect blood cells in the Pacific Northwest. Seattles Clinical Manager Hannah Erskine said this month is an important time to focus on the donation gap.

In the midst of Black History Month, its important to note that we frankly dont have enough Black and African American donors on the registry, said Erskin.

Only 4% of approximately 22 million donors on the registry are African American, lowering the chances that a Black patient can find a bone marrow donor who is a genetic match.

According to Be The Match data, the likelihood of finding a matched adult donor is only around 23% for an African American or Black patient, versus a 77% match rate for a white patient.

These matched bone marrow or blood stem cell transplants can help cure blood cancers like leukemia and lymphoma, as well as other blood conditions, such as sickle cell disease. Be The Match has coordinated more than 100,000 transplants.

Erskine said registering is a simple mouth swab that will be mailed to potential donors. They will be contacted if they are a match with a patient.

Being a matching blood stem cell donor can potentially save a life. The first step in changing the trend is to join the registry at http://www.bethematch.org.

Continue reading here:
Be The Match encourages people of color to join bone marrow registry - KING5.com

Recommendation and review posted by Bethany Smith

Leukemia is a type of cancer that affects the blood and bone marrow, where blood cells are formed. All types of leukemia cause rapid, uncontrolled growth of abnormal bone marrow and blood cells.

The main differences between the types include how fast the disease progresses and the types of cells it affects.

There are four main types of leukemia, which we describe in detail below:

Lymphocytic leukemia affects the lymphocytes, a type of white blood cell. Myeloid leukemia can affect the white blood cells, red blood cells, and platelets.

According to the National Cancer Institute, roughly 1.5% of people in the United States will receive a leukemia diagnosis at some point.

In this article, explore the four main types, their symptoms, the treatment options available, and the outlook.

The full name of this type of cancer is acute lymphocytic leukemia, and acute means that it grows quickly. Lymphocytic means that it forms in underdeveloped white blood cells called lymphocytes.

The disease starts in the bone marrow, which produces stem cells that develop into red and white blood cells and platelets.

In a healthy person, the bone marrow does not release these cells until they are fully developed. In someone with ALL, the bone marrow releases large quantities of underdeveloped white blood cells.

There are several subtypes of ALL, and the subtype may influence the best course of treatment and the prognosis.

One subtype is B-cell ALL. This begins in the B lymphocytes, and it is the most common form of ALL in children.

Another subtype is T-cell ALL. It can cause the thymus, a small organ at the front of the windpipe, to become enlarged, which can lead to breathing difficulties.

Overall, because ALL progresses quickly, swift medical intervention is key.

As research from 2020 acknowledges, healthcare providers still do not know what causes ALL. It may occur due to genetic factors or exposure to:

Although genetic factors may play a role, ALL is not a familial disease.

Learn more about ALL here.

ALL is the most common form of leukemia in children.

The risk of developing it is highest in children under 5 years old. The prevalence slowly rises again in adults over 50.

ALL symptoms can be nonspecific difficult to distinguish from those of other illnesses.

They may include:

In a person with AML, the bone marrow makes abnormal versions of platelets, red blood cells, and white blood cells called myeloblasts.

The full name of this disease is acute myeloid leukemia, and acute refers to the fact that it is fast-growing.

It forms in one of the following types of bone marrow cell:

Doctors classify AML by subtype, depending on:

AML can be difficult to treat and requires prompt medical attention.

Learn more about AML here.

The most common risk factor is myelodysplastic syndrome, a form of blood cancer that keeps the body from producing enough healthy blood cells.

Other factors that increase the risk of developing AML include:

Most people who develop AML are over 45. It is one of the most common types of leukemia in adults, though it is still rare, compared with other cancers.

It is also the second most common form of leukemia in children.

Symptoms of AML can vary and may include:

CLL is the most common form of leukemia among adults in the U.S. and other Western countries.

There are two types. One progresses slowly, and it causes the body to have high levels of characteristic lymphocytes, but only slightly low levels of healthy red blood cells, platelets, and neutrophils.

The other type progresses more quickly and causes a significant reduction in levels of all healthy blood cells.

In someone with CLL, the lymphocytes often look fully formed but are less able to fight infection than healthy white blood cells. The lymphocytes tend to build up very slowly, so a person might have CLL for a long time before experiencing symptoms.

Learn more about CLL here.

Genetic factors are the most likely cause. Others might include:

CLL is rare in children. It typically develops in adults aged 70 or over. However, it can affect people as young as 30.

CLL typically causes no early symptoms. When symptoms are present, they may include:

Also, 5090% of people with CLL have swollen lymph nodes.

CML is a slow-growing type of leukemia that develops in the bone marrow.

The full name of CML is chronic myeloid leukemia. As the American Cancer Society explain, a genetic change takes place in the early forms of the myeloid cells, and this eventually results in CML cells.

These leukemia cells then grow, divide, and enter the blood.

CML occurs due to a rearrangement of genetic material between the chromosomes 9 and 22.

This rearrangement fuses a part of the ABL1 gene from chromosome 9 with the BCR gene from chromosome 22, called the Philadelphia chromosome. The result of this fusion is called BCR-ABL1.

BCR-ABL1 produces a protein that promotes cell division and stops apoptosis, the process of cell death, which typically removes unneeded or damaged cells.

The cells keep dividing and do not self-destruct, resulting in an overproduction of abnormal cells and a lack of healthy blood cells.

This occurs during the persons lifetime and is not inherited.

CML typically affects adults. People aged 65 and older make up almost half of those who receive a CML diagnosis.

The symptoms of CML are unclear, but they may include:

The symptoms may vary, depending on the type of leukemia. Overall, a person should get in touch with a doctor if they experience:

Learn more about the symptoms of leukemia here.

Treatment for ALL typically involves three basic phases: induction, consolidation, and maintenance. We describe these in detail below.

Treatment for AML involves the first two phases. The induction phase may include treatment with the chemotherapy drugs cytarabine (Cytosar-U) and daunorubicin (Cerubidine) or idarubicin (Idamycin). The doctor may also recommend targeted drugs.

The goal of this phase is to kill the leukemia cells, causing the cancer to go into remission, using chemotherapy.

The doctor may recommend:

People having chemotherapy may need to see their doctors frequently and spend time in the hospital, due to the risk of serious infections and complications.

This phase of the treatment lasts for about 1 month.

Even if the treatment so far has led to remission, cancer cells may be hiding in the body, so more treatment is necessary.

The consolidation phase may involve taking high doses of chemotherapy. A doctor may also recommend targeted drugs or stem cell transplants.

This phase, consisting of ongoing chemotherapy treatments, usually lasts for 2 years.

Since CLL tends to progress slowly, and its treatment can have unpleasant side effects, some people with this condition go through a phase of watchful waiting before starting the treatment.

For a person with CML, the focus is often on providing the right treatment for the phase of the illness. To do this, a doctor considers how quickly the leukemia cells are building up and the extent of the symptoms. Stem cell transplants can be effective, but further treatment is necessary.

Overall, the initial treatment tends to include monoclonal antibodies, targeted drugs, and chemotherapy.

If the only concern is an enlarged spleen or swollen lymph nodes, the person may receive radiation or surgery.

If there are high numbers of CLL cells, the doctor may suggest leukapheresis, a treatment that lowers the persons blood count. This is only effective for a short time, but it allows the chemotherapy to start working.

For people with high-risk disease, doctors may recommend stem cell transplants.

A persons prognosis depends on the type of leukemia.

Learn more about survival rates for people with leukemia here.

About 8090% of adults with ALL experience complete remission for a while during treatment. And with treatment, most children recover from the disease.

Relapses are common in adults, so the overall cure rate is 40%. However, factors specific to each person play a role.

The older a person is when they receive an AML diagnosis, the more difficult it is to treat.

More than 25% of adults who achieve remission live for 3 years or more after treatment for AML.

A person may live for a long time with CLL.

Treatments can help keep the symptoms under control and prevent the disease from spreading. However, there is no cure.

Stem cell transplants can cure CML. However, this treatment is very invasive and is not suitable for most people with CML.

The United Kingdoms National Health Service estimate that 70% of males and 75% of females live for at least 5 years after receiving a CML diagnosis.

The earlier a person receives the diagnosis, the better their outlook.

Leukemia is a type of cancer that affects the blood and bone marrow. It can affect people of all ages.

There are four main types of leukemia. They differ based on how quickly they progress and the types of cells they affect.

Treatments for all types of leukemia continue to improve, helping people live longer and more fully with this condition.

Continue reading here:
Types of leukemia: Prevalence, treatment options, and prognosis - Medical News Today

Recommendation and review posted by Bethany Smith

Transparency Market Research (TMR) has published a new report titled, Cord Blood Banking Services Market Global Industry Analysis, Size, Share, Growth, Trends, and Forecast, 20192027. According to the report, the globalcord blood banking services marketwas valued atUS$ 25.8 Mnin2018and is projected to expand at a CAGR of10.9%from2019to2027.

Overview

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High Incidence of genetic disorders and rise in hematopoietic stem cell transplantation rates to Drive Market

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Cord Blood Banking Services Market projected to expand at a CAGR of 10.9% from 2019 to 2027 KSU | The Sentinel Newspaper - KSU | The Sentinel...

Recommendation and review posted by Bethany Smith

REDWOOD CITY, Calif.--(BUSINESS WIRE)--Jasper Therapeutics, Inc., a biotechnology company focused on hematopoietic cell transplant therapies, today announced the launch of a Phase 1/2 clinical trial to evaluate JSP191, Jaspers first-in-class anti-CD117 monoclonal antibody, as a targeted, non-toxic conditioning regimen prior to allogeneic transplant for sickle cell disease (SCD). Jasper Therapeutics and the National Heart, Lung, and Blood Institute (NHLBI) have entered into a clinical trial agreement in which NHLBI will serve as the Investigational New Drug (IND) sponsor for this study.

SCD is a lifelong inherited blood disorder that affects hemoglobin, a protein in red blood cells that delivers oxygen to tissues and organs throughout the body. Approximately 300,000 infants are born with SCD annually worldwide, and the number of cases is expected to significantly increase. Currently, hematopoietic stem cell transplantation (HSCT) is the only cure available for SCD.

"This clinical trial agreement with the NHLBI expands the development of JSP191 for transplant conditioning and could bring curative transplants to more patients in need," said Kevin N. Heller, M.D., Executive Vice President, Research and Development, of Jasper Therapeutics. "We look forward to collaborating with the NHLBI and learning more about the potential for JSP191 in patients living with sickle cell disease."

About JSP191

JSP191 (formerly AMG 191) is a first-in-class humanized monoclonal antibody in clinical development as a conditioning agent that clears hematopoietic stem cells from the bone marrow. JSP191 binds to human CD117, a receptor for stem cell factor (SCF) that is expressed on the surface of hematopoietic stem and progenitor cells. The interaction of SCF and CD117 is required for stem cells to survive. JSP191 blocks SCF from binding to CD117 and disrupts critical survival signals in stem cells leading to cell death. This creates space in the bone marrow for engraftment of donor or gene-corrected transplanted stem cells.

Preclinical studies have shown that JSP191, as a single agent, safely depletes normal and diseased hematopoietic stem cells, including in animal models of severe combined immunodeficiency (SCID), myelodysplastic syndromes (MDS), and sickle cell disease (SCD). Treatment with JSP191 creates the space needed for transplanted normal donor or gene-corrected hematopoietic stem cells to successfully engraft in the host bone marrow. To date, JSP191 has been evaluated in more than 90 healthy volunteers and patients.

JSP191 is currently being evaluated in two separate Jasper Therapeutics-sponsored clinical studies in hematopoietic cell transplant. The first clinical study is evaluating JSP191 as a sole conditioning agent in a Phase 1/2 dose-escalation and expansion trial to achieve donor stem cell engraftment in patients undergoing hematopoietic cell transplant for SCID. Blood stem cell transplantation offers the only potentially curative therapy for SCID. JSP191 is also being evaluated in combination with another conditioning regimen in a Phase 1 study in patients with MDS or acute myeloid leukemia (AML) who are receiving hematopoietic cell transplant. For more information about the design of these clinical trials, visit http://www.clinicaltrials.gov (NCT02963064 and NCT04429191).

Additional studies are planned to advance JSP191 as a conditioning agent for patients with other rare and ultra-rare monogenic disorders and autoimmune diseases.

About Jasper Therapeutics

Jasper Therapeutics is a biotechnology company focused on the development of novel curative therapies based on the biology of the hematopoietic stem cell. The companys lead compound, JSP191, is in clinical development as a conditioning antibody that clears hematopoietic stem cells from bone marrow in patients undergoing a hematopoietic cell transplant. This first-in-class conditioning antibody is designed to enable safer and more effective curative hematopoietic cell transplants and gene therapies. For more information, please visit us at jaspertherapeutics.com.

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Jasper Therapeutics Announces Launch of New Clinical Trial with National Heart, Lung, and Blood Institute to Evaluate JSP191 in Sickle Cell Disease -...

Recommendation and review posted by Bethany Smith

Apamistamab (Iomab-B) conditioning treatment with targeted radioimmunotherapy to the bone marrow resulted in high rates of successful allogeneic hematopoietic stem cell transplants in patients with active, relapsed, or refractory acute myeloid leukemia (AML), according to interim results from the phase 3 SIERRA trial, which were presented virtually at the 2021 Transplant and Cellular Therapies Meetings.1

In these patients with relapsed or refractory AML, we observed high rates of allogeneic stem cell transplant with curative intent [in] 88% of patients on the Iomab-B arm, 18% of patients who were randomized to the conventional care arm achieved complete remission and received standard of care allo-transplant, and an overall rate of 79% of allo-transplant in all enrolled patients, Boglarka Gyurkocza, MD, said in a virtual presentation.

Investigators sought to prove with this study that targeted radiation to the marrow with apamistamab, a radioactive iodine (131I)labeled anti-CD45 antibody, could enable the successful engraftment of patients despite active disease in the marrow. Safety and robust efficacy had previously been demonstrated with the agent in 271 patients treated in 9 different phase 1 and 2 clinical trials.

The SIERRA trial is looking to enroll 150 patients, and the trial is already over 75% enrolled. Recently, an independent data monitoring committee recommended that the trial continue to the planned full enrollment based on a positive pre-planned ad-hoc analysis.2

In the study, patients with active, relapsed, refractory AML are randomized 1:1 to receive either apamistamab conditioning therapy and allogeneic HCT or conventional care. In the control arm, patients who do not achieve a complete remission (CR) by day 42 are allowed to cross over to receive Iomab-B, and those who do have a CR undergo HCT or receive standard-of-care therapy of the physicians choice.

Durable CR (dCR) rate is the primary end point of the study, characterized as complete response at 6 months after initial CR, and the secondary end point is overall survival (OS) rate at 1 year.

Patients are eligible for enrollment if they have marrow blast count 5% or the presence of peripheral blasts, age 55 years, a Karnofsky score 70, and related/unrelated donor matching at human leukocyte antigen (HLA)-A, HLA-B, HLA-C, and DRB-1. Active, relapsed, or refractory AML was defined for the sake of the trial as primary induction failure after 2 cycles of therapy including chemotherapy or 2 cycles of venetoclax (Venclexta) with a hypomethylating agent or low-dose cytarabine, first early relapse after first CR of less than 6 months, relapse refractory to salvage chemotherapy regimen, or second or subsequent relapse. Secondary or treatment-related AML was also allowed.

In the SIERRA trial, patient-specific dosimetry was used to generate an individualized therapeutic dose to target marrow and spare non-hematopoietic organs. Patients in the investigational arm received a dosimetric dose of apamistamab ( 20 mCi) approximately 19 days prior to HCT followed by a therapeutic dose of apamistamab, which is individually calculated for each patient based on an upper limit of 24 Gy to the liver. After, patients remain on radiation isolation for several days before receiving fludarabine conditioning therapy (30 mg/m2/day for 3 days) and finally low-dose total body irradiation (200 cGy) prior to HCT.

Among the first 75% of enrolled patients (n = 113), patients in the apamistamab arm (n = 56) had a median age of 63 years (range, 55-77), 35% had intermediate risk and 61% had adverse risk, the median

percent of marrow blasts at baseline was 29% (range, 4%-95%), and had received a median of 3 prior treatment regimens (range, 1-7). At randomization, 56% were in primary induction failure, 16% were in first early relapse, 15% had relapsed or refractory disease, and 13% were in their second or later relapse.

In the conventional care arm, the median age was 65 years (range, 55-77), 32% had intermediate risk and 63% had adverse risk, median marrow blasts was 20% (range, 5%-97%), and had received a median of 3 prior regimens (range, 1-6). At randomization, 49% were in primary induction failure, 21% were in first early relapse, 21% had relapsed or refractory disease, and 8.8% were in their second or later relapse. Patients who crossed over to receive apamistamab (n = 30) had similar baseline characteristics.

Forty-nine patients in the apamistamab-randomized arm were able to go on and undergo allogeneic HCT compared with 10 patients in the conventional care arm. In the investigational arm, a median of 646 mCi (range, 3541027) of apamistamab was infused at a dose of 14.7 Gy (range, 4.6-32) to the marrow. The median infused CD34-positive cell count was 5.6 x 106/Kg (range, 1.8-208). Forty-five patients received peripheral blood stem cells (PBSCs), 3 received marrow grafts, 17 had related donors, and 31 had unrelated.

Individualized therapy of Iomab-B provided myeloablative doses of radiation to the marrow, Gyurkocza, a medical oncologist at Memorial Sloan Kettering Cancer Center, commented.

These patients had a median of 30 days (range, 23-60) to HCT after randomization and 14 days (range, 9-22) to neutrophil engraftment, with no graft failure reported. Patients also had 18 days (range, 4-39) until platelet engraftment.

We also observed 100% neutrophil and platelet engraftment in patients who received Iomab-B conditioning, despite a heavy leukemia burden, Gyurkocza said.

In patients in the conventional arm who went on to HCT, conditioning regimens for HCT consisted of fludarabine/melphalan in 2, fludarabine/melphalan/total body irradiation in 1, busulfan/fludarabine in 1, cyclophosphamide/fludarabine/total body irradiation in 2, and 4 had no data on conditioning regimens available. Eight of these patients had PBSCs, 2 had marrow, 3 had related donors, 6 had unrelated, and 1 was unreported.

Median days to HCT was 67 (range, 52-104) with 17 days (range, 13-83) to neutrophil engraftment and 22 days (range, 8-35) to platelet engraftment. There was 1 graft failure.

Among the patients who crossed over to receive apamistamab before HCT, the median infused dose was 592 mCi (range, 313-1013) with 15.5 Gy (range, 6.3-42) to the marrow. The median infused CD34-positive cell count was 5.1 x 106/Kg (range, 1.8-16.1). Twenty-eight patients had PBSCs, 2 had marrow, 10 had related donors, and 20 had unrelated.

Patients had a median of 62 days (range, 36-100) to HCT, 14 days (range, 10-37) to neutrophil engraftment, and 19 days (range, 1-38) to platelet engraftment. No graft failure was reported in this group.

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Apamistamab Conditioning Treatment Induces High Rates of HCT Success in AML - OncLive

Recommendation and review posted by Bethany Smith

Novartis and the Bill and Melinda Gates Foundation are joining forces to discover and develop a gene therapy to cure sickle cell disease with a one-step, one-time treatment that is affordable and simple enough to treat patients anywhere in the world, especially in sub-Saharan Africa where resources may be scarce but disease prevalence is high.

The three-year collaboration, announced Wednesday, has initial funding of $7.28 million.

Current gene therapy approaches being developed for sickle cell disease are complex, enormously expensive, and bespoke, crafting treatments for individual patients one at a time. The collaboration aims to instead create an off-the-shelf treatment that bypasses many of the steps of current approaches, in which cells are removed and processed outside the body before being returned to patients.

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Sickle cells cause is understood. The people it affects are known. But its cure has been elusive, Jay Bradner, president of the Novartis Institutes for BioMedical Research, told STAT.

We understand perfectly the disease pathway and the patient, but we dont know what it would take to have a single-administration, in vivo gene therapy for sickle cell disease that you could deploy in a low-resource setting with the requisite safety and data to support its use, he said. Im a hematologist and can assure you that in my experience in the clinic, it was extremely frustrating to understand a disease so perfectly but have so little to offer.

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Sickle cell disease is a life-threatening inherited blood disorder that affects millions around the world, with about 80% of affected people in sub-Saharan Africa and more than 100,000 in the U.S. The mutation that causes the disease emerged in Africa, where it protects against malaria. While most patients with sickle cell share African ancestry, those with ancestry from South America, Central America, and India, as well as Italy and Turkey, can also have the hereditary disease.

The genetic mutation does its damage by changing the structure of hemoglobin, hampering the ability of red blood cells to carry oxygen and damaging blood vessels when the misshapen cells get stuck and block blood flow. Patients frequently suffer painful crises that can be fatal if not promptly treated with fluids, medication, and oxygen. Longer term, organs starved of oxygen eventually give out. In the U.S., that pain and suffering is amplified when systemic and individual instances of racism deny Black people the care they need.

Delivering gene therapy for other diseases has been costly and difficult even in the best financed, most sophisticated medical settings. Challenges include removing patients cells so they can be altered in a lab, manufacturing the new cells in high volume, reinfusing them, and managing sometimes severe responses to the corrected cells. Patients also are given chemotherapy to clear space in their bone marrow for the new cells.

Ideally, many of those steps could be skipped if there were an off-the-shelf gene therapy. That means, among other challenges, inventing a way to eliminate the step where each patients cells are manipulated outside the body and given back the in vivo part of the plan to correct the genetic mutation.

Thats not the only obstacle. For a sickle cell therapy to be successful, Bradner said, it must be delivered only to its targets, which are blood stem cells. The genetic material carrying corrected DNA must be safely transferred so it does not become randomly inserted into the genome and create the risk of cancer, a possibility that halted a Bluebird Bio clinical trial on Tuesday. The payload itself mustnt cause such problems as the cytokine storm of immune overreaction. And the intended response has to be both durable and corrective.

In a way, the gene delivery is the easy part because we know that expressing a normal hemoglobin, correcting the mutated hemoglobin, or reengineering the switches that once turned off normal fetal hemoglobin to turn it back on, all can work, Bradner said. The payload is less a concern to me than the safe, specific, and durable delivery of that payload.

For each of these four challenges delivery, gene transfer, tolerability, durability there could be a bespoke technical solution, Bradner said. The goal is to create an ensemble form of gene therapy.

Novartis has an existing sickle-cell project using CRISPR with the genome-editing company Intellia, now in early human trials, whose lessons may inform this new project. CRISPR may not be the method used; all choices are still on the table, Bradner said.

Vertex Pharmaceuticals has seen encouraging early signs with its candidate therapy developed with CRISPR Therapeutics. Other companies, including Beam Therapeutics, have also embarked on gene therapy development.

The Novartis-Gates collaboration is different in its ambition to create a cure that does not rely on an expensive, complicated framework. Novartis has worked with the Gates Foundation on making malaria treatment accessible in Africa. And in October 2019, the Gates Foundation and the National Institutes of Health said together they would invest at least $200 million over the next four years to develop gene-based cures for sickle cell disease and HIV that would be affordable and available in the resource-poor countries hit hardest by the two diseases, particularly in Africa.

Gene therapies might help end the threat of diseases like sickle cell, but only if we can make them far more affordable and practical for low-resource settings, Trevor Mundel, president of global health at the Gates Foundation, said in a statement about the Novartis collaboration. Its about treating the needs of people in lower-income countries as a driver of scientific and medical progress, not an afterthought.

Asked which is the harder problem to solve: one-time, in vivo gene therapy, or making it accessible around the world, David Williams, chief of hematology/oncology at Boston Childrens Hospital, said: Both are going to be difficult to solve. The first will likely occur before the therapy is practically accessible to the large number of patients suffering the disease around the world.

Williams is also working with the Gates Foundation, as well as the Koch Institute for Integrative Cancer Research at MIT, Dana-Farber Cancer Institute, and Massachusetts General Hospital, on another approach in which a single injection of a reagent changes the DNA of blood stem cells. But there are obstacles to overcome there, too, that may be solved by advances in both the technology to modify genes and the biological understanding of blood cells.

Bradner expects further funding to come to reach patients around the world, once the science progresses more.

There is no plug-and-play solution for this project in the way that mRNA vaccines were perfectly set up for SARS-CoV-2. We have no such technology to immediately redeploy here, he said. Were going to have to reimagine what it means to be a gene therapy for this project.

Here is the original post:
Novartis, Gates Foundation pursue a simpler gene therapy for sickle cell - STAT

Recommendation and review posted by Bethany Smith

One-year-old Max Gardner was diagnosed with aplastic anaemia, in October 2020, a serious condition in which the bone marrow and stem cells do not produce enough blood cells.

After Max developed significant bruises and a rash over his body, parents, Connor Gardner and Rachel Nicholson, from Hebburn, were referred to South Tyneside District Hospital, where their brave little boy underwent tests.

Doctors initially believed that Max had an immune disorder but after he was admitted to the Royal Victoria Infirmary (RVI) further tests helped to diagnose him with aplastic anaemia.

The family was told that the condition could be fatal if not treated properly.

Doctors said Max needed to have a bone marrow transplant, which has the potential to cure him.

Dad Connor, 29, and mum Rachel, 27, were both tested to see if they would be a bone marrow match and the pair were overjoyed when Rachel was found to be a 9/10 match.

Max started chemotherapy on January 7 at the RVI and mum Rachel donated stem cells on January 13 at Newcastles Freeman Hospital.

The following day, January 14, Max underwent the transplant at the RVI.

The family is now waiting for the results of a Chimerism Test which will tell them for definite whether the stem cells have worked but signs are already looking positive.

Delighted dad, Connor, said: "His neutrophils [a type of white blood cell that protect us from infections] have been more than 0.50 for three days in a row, which means that he is essentially engrafted, which means that his body is accepting the transplant.

"So it is working, but we still have to wait for the test results."

Doctors say there is no doubt that it has worked with the way the numbers have gone up but they have to officially do it like that to make sure, Connor continued.

"But there is no reason why it shouldnt have [doctors] say.

"He has done really well to get to this stage, he has absolutely sailed through it, everyone is surprised with how well he has done.

This the best outcome we could have hoped for.

But it hasnt been plain sailing for the family, who have also had to face additional challenges during the treatment.

Parents Connor and Rachael initially were not allowed to visit Max at the same time due to Covid rules, however the hospital has now eased the restriction in their case.

The family also became sick with Norovirus in the run-up to the transplant, causing concern over whether it would have to be pushed back.

Thankfully, the transplant went ahead as planned and the family made a good recovery, although Max still needs help with his eating.

Max will now have to remain in hospital for a while longer as he recovers from the transplant.

Connor added: We can feel that we are nearly at the end of it.

"His neutrophils are the highest they have ever been since he became poorly so we feel like we are coming to the end.

The family are sharing Maxs journey to health on Instagram under the name @maxinamillionaajourney and hope his story will encourage people to sign up to the Anthony Nolan register to become a potential donor and help others like Max.

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See the article here:
Bone marrow transplant shows signs of curing brave little boy with one in a million condition - Shields Gazette

Recommendation and review posted by Bethany Smith

RESEARCH TRIANGLE PARK After 13 years as a clinical-stage oncology company,G1 Therapeuticsof Research Triangle Park transformed into a commercial-stage company overnight upon the approval of its first drug by the U.S. Food and Drug Administration.

The FDA on Feb. 12 approved G1s trilaciclib, to be marketed as Cosela, for protecting bone marrow from chemotherapy damage in adult patients with extensive-stage small cell lung cancer (ES-SCLC).

Cosela will help change the chemotherapy experience for people who are battling ES-SCLC, said Jack Bailey, the companys chief executive officer. G1 is proud to deliver Cosela to patients and their families as the first and only therapy to help protect against chemotherapy-induced myelosuppression.

Myelosuppression, or damage to the bone marrow, is the most serious and life-threatening side effect of chemotherapy. Chemotherapy-induced myelosuppression reduces the bodys essential supply of white blood cells, red blood cells and platelets, and can lead to increased risks of infection, severe anemia and bleeding.

RTP drug firm G1 secures FDA approval for treatment to prevent chemo damage to bone marrow

These complications impact patients quality of life and may also result in chemotherapy dose reductions and delays, said Jeffrey Crawford,M.D., Geller Professorfor Research in Cancer in theDepartment of MedicineandDuke Cancer Institute. In clinical trials, the addition of trilaciclib to extensive-stage small cell lung cancer chemotherapy treatment regimens reduced myelosuppression and improved clinical outcomes.The good news is that these benefits of trilaciclib will now be available for our patients in clinical practice.

Cosela is expected to be commercially available through G1s specialty distributor partner network in early March, the company said.

G1 is committed to helping patients with in theU.S.gain access to treatment with Cosela through access and affordability programs. Patients and healthcare can call the companys support center at 833-418-6663 for information.

Cosela is intended to be given as a 30-minute infusion four hours prior to chemotherapy treatments containing platinum/etoposide or topotecan. About 90 percent of all patients with ES-SCLC receive at least one of these chemotherapy regimens during their treatment, according to G1.

The approval of Cosela is based on data from three randomized, placebo-controlled trials. Data showed that patients receiving Cosela before the start of chemotherapy had less neutropenia, an abnormally low number of neutrophils, white blood cells that fight bacterial and fungal infection.

Data also showed a positive impact on red blood cell transfusions and other myeloprotective measures.

Chemotherapy is the most effective and widely used approach to treating people diagnosed with extensive-stage small cell lung cancer, Bailey said. However, standard-of-care chemotherapy regimens are highly myelosuppressive and can lead to costly hospitalizations and rescue interventions.

To date, oncologists have relied on rescue therapy, a mix of growth factor agents, antibiotics and red blood cell transfusions, to restore bone marrow after it has been damaged by chemotherapy.

By contrast, trilaciclib provides the first proactive approach to myelosuppression through a unique mechanism of action that helps protect the bone marrow from damage by chemotherapy, Crawford said.

Cosela helps protect bone marrow cells from chemotherapy damage by inhibiting cyclin- dependent kinase 4 and 6, two enzymes involved in cancer cell growth. Inhibiting these enzymes temporarily stops hematopoietic stem cells and progenitor cells in the bone marrow from dividing, making them resistant to damage from chemotherapy drugs that target dividing cells.

Bonnie J. Addario, lung cancer survivor, co-founder and board chair of theGo2 Foundation for Lung Cancer, said many people with extensive-stage small cell lung cancerrely on chemotherapy to extend their lives and alleviate their symptoms.

Unfortunately, the vast majority will experience chemotherapy-induced side effects, resulting in dose delays and reductions, and increased utilization of healthcare services, she said.

G1 shares our organizations goal to improve the quality of life of those diagnosed with lung cancer and to transform survivorship among people living with this insidious disease. We are thrilled to see new advancements that can help improve the lives of those living with small cell lung cancer.

About 30,000 small cell lung cancer patients are treated inthe United Statesannually. SCLC, one of the two main types of lung cancer, accounts for about 10 to 15 percent of all lung cancers but is the more aggressive disease, tending to grow and spread faster than the other type, non-small cell lung cancer.

InJune 2020, G1 announced a three-yearco-promotion agreementwithBoehringer Ingelheimfor Cosela in small cell lung cancer in theU.S.andPuerto Rico. G1 will lead marketing, market access and medical engagement initiatives for Cosela whileBoehringer Ingelheimsoncology commercial team will lead sales force engagement initiatives.

G1 will book revenue and retain development and commercialization rights to Cosela and payBoehringer Ingelheima promotional fee based on net sales.

The three-year agreement does not extend to additional indications that G1 is evaluating for trilaciclib: breast, colorectal, bladder and non-small cell lung cancers.

G1 is a 2008 spin-out of the University of North Carolina at Chapel Hill.

The company raised $108 million in an initial public offering of stock in 2017 after receiving more than $95 million in three rounds of venture capital funding. The North Carolina Biotechnology Center provided two early-stage loans totaling $500,000.

G1s stock is traded on the Nasdaq Global Select Market under the ticker symbol GTHX.

(C) N.C. Biotech Center

Link:
After 13 years of trials and tribulations RTP firm G1 wins first FDA approval for cancer drug - WRAL Tech Wire

Recommendation and review posted by Bethany Smith

Newark, NJ, Feb. 11, 2021 (GLOBE NEWSWIRE) -- As per the report published by Fior Markets, theglobal haematological cancer therapeutics market is expected to grow from USD 37.88 billion in 2020 and to reach USD 82.40 billion by 2028, growing at a CAGR of 10.2% during the forecast period 2021-2028.

The global hematological cancers therapeutics market is witnessing significant growth in recent years. This growth is attributed to the increased government spending and infrastructure development rate across the globe, increasing blood cancer incidences, and increasing investment in research and development. Other factors propelling the market growth include inventions of novel drugs and growing investment in research and development.

The haematological cancer is a class of cancer that affects one marrow, blood, and lymph nodes. It is mostly caused due to a long exposure of toxic substances like genetic predisposition, ionized radiation and chemical agents, improper assessment, viral infections, and other risks associated with other diseases with decreased immunity. Further, the bone marrow's stem cells develop into red blood cells, white blood cells, or platelets.

The global haematological cancer therapeutics market is expected to witness significant growth, owing to the increasing awareness about the possibility of early diagnosis, rising diagnostics rate, and advancements in biotechnology and pharmaceutical industries. The factors restraining the market growth are lack of awareness among people, high cost of medications, and haematological therapeutics' side effects.

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The key players operating in the global haematological cancer therapeutics market are Johnson & Johnson, Roche, Mindray Medical, Karyopharm Therapeutics, AbbVie, Abbott Laboratories, Celgene, Novartis, Bio-Rad Laboratories, HemoCue AB, Sysmex, and Siemens AG. To gain a significant market share in the global haematological cancer therapeutics market, the key players are now focusing on adopting strategies such as product innovations, mergers & acquisitions, recent developments, joint ventures, collaborations, and partnerships.

Pharmacological therapies segment dominated the market growth and held the largest share of 23.76% in the year 2020On the basis of type, the global haematological cancers therapeutics market is segmented into anaemia treatment, pharmacological therapies, steam cell transplantation, thrombosis treatment, surgery and radiation therapy, neutropenia treatment, and others. Pharmacological therapies segment dominated the market growth and held the largest share of 23.76% in the year 2020. This growth is attributed to the growing pharmaceutical sector, increasing research and developments, and rising cancer prevalence.

Hospitals segment dominated the market and held the largest share of 36.65% in the year 2020On the basis of end-user, the global hematological cancer therapeutics market is segmented into clinical laboratories, hospitals, academic and research institutes, and others. The hospitals segment dominated the market and held the largest share of 36.65% in the year 2020. This growth is attributed to the government and private bodies reimbursement and increased government spending on the hospital infrastructures.

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Regional Segment of Hematological Cancer Therapeutics Market

On the basis of geography, the global haematological cancer therapeutics market is classified into North America, Europe, Asia-Pacific, Middle East & Africa, and South America. Asia-Pacific region held the largest share of 39.68% in the year 2020. This growth is attributed to the increased government hospital expenditure, growing investment in research and development, and increasing awareness about cancer treatments. China holds the largest market share in the region due to investments by key pharmaceutical players to develop new drugs. North America is expected to witness significant growth, owing to the high prevalence of blood cancer patients and rising healthcare infrastructure.

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About the report:The global haematological cancer therapeutics market is analyzed on the basis of value (USD billion). All the segments have been analyzed on global, regional and country basis. The study includes the analysis of more than 30 countries for each segment. The report offers in-depth analysis of driving factors, opportunities, restraints, and challenges for gaining the key insights of the market. The study includes porters five forces model, attractiveness analysis, raw material analysis, and competitors position grid analysis.

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Global Hematological Cancers Therapeutics Market Is Expected to Reach USD 82.40 billion by 2028 : Fior Markets - GlobeNewswire

Recommendation and review posted by Bethany Smith

Introduction

Extracellular vesicles (EVs) including exosomes, microvesicles, and apoptotic bodies are produced and released by almost all types of cell. EVs vary in size, properties, and secretion pathway depending on the originating cell.1,2 Exosomes are small EVs (sEVs) which are formed by a process of inward budding in early endosomes to form multivesicular bodies (MVBs) with an average size of 100 nm, and released into the extracellular microenvironment to transfer their components.3,4 Microvesicles are composed of lipid components of the plasma membrane and their sizes range from 1001000 nm, whereas apoptotic bodies result from programmed cell death.5 Initially, EVs were considered to maintain cellular waste through release of unwanted proteins and biomolecules; later, these organelles were considered important for intercellular communications through various cargo molecules such as lipids, proteins, DNA, RNA, and microRNAs (miRNAs).6 Previously, it was suggested that EVs play a critical role in normal cells to maintain homeostasis and prevent cancer initiation. Inhibition of EVs secretion causes accumulation of nuclear DNA in the cytoplasm, leading to apoptosis.1 The induction of apoptosis is the principal event of the reactive oxygen species (ROS) dependent DNA damage response.7,8

Several studies reported that exosomes are synthesized by means of two major pathways, the endosomal sorting complexes required for transport (ESCRT)-dependent and ESCRT-independent, and the processes are highly regulated by multiple signal transduction cascades.18 Exosomes released from the cell through normal exocytosis mechanisms are characterized by vesicular docking and fusion with the aid of SNARE complexes. Exosomes are considered to be organelle responsible for garbage disposal agents. However, at a later stage, these secretory bodies play a critical role in maintaining the physiological and pathological conditions of the surrounding cells by transferring information from donor cells to recipient cells. Exosome development begins with endocytosis to form early endosomes, later forming multivesicular endosomes (MVEs), and finally generating late endosomes by inward budding. MVEs merge with the cell membrane and release intraluminal endosomal vesicles that become exosomes into the extracellular space.9,10 Exosome biogenesis is dependent on various critical factors including the site of biogenesis, protein sorting, physicochemical aspects, and transacting mediators.11

Exosomes contain various types of cargo molecules including lipids, proteins, DNAs, mRNAs, and miRNAs. Most of the cargo is involved in the biogenesis and transportation ability of exosomes.12,13 Exosomes are released by fusion of MVBs with the cell membrane via activation of Rab-GTPases and SNAREs. Exosomes are abundant and can be isolated from a wide variety of body fluids and also cell culture medium.14 Exosomes contain tetraspanins that are responsible for cell penetration, invasion, and fusion events. Exosomes are released onto the external surface by the MVB formation proteins Alix and TSG101. Exosome-bound proteins, annexins and Rab protein, govern membrane transport and fusion whereas Alix, flotillin, and TSG101 are involved in exosome biogenesis.15,16 Exosomes contain various types of proteins such as integral exosomal membrane proteins, lipid-anchored outer and inner membrane proteins, peripheral surface and inner membrane proteins, exosomal enzymes, and soluble proteins that play critical roles in exosome functions.11

The functions of exosomes depend on the origin of the cell/tissue, and are involved in the immune response, antigen presentation programmed cell death, angiogenesis, inflammation, coagulation, and morphogen transporters in the creation of polarity during development and differentiation.1720 Ferguson and Nguyen reported that the unique functions of exosomes depend on the availability of unique and specific proteins and also the type of cell.21 All of these categories influence cellular aspects of proteins such as the cell junction, chaperones, the cytoskeleton, membrane trafficking, structure, and transmembrane receptor/regulatory adaptor proteins. The role of exosomes has been explored in different pathophysiological conditions including metabolic diseases. Exosomes are extremely useful in cancer biology for the early detection of cancer, which could increase prognosis and survival. For example, the presence of CD24, EDIL3, and fibronectin proteins on circulating exosomes has been proposed as a marker of early-stage breast cancer.22 Cancer-derived exosomes promoted tumor growth by directly activating the signaling pathways such as P13K/AKT or MAPK/ERK.23 Tumor-derived exosomes are significantly involved in the immune system, particularly stimulating the immune response against cancer and delivering tumor antigens to dendric cells to produce exosomes, which in turn stimulates the T-cell-mediated antitumor immune response.24 Exosomal surface proteins are involved in immunotherapies through the regulation of the tumor immune microenvironment by aberrant cancer signaling.25 A study demonstrated that exosomes have the potential to affect health and pathology of cells through contents of the vesicle.26 Exosomes derived from mesenchymal stem cells exhibit protective effects in stroke models following neural injury resulting from middle cerebral artery occlusion.27 The structural region of the exosome facilitate the release of misfolded and prion proteins, and are also involved in the propagation of neurodegenerative diseases such as Huntington disease, Alzheimers disease (AD), and Parkinsons disease (PD).28,29

Exosomes serve as novel intercellular communicators due to their cell-specific cargo of proteins, lipids, and nucleic acids. In addition, exosomes released from parental cells may interact with target cells, and it can influence cell behavior and phenotype features30 and also it mediate the horizontal transfer of genetic material via interaction of surface adhesion proteins.31 Exosomes are potentially serving as biomarkers due to the wide-spread and cell-specific availability of exosomes in almost all body fluids.13 Therefore, exosomes are exhibited as delivery vehicles for the efficient delivery of biological therapeutics across different biological barriers to target cells.3234

In this review, first, we comprehensively describe the factors involved in exosome biogenesis and the role of exosomes in intercellular signaling and cell-cell communications, immune responses, cellular homeostasis, autophagy, and infectious diseases. In addition, we discuss the role of exosomes as diagnostic markers, and the therapeutic and clinical implications. Finally, we discuss the challenges and outstanding developments in exosome research.

The extracellular vesicles play critical role in inter cellular communication by serving as vehicles for transfer of biomolecules. These vesicles are generally classified into microvesicles, ectosomes, shedding vesicles, or microparticles. MVs bud directly from the plasma membrane, whereas exosomes are represented by small vesicles of different sizes that are formed as the ILV by budding into early endosomes and MVBs and are released by fusion of MVBs with the plasma membrane (Figure 1). Invagination of late endosomal membranes results in the formation of intraluminal vesicles (ILVs) within large MVBs.35 Biogenesis of exosomes occurs in three ways including vesicle budding into discrete endosomes that mature into multivesicular bodies, which release exosomes upon plasma membrane fusion; direct vesicle budding from the plasma membrane; and delayed release by budding at intracellular plasma membrane-connected compartments (IPMCs) followed by deconstruction of IPMC neck(s).11 The mechanisms of biogenesis of exosomes are governed by various types of proteins including the ESCRT proteins Hrs, CHMP4, TSG101, STAM1, VPS4, and other proteins such as the Syndecan-syntenin-ALIX complex, nSMase2, PLD2, and CD9.14,3639 After formation, the MVB can either fuse with the lysosome to degrade its content or fuse with the plasma membrane to release the ILVs as exosomes. The release of exosomes to the extracellular milieu is driven by proteins of the Rab-GTPase family including RAB2B, 5A, 7, 9A, 11, 27, and 35. SNARE family proteins VAMP7 and YKT6 have also been implicated in the release.14,38,4042 Biogenesis of exosomes is influenced by several external factors including cell type, cell confluency, serum conditions, and the presence and absence of cytokines and growth factors. In addition, biogenesis is also regulated by the sites of exosomes, protein sorting, physico-chemical aspects, and trans-acting mediators (Figure 2). For example, THP-1 cells were cultured in RPMI-1640 cell culture medium supplemented with 10% FCS secreted low level of exosomes compared to cells grown on cell culture medium supplemented with 1% FCS (Figure 3). The exogenous factor like serum starvation influences biogenesis and secretion of exosomes.

Figure 1 Biogenesis and cargoes of exosomes.

Figure 2 Effect of various factors on biogenesis of exosomes.

Figure 3 Serum deprivation causes an increase of the number of cellular exosomes in THP-1 cells. Panel (A); 10% FCS. Panel (B); 1% FCS. Panel (C) Quantification of exosomes using DLS and NTA.

Exosome release depends on expression of Rab27 or Ral. For example, exosomes released from the MVB significantly decrease in cells depleted of Rab2741 or Ral.43 The most efficient EV-producing cell types have yet to be determined44 and few reports suggest that immature dendritic cells produce limited amounts of EVs45,46 whereas mesenchymal stem cells secrete vast amounts, relevant for the production of EV therapeutics on a clinical scale.47,48 A few proteins play a critical role in the biogenesis of EVs, such as Rab27a and Rab27b.49 Over expression of Rab27a and Rab27b produce significant amounts of EVs in cancer cells. For example, overexpression of Rab27a and Rab27b in breast cancer cells,50 hepatocellular carcinoma cells,51 glioma cells,52 and pancreas cancer cells53 produces significant levels of EVs. Although all types of cells secrete and release EVs, cancer cells seem to produce higher levels than normal cells.54 Furthermore, the presence of invadopodia that are docking sites for Rab27a-positive MVBs induces secretion of EVs, and also enhances secretion of EVs in cancer cells.55 Thus, inhibition of invadopodia formation greatly reduces exosome secretion into conditioned media. This evidence demonstrates that cancer cells potentially release more EVs than non-cancer cells.

The rate of origin of exosomes from the plasma membrane of stem cells is vigorous, at rates equal to the production of exosomes,56 which is consistent with a report suggesting that stem cells bud ~50100 nm-diameter vesicles directly from the plasma membrane.57 Plasma membrane-derived exosomes contain selectively enriched protein and lipid markers in leukocytes.58 Plasma membrane exosomal budding is also observed for glioblastoma exosomes.59 Conventional transmission electron microscopy revealed that certain cell types contain deep invaginations of the plasma membrane that are indistinguishable from MVBs.6062 Certain cell types secrete exosomes containing cargo proteins, which primarily bud from the plasma membrane, and exosome composition is determined predominantly by intracellular protein trafficking pathways, rather than by the distinct mechanisms of exosome biogenesis.63 Biogenesis of exosomes is regulated by syndecan heparan sulphate proteoglycans and their cytoplasmic adaptor syntenin. Syntenin interacts directly with ALIX through LYPX (n) L motifs.64 Glycosylation is an essential factor in the biogenesis of exosomes and N-linked glycosylation directs glycoprotein sorting into EMVs.65 Collectively, these reports suggest that exosomes are made at both plasma and endosome membranes rather than endosome alone. Oligomerization is a critical factor for exosomal protein sorting and it was found to be sufficient to target plasma membrane proteins to exosomes. High-order oligomeric proteins target them to exosomes.66 Further, plasma membrane anchors support exosomal protein budding. For example, budding of CD63 and CD9 from the plasma membrane is much more efficient than endosome-targeted budding of CD63 and CD9.63 Protein clustering is another factor that induces membrane scission.67

Physico-chemical properties determine budding efficiency and are crucial factors of exosome biogenesis, a fundamental process involving the budding of vesicles that are 30200 nm in size. In particular, lipids are critical players in exosome biogenesis, especially those able to form cone and inverse cone shapes. Generally, exosome membranes contain phosphatidylcholine (PC), phosphatidylserine (PS), phosphatidylethanolamine (PE), phosphatidylinositols (PIs), phosphatidic acid (PA), cholesterol, ceramides, sphingomyelin, glycosphingolipids, and a number of lower abundance lipids.68,69 Exosomes have a rich content of PE and PS, which increase budding efficiency and promote exosome genesis and release. PA promotes exosome biogenesis and PLD2 is involved in the budding of certain exosomal cargoes.70 Besides these factors, ceramide is an important lipid molecule regulating exosome biogenesis and facilitating membrane curvature, which is essential for vesicular budding. Inhibition of an enzyme that generates ceramide impairs exosome biogenesis.71

The next critical factor is trans-acting mediators that are involved in the biogenesis of exosomes through regulating plasma membrane homeostasis, intracellular protein trafficking pathways, MVB maturation and trafficking, IPMC biogenesis, vesicle budding, and scission.11 For example, Rab proteins regulate exosome biogenesis via endosomes and the plasma membrane by determining organelle membrane identity, recruiting mechanistic effectors, and mediating organelle dynamics.72 The functions of Rab proteins in the control and biogenesis of exosomes depends on cell type. MVB biogenesis is regulated by Rab27a, Rab27b, their effectors Slp4, Slac2b, and Munc13-4, and also Rab 35 and Rab 11.73 Loss of Rab27 function leads to a ~5075% drop in exosome production, and is also involved in assembling the plasma membrane microdomains involved in plasma membrane vesicle budding, by regulating plasma membrane PIP2 dynamics.74 Overall, Rab27 proteins control exosome biogenesis at both endosomes and plasma membranes. In addition, Rab35 also contributes to exosome biogenesis by regulating PIP2 levels of plasma membrane, and its loss leads to a reduction of exosome release by ~50%.75 Gurunathan et al76 reported that yeast produces two classes of secretory vesicles, low density and high density, and dynamin and clathrin are required for the biogenesis of these two different types of vesicle.

The Ral family is involved in the biogenesis of exosomes, and inhibition of Ral causes an accumulation of MVBs near the plasma membrane and a ~50% decrease in the vesicular secretion of exosomes and exosomal marker proteins.43 Ral GTPases function through various effectors proteins, including Arf6 and the phospholipase PLD2, which are involved in exosomal release of SDCs.37 The ESCRT complex machinery (0 through III) are involved in MVB biogenesis on a major level including membrane deformation, sealing, and repair during a wide array of processes. The major contributions of the ESCRT complex to the biogenesis of vesicles are the recognition and sequestration of ubiquitinated proteins to specific domains of the endosomal membrane via ubiquitin binding subunits of ESCRT-0. After interaction with the ESCRT-I and -II complexes, the total complex will then combine with ESCRT-III, a protein complex that is involved in promoting the budding process. Finally, following cleaving of the buds to form ILVs, the ESCRT-III complex separates from the MVB membrane using energy supplied by the sorting protein Vps4.77 In addition, other proteins such as Alix, which is associated with several ESCRT (TSG101 and CHMP4) proteins, are involved in endosomal membrane budding and abscission, as well as exosomal cargo selection via interaction with syndecan.39 Another important factor, autophagy, is critically involved in exosome secretion. Autophagy related (Atg) proteins coordinate initiation, nucleation, and elongation during autophagosome biogenesis in the presence of ESCRT-III components including CHMP2A and VPS4. For instance, the absence of Atg5 in cancer cells causes a reduction in exosome production.78 Conversely, CRISPR/Cas9-mediated knockout of Atg5 in neuronal cells increases the release of exosomes and exosome-associated prions from neuronal cells.79

Exosomes play a critical role in the physiologic regulation of mammary gland development and are important mediators of breast tumorigenesis.80 Biogenesis of exosomes occurs in all cell types; however, production depends on cell type. For example, breast cancer cells (BCC) produce increased numbers of exosomes compared to normal mammary epithelial cells. Studies revealed that patients with BC have increased numbers of MVs in their blood.81 Kavanagh et al reported that several fold changes were observed from exosomes isolated from triple negative breast cancer (TNBC) chemoresistant therapeutic induced senescent (TIS) cells compared with control EVs.82 TIS cells release significantly more EVs compared with control cells, containing chemotherapy and key proteins involved in cell proliferation, ATP depletion, and apoptosis, and exhibit the senescence-associated secretory phenotype (SASP). Cannabidiol (CBD), inhibits exosome and microvesicle (EMV) release in three different types of cancer cells including prostate cancer (PC3), hepatocellular carcinoma (HEPG2), and breast adenocarcinoma (MDA-MB-231). All three different cell lines show variability in the release of exosomes in a dose-dependent manner. These variabilities are all due to mitochondrial function, including modulation of STAT3 and prohibitin expression. This study suggests that the anticancer agent CBD plays critical role in EMV biogenesis.83 Sulfisoxazole (SFX) inhibits sEV secretion from breast cancer cells through interference with endothelin receptor A (ETA) through the reduced expression of proteins involved in the biogenesis and secretion of sEV, and triggers co-localization of multivesicular endosomes with lysosomes for degradation.84 Secreted EVs from human colorectal cancer cells contain 957 vesicular proteins. The direct protein interactions between cellular proteins play a critical role in protein sorting during EV formation. SRC signaling plays a major role in EV biogenesis, and inhibition of SRC kinase decreases the intracellular biogenesis and cell surface release of EVs.85 Proteomic analysis revealed that the exosomes released from imatinib-sensitive GIST882 cell line exhibit 764 proteins. The authors found that significant amount of proteins belong to protein release function and involved in the classical pathway and overlap to a high degree with proteins of exosomal origin.86 Exosomes secreted by antigen-presenting cells contain high levels of MHC class II proteins and costimulatory proteins, whereas exosomes released from other cell types lack these proteins.1,87

The biogenesis of exosomes depends on a percentage of confluency of approximately 6090%, which influences the yield and functions of EVs.44 Gal et al88 observed a 10-fold decreased level of cholesterol metabolism in confluent cell cultures compared to cells in the preconfluent state. The high level of cholesterol content in confluent cells leads to a decreased level of EVs in prostate cancer.68 The major reason behind for the reduced level of vesicle production is contact inhibition, which triggers confluent cells to enter quiescence and/or alters their characteristics compared to actively dividing cells.89,90 Exogenous stimulation could influence the condition of the cells including the phenotype and efficacy of secretion. Previously, several studies demonstrated that various external factors increase biogenesis of EVs such as Ca2+ ionophores,91 hypoxia,9294 and detachment of cells,95 whereas lipopolysaccharide reduces biogenesis and release of EVs.96 Furthermore, serum, which supports adherence of the cells, plays a critical role in the biogenesis of EVs.97 For example, FCS has noticeable effects on cultured cells; however, the effects depend on cell type and differentiation status.97,98 To avoid the immense amounts of vesicles present in FCS, the use of conditioned media has been suggested. Culture viability and health status of cells are important aspects for producing an adequate amount of vesicles with proper cargo molecules such as protein and RNA.99,100 Exogenous stress, such as starvation, can induce phenotypic alterations and changes in proliferation. These changes cause alterations in the cells metabolism and eventually lead to low yields.101,102

Cellular stresses, such as hypoxia, inflammation, and hyperglycemia, influence the RNA and protein content in exosomes. To examine these factors, the effects of cellular stresses on endothelial cells were studied.99 Endothelial cells were exposed to different types of cellular stress such as hypoxia, tumor necrosis factor- (TNF-)-induced activation, and high glucose and mannose concentrations. The mRNA and protein content of exosomes produced by these cells were compared using microarray analysis and a quantitative proteomics approach. The results indicated that endothelial cell-derived exosomes contain 1354 proteins and 1992 mRNAs. Several proteins and mRNAs showed altered levels after exposure of their producing cells to cellular stress. Interestingly, cells exposed to high sugar concentrations had altered exosome protein composition only to a minor extent, and exosome RNA composition was not affected. Low-intensity ultrasound-induced (LIUS) anti-inflammatory effects have been achieved by upregulation of extracellular vesicle/exosome biogenesis. These exosomes carry anti-inflammatory cytokines and anti-inflammatory microRNAs, which inhibit inflammation of target cells via multiple shared and specific pathways. A study suggested that exosome-mediated anti-inflammatory effects of LIUS are feasible and that these techniques are potential novel therapeutics for cancers, inflammatory disorders, tissue regeneration, and tissue repair.103 Another factor, called manumycin-A (MA), a natural microbial metabolite, was analyzed in exosome biogenesis and secretion in castration-resistant prostate cancer (CRPC) C4-2B, cells. The effect of MA on cell growth was observed, and the results revealed that there was no effect on cell growth. However, MA attenuated the ESCRT-0 proteins Hrs, ALIX, and Rab27a, and exosome biogenesis and secretion by CRPC cells. The inhibitory effect of MA on exosome biogenesis and secretion was primarily mediated via targeted inhibition of Ras/Raf/ERK1/2 signaling. These findings suggest that MA is a potential drug candidate for the suppression of exosome biogenesis and secretion by CRPC cells.104

Methods of isolation of exosomes play critical roles in functions and delivery. Although several methods such as ultracentrifugation, density gradient centrifugation, chromatography, filtration, polymer-based precipitation, and immunoaffinity have been adopted to isolate pure exosomes without contamination, there is still a lack of consistency and agreement.105 Isolation of exosomes along with non-exosomal materials and damaged exosomal membranes creates artifacts and alters the protein and RNA profiles. Since exosomes are obtained from a variety of sources, the composition of proteins/lipids influences the sedimentation properties and isolation. Thus, precise and consistent techniques are warranted for the isolation, purification, and application of exosomes.

Although several functions of exosomes have been explored, the precise function of exosomes remains a mystery. Historically, exosomes have been known to function as cellular garbage bags, recyclers of cell surface proteins, cellular signalers, intercellular signaling and cell-cell communications, immune responses, cellular homeostasis, autophagy, and infectious diseases.106 (Figure 4) ECVs are secreted cell-derived membrane particles involved in intercellular signaling and cell-cell communications, and contain immense bioactive information. Most cell types produce exosomes and release these into the extracellular environment, circulating through different bodily fluids such as urine, blood, and saliva and transferring their cargo to recipient cells. These vesicles play a significant role in various pathological conditions, such as different types of cancer, neurodegenerative diseases, infectious diseases, pregnancy complications, obesity, and autoimmune diseases, as reviewed elsewhere.107 Exosomes play a significant role in intercellular communication between cells by interacting with target cells via endocytosis.108 More specifically, exosomes are involved in cancer development, survival and metastasis of tumors, drug resistance, remodeling of the extracellular matrix, angiogenesis, thrombosis, and proliferation of tumor cells.94,109111 Exosomes contribute significantly to tumor vascularization and hypoxia-mediated inter-tumor communication during cancer progression, and premetastatic niches, which are significant players in cancer.16,94,109,112 Exosomes derived from hepatic epithelial cells increase the expression of enhancer zeste homolog 2 (EZH2) and cyclin-D1, and subsequently promotes G1/S transition.113

Figure 4 Multifunctional aspects biological functions of exosomes.

Conventionally, cells communicate with adjacent cells through direct cell-cell contact through gap junctions and cell surface protein/protein interactions, whereas cells communicating with distant cells do so through secreted soluble factors, such as hormones and cytokines, to facilitate signal propagation.114 Cells also communicate through electrical and chemical signals.115 Several studies have suggested that exosomes play vital roles in intercellular communication by serving as vehicles for transferring various cellular constituents, such as proteins, lipids, and nucleic acids, between cells.6,116118 Exosomes function as exosomal shuttle RNAs in which some exosomal RNAs from donor cells functions in recipient cells,6 a form of genetic exchange. Recently, researchers found that cells communicating with other cells through exosomes carrying cell-specific cargoes of proteins, lipids, and nucleic acids may employ novel intercellular communication mechanisms.30 Exosomes exert influences through various mechanistic approaches, such as direct stimulation of target cells via surface-bound ligands; transfer of activated receptors to recipient cells; and epigenetic reprogramming of recipient cells.119,120 Exosomes play critical roles in immunoregulation, including antigen presentation, immune activation, immune suppression, and immune tolerance via exosome-mediated intercellular communication. Mesenchymal stem cell (MSC)-derived exosomes play significant roles in wound healing processes.121 Exosomes from platelet-rich plasma (PRP) inhibit the release of TNF-. PRP-Exos significantly decreases the apoptotic rate of osteoarthritis (OA) chondrocytes compared with activated PRP (PRP-As).122 Extracellular vesicle (ECV)-modified polyethylenimine (PEI) complexes enhance short interfering RNA (siRNA) delivery by forming non-covalent complexes with small RNA molecules, including siRNAs and anti-miRs, in both conditions, in vitro and in vivo.123 Non-GSC glioma cells were treated with GSC-released exosomes. The results showed that GSC-released exosomes increase proliferation, neurosphere formation, invasive capacities, and tumorigenicity of non-GSC glioma cells through the Notch1 signaling pathway and stemness-related protein expressions.124

Exosomal miR-1910-3p promotes proliferation and migration of breast cancer cells in vitro and in vivo through downregulation of myotubularin-related protein 3 and activation of the nuclear factor-B (NF-B) and wnt/-catenin signaling pathway, and promotes breast cancer progression.125 Human hepatic progenitor cell (CdH)-derived exosomes (EXOhCdHs) play a crucial role in maintaining cell viability and inhibit oxidative stress-induced cell death. Experimental evidence suggests that inhibition of exosome secretion treatment with GW4869 results in the acceleration of reactive oxygen species (ROS) production, thereby causing a decrease in cell viability.126 Tumor-derived EXs (TDEs) are vehicles that enable communication between cells by transferring bioactive molecules, also delivering oncogenic molecules and containing different molecular cargoes compared to EXs delivered from normal cells. They can therefore be used as non-invasive biomarkers for the early diagnosis and prognosis of most cancers, including breast and ovarian cancers.127 Exosomes released by ER-stressed HepG2 cells significantly enhance the expression levels of several cytokines, including IL-6, monocyte chemotactic protein-1, IL-10, and tumor necrosis factor- in macrophages. ER stress-associated exosomes mediate macrophage cytokine secretion in the liver cancer microenvironment, and also indicate the potential of treating liver cancer via an ER stress-exosomal-STAT3 pathway.128 Mesenchymal stem cell-derived exosomal miR-223 protects neuronal cells from apoptosis, enhances cell migration and increases miR-223 by targeting PTEN, thus activating the PI3K/Akt pathway. In addition, exosomes isolated from the serum of AD patients promote cell apoptosis through the PTEN-PI3K/Akt pathway and these studies indicate a potential therapeutic approach for AD.129 A mouse model of diabetes demonstrated that mesenchymal stromal cell-derived exosomes ameliorate peripheral neuropathy through increased nerve conduction velocity. In addition, MSC-derived exosomes substantially suppress proinflammatory cytokines.130

Exosomes derived from activated astrocytes promote microglial M2 phenotype transformation following traumatic brain injury (TBI). miR-873a-5p significantly inhibits LPS-induced microglial M1 phenotype transformation.131 Several studies reported that exosomes are involved in cancer progression and metastasis; however, this depends on the type of cells the exosomes were derived from. For example, human umbilical vein endothelial cells (HUVEC) were treated with exosomes derived from HeLa cells (ExoHeLa), and the expression of tight junctions (TJ) proteins, such as zonula occludens-1 (ZO-1) and Claudin-5, was significantly reduced compared with exosomes from human cervical epithelial cells. Thus, permeability of the endothelial monolayer was increased after the treatment with ExoHeLa. Mice studies have shown that injection of ExoHeLa into mice increased vascular permeability and tumor metastasis. The results from this study demonstrated that HeLa cell-derived exosomes promote metastasis by triggering ER stress in endothelial cells and break down endothelial integrity. Such effects of exosomes are microRNA-independent.132 Exosomes mediate the gene expression of target cells and regulate pathological and physiological processes including promoting angiogenesis, inhibiting ventricular remodeling and improving cardiac function, as well as inhibiting local inflammation and regulating the immune response. Accumulating evidence shows that exosomes possess therapeutic potential through their anti-apoptotic and anti-fibrotic roles.

The functions of exosomes in immune responses are well established and do not cause any severe immune responses. A mouse study demonstrated that administration of a low dose of mouse or human cell-derived exosomes for extended periods of time caused no severe immune reactions.133 The function of exosomes in immune regulation is regulated by the transfer and presentation of antigenic peptides. Exosomes contain antigen-presenting cells (APCs) carrying peptide MHC-II and costimulatory signals and directly present the peptide antigen to specific T cells to induce their activation.134 For example, intradermal injection of APC-derived exosomes with MHC-II loaded with tumor peptide delayed tumor progression and growth.135 Exosome-derived immunogenic peptides activate immature mouse dendritic cells and indirectly activate APCs, and induce specific CD4+ T cell proliferation.136 Exosomes containing IFNa and IFNg, tumor necrosis factor a (TNFa), and IL from macrophages promoted dendritic cell maturation, CD4+ and CD8+ T cell activation, and the regulation of macrophage IL expression.137 The cargo of exosomes, such as DNA and miRNA, regulate the innate and adaptive immune responses. Exosomes are able to regulate the immune response by controlling gene expression and signaling pathways in recipient cells through transfer of miRNAs, and eventually control dendritic cell maturation.138 Exosomes containing miR-212-3p derived from tumors down-regulate the MHC-II transcription factor RFXAP (regulatory factor X associated protein) in dendritic cells, possibly promoting immune evasion by cancer cells.139 Exosomes containing miR-222-3p down regulate expression of SOCS3 (suppressor of cytokine signaling 3) in monocytes, which is involved in STAT3-mediated M2 polarization of macrophages.140 In mice, exosomes stimulate adaptive immune responses, including the activation of dendritic cells, with the uptake of breast cancer cell-derived exosomal genomic DNA and activation of cGAS-STING signaling and antitumor responses.141 The priming of dendritic cells is associated with the uptake of exosomal genomic and mitochondrial DNA (mtDNA) from T cells, inducing type I IFN production by cGAS-STING signaling.142 Inhibition of EGFR leads to increased levels of DNA in the exosomes and induces cGAS-STING signaling in dendritic cells, contributing to the overall suppression of tumor growth.143 Conversely, uptake of tumor-derived exosomal DNA by circulating neutrophils was shown to enhance the production of tissue factor and IL-8, which play a role in promoting tumor inflammation and paraneoplastic events.144 Melanoma-derived exosomes containing PD-L1 (programmed cell death ligand 1) suppress CD8+ T cell antitumor function and cancer cell-derived exosomes block dendritic cell maturation and migration in a PD-L1-dependent manner. Engineered cancer cell-derived exosomes promote dendritic cell maturation, resulting in increased proliferation of T cells and antitumor activity.145147

Inflammation is an important process for maintaining homeostasis in cellular systems. Systemic inflammation is an essential component in the pathogenesis of several diseases.148,149 Exosomes seem to play a crucial role in inflammation processes through cargo molecules, such as miRNA and proteins, which act on nearby as well as distant target tissues. Exosomes play a vital role in intercellular communication between cells via endocytosis and are associated with modulation of inflammation, coagulation, angiogenesis, and apoptosis.20,150153 Exosomes derived from dendritic cells, B lymphocytes, and tumor cells release exosomes that can regulate immunological memory through the surface expression of antigen-presenting MHC I and MHC II molecules, and subsequently elicit T cell activation and maturation.134,137,154156 Exosomes play a crucial role in carrying and presenting functional MHC-peptide complexes to modulate antigen-specific CD8+ and CD4+ responses.157,158 Exosomes containing miR-Let-7d influence the growth of T helper 1 (Th1) cells and inhibit IFN- secretion.159 Exosomes derived from choroid plexus epithelial cells containing miR-146a and miR-155 upregulate the expression of inflammatory cytokines in astrocytes and microglia.160 Exosomes containing miR-181c suppress the expression of Toll-like receptor 4 (TLR-4) and subsequently lower TNF- and IL-1 levels in burn-induced inflammation.161 Exosomal miR-155 from bone marrow cells (BMCs) increases the level of TNF- and subsequently enhances innate immune responses in chronic inflammation.162 Exosomes containing miR-150-5p and miR-142-3p derived from dendritic cells (DCs) increase expression of interleukin 10 (IL-10) and a decrease in IL-6 expression.163 Exosomal miR-138 can protect against inflammation by decreasing the expression level of NF-B, a transcription factor that regulates inflammatory cytokines such as TNF- and IL-18.164 HIF-1-inducing exosomal microRNA-23a expression from tubular epithelial cells mediates the cross talk between tubular epithelial cells and macrophages, promoting macrophage activation and triggering tubulointerstitial inflammation.165 A rat model study demonstrated that bone marrow mesenchymal stem cell (BMSC)-derived exosomes reduced inflammatory responses by modulating microglial polarization and maintaining the balance between M2-related and M1-related cytokines.165 Melatonin-stimulated mesenchymal stem cell (MSC)-derived exosomes improve diabetic wound healing through regulating macrophage M1 and M2 polarization by targeting the PTEN/AKT pathway, and significantly suppressed the pro-inflammatory factors IL-1 and TNF- and reduced the relative gene expression of IL-1, TNF-, and iNOS. Increasing levels of anti-inflammatory factor IL-10 are associated with increasing relative expression of Arg-1.166

Immunomodulators are essential factors for the prevention and treatment of disorders occurring due to an over high-spirited immune response, such as the SARS-CoV-2-triggered cytokine storm leading to lung pathology and mortality seen during the ongoing viral pandemic.167 MSC-secreted extracellular vesicles exhibit immunosuppressive capacity, which facilitates the regulation of the migration, proliferation, activation, and polarization of various immune cells, promoting a tolerogenic immune response while inhibiting inflammatory responses.168 Collagen scaffold umbilical cord-derived mesenchymal stem cell (UC-MSC)-derived exosomes induce collagen remodeling, endometrium regeneration, increasing the expression of the estrogen receptor /progesterone receptor, and restoring fertility. Furthermore, exosomes modulate CD163+ M2 macrophage polarization, reduce inflammation, increase anti-inflammatory responses, facilitate endometrium regeneration, and restore fertility through the immunomodulatory functions of miRNAs.169 Exosomes released into the airways during influenza virus infection trigger pulmonary inflammation and carry viral antigens and it facilitate the induction of a cellular immune response.170 Shenoy et al171 reported that exosomes derived from chronic inflammatory microenvironments contribute to the immune suppression of T cells. These exosomes arrest the activation of T cells stimulated via the T cell checkpoint (TCR). Exosomes secreted by normal retinal pigment epithelial cells (RPE) by rotenone-stimulated ARPE-19 cells induce apoptosis, oxidative injury, and inflammation in ARPE-19 cells. Exosomes secreted under oxidative stress induce retinal function damage in rats and upregulate expression of Apaf1. Overexpression of Apaf1 in exosomes secreted under oxidative stress (OS) can cause the inhibition of cell proliferation, increase in apoptosis, and elicitation of inflammatory responses in ARPE-19 cells. Exosomes derived from ARPE-19 cells under OS regulate Apaf1 expression to increase apoptosis and to induce oxidative injury and inflammatory response through a caspase-9 apoptotic pathway.172 Collectively, these findings highlight the critical role of exosomes in inflammation and suggest the possibility of utilizing exosomes as an inducer to attenuate inflammation and restore impaired immune responses in various diseases including cancer.

The endomembrane system of eukaryotic cells is a complex series of interconnected membranous organelles that play vital roles in protecting cells from adverse conditions, such as stress, and maintaining cell homeostasis during health and disease.173 To preserve cellular homeostasis, higher eukaryotic cells are equipped with various potent self-defense mechanisms, such as cellular senescence, which blocks the abnormal proliferation of cells at risk of neoplastic transformation and is considered to be an important tumor-suppressive mechanism.174,175 Exosomes contribute to reduce intracellular stress and preservation of cellular homeostasis through clearance of damaged or toxic material, including proteins, lipids, and even nucleic acids. Therefore, exosomes serve as quality controller in cells.176 The vesicular transport system plays pivotal roles in the maintenance of cell homeostasis in eukaryote cells, which involves the cytoplasmic trafficking of biomolecules inside and outside of cells. Several types of membrane-bound organelles, such as the Golgi apparatus, endoplasmic reticulum (ER), endosomes and lysosomes, in association with cytoskeleton elements, are involved in the intracellular vesicular system. Molecules are transported through exocytosis and endocytosis to maintain homeostasis through the intracellular vesicular system and regulate cells responses to the internal and external environment. To maintain homeostasis and protect cells from various stress conditions, autophagy is an intracellular vesicular-related process that plays an important role through the endocytosis/lysosomal/exocytosis pathways through degradation and expulsion of damaged molecules out of the cytoplasm.177179 Autophagy, as an intracellular waste elimination system, is a synchronized process that actively participates in cellular homeostasis through clearance and recycling of damaged proteins and organelles from the cytoplasm to autophagosomes, and then to lysosomes.38,180182 Cells maintain homeostasis by autophagosomes, which are vesicles derived from autophagic and endosomal compartments. These processes are involved in adaption to nutrient deprivation, cell death, growth, and tumor progression or suppression. Autophagy flux contributes to maintaining homeostasis in the tumor microenvironment of endothelial cells. To support this concept, a study provided evidence suggesting that depletion of Atg5 in ECs could intensify the abnormal function of tumor vessels.183 Exosome secretion plays a crucial role in maintaining cellular homeostasis in exosome-secreting cells. As a consequence of blocking exosome secretion, nuclear DNA accumulates in the cytoplasm, thereby causing the activation of cytoplasmic DNA sensing machinery. Blocking exosome secretion aggravates the innate immune response, leading to ROS-dependent DNA damage responses and thus inducing senescence-like cell-cycle arrest or apoptosis in normal human cells. Thus, cells remove harmful cytoplasmic DNA, protecting them from adverse effects.182 Salomon and Rice reported that the involvement of exosomes in placental homeostasis and pregnancy disorders. EVs of placental origin are found in a variety of body fluids including urine and blood. Moreover, the number of exosomes throughout gestation is higher in complications of pregnancy, such as preeclampsia and gestational diabetes mellitus, compared to normal pregnancies.184

The endolysosomal system is critically involved in maintaining homeostasis through the highly regulated processes of internalization, sorting, recycling, degradation, and secretion. For example, endocytosis allows the internalization of various receptor proteins into cells, and vesicles formed from the plasma membrane fuse and deliver their membrane and protein content to early endosomes. Similarly, significant amounts of internalized content are recycled back to the plasma membrane via recycling endosomes,76 while the remaining material is sequestered in ILVs in late endosomes, also known as multivesicular bodies.185,186 Tetraspanin proteins, such as CD63 and CD81, are regulators of ILV formation. Once ILVs are formed, MVBs can degrade their cargo by fusing with lysosomes or, alternatively, MVBs can secrete their ILVs by fusing with the plasma membrane and release their content into extracellular milieu.187190 Exosomes play an important role in regulating intracellular RNA homeostasis by promoting the release of misfolded or degraded RNA products, and toxic RNA products. Y RNAs are involved in the degradation of structured and misfolded RNAs. Further studies have demonstrated that proteins involved in RNA processing are abundant in exosomes, and the half-lives of secreted RNAs are almost twice as short as those of intracellular mRNAs. These studies suggest that cells maintain intracellular RNA homeostasis through the release of distinct RNA species in extracellular vesicles.191193 Exosomes reduce cholesterol accumulation in Niemann-Pick type C disease, a lysosomal storage disease in which cells accumulate unesterified cholesterol and sphingolipids within the endosomal and lysosomal compartment.194

Autophagy is the intracellular vesicular-related process that regulates the cell environment against pathological and stress conditions. In order to maintain homeostasis and protect the cells against stress conditions, internal vesicles or secreted vesicles serve as a canal to degrade and expel damaged molecules out of the cytoplasm.38,181,182 Autophagy protects the cell from various stress conditions and maintains cellular homeostasis, regulating cell survival and differentiation through clearance and recycling of damaged proteins and organelles from the cytoplasm to autophagosomes, and then to lysosomes.180 Several studies have demonstrated that proteins are involved in controlling tumor cell function and fate, and mediate crosstalk between exosome biogenesis and autophagy. Coordination between exosome-autophagy networks serves as a tool to conserve cellular homeostasis via the lysosomal degradative pathway and/or secretion of cargo into the extracellular milieu.176,195 Autophagy is a multi-step process that occurs by initiation, membrane nucleation, maturation and finally the fusion of autophagosomes with lysosomes. The autophagy process is not only linked with endocytosis but is also linked with the biogenesis of exosomes. For example, subsets of the autophagy machinery involved in the biogenesis of exosomes and the autophagic process itself appear dispensable.78,196 Crosstalk between exosomal and autophagic pathways has been reported in a growing number of diseases. Proteomic studies were performed to analyze the involvement of key proteins in the interconnection between exosome and autophagy pathways. They found that almost all proteins were identified; however, their involvement differed between them. Among 100 proteins, four proteins were highly ranked including HSPA8 (3/100), HSP90AA1 (8/100), VCP (24/100), and Rab7A (81/100). These data suggest an interconnection between the exosome and autophagy.197,198 Endosomal autophagy plays a significant role in the interconnection between exosomes and autophagy. Stress is a major factor for autophagy. In particular, the starvation of cells is a key inducer of autophagy, and induces enlargement of MVB structures and a co-localization of Rab11 and LC3 in these structures, an indication that autophagy-related processes are associated with the MVB.199 The sorting of autophagy-related cargo into MVBs is dependent on Hsc70 (HSPA8), VPS4, and TSG101, and independent on LAMP-2A, thereby excluding a role for, the lysosome.200 Several proteins are involved in the regulation and biogenesis of secretory autophagy compartments such as GRASPs, LC3, Rab8a, ESCRTs, and SNAREs, along with several Atg proteins.181,201,202 Autophagosomes could fuse with MVBs to form amphisomes and release vesicles to the external environment.203

Autophagy and exosome biogenesis and function are interconnected by microRNA. Over-expression of miR-221/222 inhibits the level of PTEN and activates Akt signaling, and subsequently reduces the expression of hallmarks that positively relate to autophagy including LC3, ATG5 and Beclin1, and increases the expression of SQSTM1/p62.204 MiR-221/222 from human aortic smooth muscle cell (HAoSMC)-derived exosomes inhibit autophagy in HUVECs by modulating the PTEN/Akt signaling pathway. miRNA-223 attenuates hypoxia-induced apoptosis and excessive autophagy in neonatal rat cardiomyocytes and H9C2 cells via the Akt/mTOR pathway, by targeting poly(ADP-ribose) polymerase 1 (PARP-1) through increased autophagy via the AMPK/mTOR and Akt/mTOR pathways205 ATG5 mediates the dissociation of vacuolar proton pumps (V1Vo-ATPase) from MVBs, which prevents acidification of the MVB lumen and allows MVB-PM fusion and exosome release. Accordingly, knockout of ATG5 or ATG16L1 significantly reduces exosome release and attenuates the exosomal enrichment of lipidated LC3B. These findings demonstrate that autophagic mechanisms possibly regulate the fate of MVBs and subsequent exosome biogenesis.78 Bone marrow MSC (BMMSC)-derived exosomes contain a high level of miR-29c, which regulates autophagy under hypoxia/reoxygenation (H/R) conditions.206 Human umbilical cord MSC-derived exosomes (HucMDEs) promote hepatic glycolysis, glycogen storage, and lipolysis, and reduce gluconeogenesis. Additionally, autophagy potentially contributes to the effects of HucMDE treatment and increases formation of autophagosomes and the autophagy marker proteins BECN1, MAP, and 1LC3B. These findings suggest that HucMDEs improve hepatic glucose and lipid metabolism in T2DM rats by activating autophagy via the AMPK pathway.207 Liver fibrosis is a serious disorder caused by prolonged parenchymal cell death, leading to the activation of fibrogenic cells, extracellular matrix accumulation, and eventually liver fibrosis. Exosomes derived from adipose-derived mesenchymal stem cells (ADSCs) have been used to deliver circular RNAs mmu_circ_0000623 to treat liver fibrosis. The findings from this study suggest that Exos from ADSCs containing mmu_circ_0000623 significantly suppress CCl4-induced liver fibrosis by promoting autophagy activation. Autophagy inhibitor treatment significantly reverses the treatment effects of Exos.208 Inhibition of autophagy by PDGF and its downstream molecule SHP2 (Src homology 2-containing protein tyrosine phosphatase 2) increased hepatic stellate cell (HSC)-derived EV release. Disruption of mTOR signaling abolishes PDGF-dependent EV release. Activation of mTOR signaling induces the release of MVB-derived exosomes by inhibiting autophagy, as well as microvesicles, through activation of ROCK1 signaling. Furthermore, deletion of SHP2 attenuates CCl4 or BDL-induced liver fibrosis.209 The therapeutic effects of exosomes containing high concentrations of mmu_circ_0000250 were analyzed in diabetic mice. The findings indicated that a high concentration of mmu_circ_0000250 had a better therapeutic effect on wound healing when compared with wild-type exosomes from ADSCs. The results also showed that exosome treatment with mmu_circ_0000250 increased angiopoiesis in wounded skin and suppressed apoptosis by inducing miR-128-3p/SIRT1-mediated autophagy.210 A study showed that mice treated with differentiated cardiomyocyte (iCM) exosomes exhibited significant cardiac improvement post-myocardial infarction, with significantly reduced apoptosis and fibrosis. Apoptosis was associated with reduced levels of hypoxia and inhibition of exosome biogenesis. iCM-exosome-treated groups showed upregulation of autophagosome production and autophagy flux. Hence, these findings indicate that iCM-Ex can improve post-myocardial infarction cardiac function by regulating autophagy in hypoxic cardiomyocytes.211 Exosomes of hepatocytes play a crucial role in inhibiting hepatocyte apoptosis and promoting hepatocyte regeneration. Mesenchymal stem cell-derived hepatocyte-like cell exosomes (MSC-Heps-Exo) were injected into a mouse hepatic Ischemia/reperfusion (I/R) I/R model through the tail. The results demonstrated that MSC-Heps-Exo effectively relieve hepatic I/R damage, reduce hepatocyte apoptosis, and decrease liver enzyme levels. A possible mechanism of reduced hepatic ischemia/reperfusion injury is the enhancement of autophagy.212

Exosomes play a critical role in viral infections, particularly of retroviruses and retroviruses, and use preexisting pathways for intracellular protein trafficking and formation of infectious particles. Exosomes and viruses share several features including biogenesis, uptake by cells, and the intracellular transfer of RNAs, mRNAs, and cellular proteins. Some features are different, including self-replication after infection of new cells, regulation of viral expression, and complex viral entry mechanisms.213,214 Exosomes secreted from virus-infected cells carry mostly cargo molecules such as viral proteins, genomic RNA, mRNA, miRNA, and genetic regulatory elements.215218 These cargo molecules are involved in the alteration of recipient cell behavior, regulating cellular responses, and enabling infection by various types of viruses such as human T-cell lymphotropic virus (HTLV), hepatitis C virus (HCV), dengue virus, and human immunodeficiency virus (HIV).215 Exosomes communicate with host cells through contact between exosomes and their recipient cells, via different kinds of mechanisms. Initially, the transmembrane proteins of exosomes build a network directly with the signaling receptors of target cells and then join with the plasma membrane of recipient cells to transport their content to the cytosol. Finally, the exosomes are incorporated into the recipient cells.219221 A report suggested that disruption of exosomal lipid rafts leads to the inhibition of internalization of exosomes.95 Exosomes derived from HIV-infected patients contain the trans-activating response element, which is responsible for HIV-1 replication in recipient cells through downregulation of apoptosis.222 While exosomes serving as carrier molecules, exosomes contain miRNAs that induce viral replication and immune responses either by direct targeting of viral transcripts or through indirect modulation of virus-related host pathways. In addition, exosomes have been found to act as nanoscale carriers involved in HIV pathogenesis. For example, exosomes enhance HIV-1 entry into human monocytic and T cell lines through the exosomal tetraspanin proteins CD9 and CD81.223 Influenza virus infection causes accumulation of various types of microRNAs in bronchoalveolar lavage fluid, which are responsible for the potentiation of the innate immune response in mouse type II pneumocytes. Serum of influenza virus-infected mice show significant levels of miR-483-3p, which increases the expression of proinflammatory cytokine genes and inflammatory pathogenesis of H5N1 influenza virus infection in vascular endothelial cells.224 Exosomes are involved in the transmission of inflammatory, apoptotic, and regenerative signals through RNAs. Chen et al investigated the potential functions of exosomal RNAs by RNA sequencing analysis in exosomes derived from clinical specimens of healthy control (HC) individuals and patients with chronic hepatitis B (CHB) and acute-on-chronic liver failure caused by HBV (HBV-ACLF). The results revealed that the samples contained unique and distinct types of RNAs in exosomes.225 Zika virus (ZIKV) infection causes severe neurological malfunctions including microcephaly in neonates and other complications associated with Guillain-Barr syndrome in adults. Interestingly, ZIKV uses exosomes as mediators of viral transmission between neurons and increases production of exosomes from neuronal cells. Exosomes derived from ZIKV-infected cells contained both ZIKV viral RNA and protein(s) which are highly infectious to nave cells. ZIKV uses neutral Sphingomyelinase (nSMase)-2/SMPD3 to regulate production and release of exosomes.226

During infections, viruses replicate in host cells through vesicular trafficking through a sequence of complexes known as ESCRT, and assimilate viral constituents into exosomes. Exosomes encapsulate viral antigens to maximize infectivity by hiding viral genomes, entrapping the immune system, and maximizing viral infection in uncontaminated cells. Exosomes can be used as a source of viral antigens that can be targeted for therapeutic use. A Variety of infectious diseases caused by viruses such as HCV, ZIKV, West Nile virus (WNV), and DENV enter into the host cells using clathrin-mediated or receptor-mediated endocytosis. For example, HCV infects host cells by specific targeting of cells through cellular contact, and hepatocyte-derived exosomes that contain HCV RNA can stimulate innate immune cells.217,227230 Exosomes show structural and molecular similarity to HIV-1 and HIV-2, which are enclosed by a lipid bilayer, and in the vital features of size and density, RNA species, and macro biomolecules including carbohydrates, lipids, and proteins. HIV-infected cells release enriched viral RNAs containing exosomes derived from HIV-infected cells and are enhanced with viral RNAs and Nef protein.6,38,231236 Izquierdo-Useros et al reported that both exosomes and HIV-1 express sialyllactose-containing gangliosides and interact with each other via sialic-acid-binding immunoglobulin-like lectins (Siglecs)-1. Siglecs-1 stimulates mature dendritic cell (mDC) capture and storage of both exosomes and HIV-1 in mDCs.237 Exosomes released from HIV-infected T cells contain transactivation response (TAR) element RNA, which stimulate proliferation, migration, and invasion of oral/oropharyngeal and lung cancer cells.238 Nuclear VP40 from Ebola virus VP40 upregulates cyclin D1 levels, resulting in dysregulated cell cycle and EV biogenesis. Synthesized extracellular vesicles contain cytokines and EBOV proteins from infected cells, which are responsible for the destruction of immune cells during EBOV pathogenesis.239 HIV enters into the host cells through human T-cell immunoglobin mucin (TIM) proteins. TIMs are a group of proteins (TIM-1, TIM-3, and TIM-4) that promote phagocytosis of apoptotic cells.240 TIM-4 is involved in HIV-1 exosome-dependent cellular entry mechanisms. Substantiating this hypothesis, neural stem cell (NSC)-derived exosomes containing TIM-4 protein increase HIV-1 exosome-dependent cellular entry into host cells, and antibody against TIM4 inhibits exosome-mediated entry of HIV in various types of cell.241

Exosomes show immense promise in biomedical applications due to their potential in drug delivery, the carriage of biomolecular markers of many diseases, and cellular protection. In addition, they can be used in non-invasive diagnostics or minimum invasive diagnostics.150 Detection of biomarkers is vital for early diagnosis of cancer and also critical for treatment. Several studies have documented the importance of exosomes in a variety of diseases, although further examination of the biology and functions of exosomes is warranted due to the continuing emergence of new diseases in the present world. The complex cargo of exosomes facilitates the exploration of a variety of diagnostic windows into disease detection, monitoring, and treatment. Exosomes are found in all biological fluids and are secreted by all cells, rendering them attractive for use through minimally invasive liquid biopsies, and they have the potential for use in longitudinal sampling to follow disease progression.242 Exosomes are produced and secreted by almost all body fluids, including blood, urine, saliva, breast milk, cerebrospinal fluid, semen, amniotic fluid, and ascites. These exosomes contain micro RNAs, proteins, and lipids serving as diagnostic markers.120 Exosomes are used in diagnostic applications in various kinds of diseases, such as cardiovascular diseases (CVDs),243 diseases of the central nervous system (CNS),244 cancer,245 and other prominent diseases including in the liver,246 kidney,247 and lung.248 Exosomes are potentially used to detect cancer-associated mutations in serum and also for the transfer of genomic DNA from donor cells to recipient cells.249 Exosomes carrying specific miRNAs or groups of miRNAs can be used as diagnostic markers to detect cancer. For example, exosomes containing oncogenic Kras, which have tumor-suppressor miRNAs-100, seem to have high diagnostic value, which could facilitate the differentiation of the expression pattern between cancer cells and normal cells.250,251 Similarly, miR-21 is considered to be diagnostic marker for various types of cancer including glioblastomas and pancreatic, colorectal, colon, liver, breast, ovarian, and esophageal cancers.252 Tumor suppressor miRNAs, such as miR-146a and miR-34a, function as diagnostic tools to detect liver, breast, colon, pancreatic, and hematologic malignancies.251 Exosomes containing GPC1 (glypican 1) are used as diagnostic markers to detect pancreatic, breast, and colon cancer.253,254

Exosomes play critical roles in various types of disease, and particularly in cancer progression and resistance to therapy. The unique biogenesis of exosomes and their biological features have generated excitement for their potential use as biomarkers for cancer.255 Generally, exosomes are produced and secreted by most cells and contain all the biological components of a cell. Hence, exosomes are found in all biological fluids and provide excellent opportunities for use as biomarkers.242 Surface proteins of exosomes are involved in the regulation of the tumor immune microenvironment and the monitoring of immunotherapies. Hence, exosome proteins play a critical role in cancer signaling.256 Exosomes from patients with metastatic pancreatic cancer show a higher mutant Kras allele frequency than exosomes from patients with local disease. In addition, the exosomes also accumulate a significantly higher level of cancer cell-specific DNA such as cytoplasmic DNA.8,257 Exosomes protect DNA and RNA from enzymatic degradation by encapsulation and stability in exosomes. The enhanced stability and retention of exosomes in liquid biopsies increases the availability and performance of exosomes as cancer biomarkers.258 Cancer cells contain cargo molecules, such as nucleic acid, proteins, metabolites, and lipids that are relatively different from normal cells, which is a contributing factor for their candidacy as cancer biomarkers. Exosomes isolated and purified from patient plasma samples enriched for miR-10b-5p, miR-101-3p, and miR-143-5p have been identified as potential diagnostic markers for gastric cancer with lymph node metastasis, gastric cancer with ovarian metastasis, and gastric cancer with liver metastasis, respectively.259 Kato et al analyzed the expression of CD44 protein and mRNA from cell lysates and exosomes from prostate cancer cells.260 Exosomes from serum containing CD44v8-10 mRNA was used as a diagnostic marker for docetaxel resistance in prostate cancer patients. The study was performed to evaluate plasma exosomal mRNA-125a-5p and miR-141-5p miRNAs as biomarkers for the diagnosis of prostate cancer from 19 healthy individuals and 31 prostate cancer patients. In comparing the miR-125a-5p/miR-141-5p level ratio, prostate cancer patients had significantly higher levels of miR-125a-5p/miR-141-5p. The findings from this study demonstrated that plasma exosomal expression of miR-141-3p and miR-125a-5p are markers of specific tumor traits associated with prostate cancer.261 Serum samples from 81 patients with gastric cancer showed that exosomes contained significant levels of long non-coding RNA (lncRNA) H19, which could be a diagnostic marker for gastric cancer.262 Plasma exosomes are suitable candidates as biomarkers for various diseases. For instance, plasma exosome lncRNA expression profiles were examined in esophageal squamous cell carcinoma (ESCC) patients. The findings suggest that five different types of lncRNAs were at significantly higher levels in exosomes from ESCC patients than in non-cancer controls. These lncRNAs may serve as highly effective, noninvasive biomarkers for ESCC diagnosis.263 Differential expression of lncRNAs, such as LINC00462, HOTAIR, and MALAT1, are significantly upregulated in hepatocellular carcinoma (HCC) tissues. The exosomes of the control group had a larger number of lncRNAs with a high amount of alternative splicing compared to hepatic disease patients.264 To demonstrate exosomes as a non-invasive cancer diagnostic tool, RNA-sequencing analysis was performed between three pairs of non-small-cell lung cancer (NSCLC) patients and controls from Chinese populations. The results show that circ_0047921, circ_0056285, and circ_0007761 were significantly expressed and that these exosomal circRNAs are promising biomarkers for NSCLC diagnosis.265 Exosomes were isolated from the serum of 34 patients with acute myocardial infarction (AMI), 31 patients with unstable angina (UA), and 22 healthy controls. The isolated exosomes exhibited higher levels of miR-126 and miR-21 in the patients with UA and AMI than in the healthy controls.266 Xu et al designed a study to examine tumor-derived exosomes as diagnostic biomarkers. In this study exosome miRNA microarray analysis was performed in the peripheral blood from four lung adenocarcinoma patients, including two with metastasis and two without metastasis. The results found that miR-4436a and miR-4687-5p were upregulated in the metastasis and non-metastasis group, while miR-22-3p, miR-3666, miR-4448, miR-4449, miR-6751-5p, and miR-92a-3p were downregulated. Exosomes containing miR-4448 have served as a diagnostic marker of patients with adenocarcinoma metastasis. Increased understanding of exosome biogenesis, structure, and function would enhance the performance of biomarkers in various kinds of disease diagnosis, prognosis, and surveillance.267

Exosomes have unique features such as ease of handling, molecular composition, and critical immunogenicity, and it is particularly easy to use them to transfer genes and proteins into cells. These unique characteristic features can inhibit angiogenesis and cancer metastasis, which are the two main targets of cancer therapy.268,269 Exosomes have potential therapeutic applications in a variety of diseases due to their potential capacity as vehicles for the delivery of therapeutic agents (Figure 5). Exosomes from colon cancer cells contain the highly immunogenic antigens MelanA/Mart-1 and gp100, serving as an indicator of tumor origin in particular organelles. Animal studies have demonstrated that tumor-derived antigen-containing exosomes induce potent antitumor T-cell responses and tumor regression.270 Exosomes containing tumor antigens are able to stimulate CD4+and CD8+T cells, and antigen-presenting exosomes inhibit tumor growth.135,271,272 MSC-derived exosomes exhibit the immunomodulatory and cytoprotective activities of their parent cells.273,274 Similarly, exosomes derived from bone marrow show protective roles in myocardial ischemia/reperfusion injury,109 hypoxia-induced pulmonary hypertension,275 and brain injury,276,277 and inhibit breast cancer growth via vascular endothelial growth factor down-regulation and miR-16 transfer in mice.278 Mesenchymal cell- and epithelial cell-derived exosomes exhibit tolerance and without any undesired side effects in patients and also act as therapeutic agents themselves.48,279 Exosomes engineered with ligands containing RGD peptide are used to induce signaling in specific cell types, and doxorubicin-loaded exosomes derived from dendritic cells show therapeutic responses in mammary tumor-bearing mice.46 Exosomal microRNAs are able to control other cells, and the delivery of miRNA or siRNA payload promotes anticancer activity in mammary carcinoma and glioma.280,281 Rabies virus glycoprotein (RVG)-modified dendritic cell-derived exosomes suppress the expression of BACE1 in the brain, which indicates the therapeutic potential of exosomes to target AD.282 Furthermore, these exosomes stimulated neurite outgrowth in cultured astrocytes by transferring miR-133b between cells.27 Immunotherapy is able to induce tumor-targeting immunity or an antitumor host immune response. For example, tumor-associated antigen-loaded mature autologous dendritic cells increase survival of metastatic castration-resistant patients.283 Exosome therapy induces upregulation of CD122 molecules in CD4+ T cells, whereas the lymphocyte pool is stable. Multiple vaccinations with exosomes increase circulating CD3-/CD56+ natural killer (NK) cells.284 An in vitro study demonstrated that adipose stem cell-derived exosomes up-regulate the peroxisome proliferator-activated receptor gamma coactivator 1, phosphorylate the cyclic AMP response element binding protein, and ameliorate abnormal apoptotic protein levels.285 Exosomes are used as potential carriers to carry anti-inflammatory drugs. Curcumin-encapsulated exosomes show significant anti-inflammatory activity, and exosomes are also used to deliver anti-inflammatory drugs to the brain through a noninvasive intranasal route.286,287 Turturici et al reported that specific progenitor cell-derived EVs contain biological cargo that promotes angiogenesis and tissue repair, and modulates immune functions.288

Figure 5 Therapeutic potential and versatile clinical implications of exosomes.

Generally, exosomes serve as vehicles for the delivery of drugs and are also actively involved as therapeutic agents. Conversely, injected exosomes enter into other cells and deliver functional cargo molecules very efficiently and rapidly, with minimal immune clearance and are well tolerated.16,21,245,289,290 Intravenous administration of human MSC-derived exosomes supports neuroprotection in a swine model of traumatic brain injury.291 In vitro and in vivo models demonstrate that exosomes from human-induced pluripotent stem cell-derived mesenchymal stromal Cells (hiPSC-MSCs) protect the liver against hepatic ischemia/reperfusion injury through increasing the level of proliferation of primary hepatocytes, activity of sphingosine kinase, and synthesis of sphingosine-1-phosphate (S1P).292 Exosomes derived from macrophages show potential for use in neurological diseases because of their easy entry into the brain by crossing the blood-brain barrier (BBB). Catalase-loaded exosomes displayed a neuroprotective effect in a mouse model of PD and exosomes loaded with dopamine entered into the brain better in comparison to free dopamine.33,293 Treatment of tumor-bearing mice with autologous exosomes loaded with gemcitabine significantly suppressed tumor growth and increase longevity, and caused only minimal damage to normal tissues. The study demonstrated that autologous exosomes are safe and effective vehicles for targeted delivery of GEM against pancreatic cancer.294

Generally, lipid-based nanoparticles such as liposomes or micelles, or synthetic delivery systems have been adopted to transport active molecules. However, the merits of synthetic systems are limited due to various factors including inefficiency, cytotoxicity and/or immunogenicity. Therefore, the development of natural carrier systems is indispensable. One of the most prominent examples of such natural carriers are exosomes, which are used to transport drug and active biomolecules. Exosomes are more compatible with other cells because they carry various targeting molecules from their cells of origin. Exosomes are nano-sized membrane vesicles derived from almost all cell types, which carry a variety of cargo molecules from their parent cells to other cells. Due to their natural biogenesis and unique qualities, including high biocompatibility, enhanced stability, and limited immunogenicity, they have advantages as drug delivery systems (DDSs) compared to traditional synthetic delivery vehicles. For instance, extracellular vesicles, including exosomes, carry and protect a wide array of nucleic acids and can potentially deliver these into recipient cells.6 EVs possess inherent targeting properties due to their lipid composition and protein content enabling them to cross biological barriers, and these salient features exploit endogenous intracellular trafficking mechanisms and trigger a response upon uptake by recipient cells.45,295297 The lipid composition and protein content of exocytic vesicles have specific tropism to specific organs.296 The integrin of exosomes determines the ability to alter the pharmacokinetics of EVs and increase their accumulation in various type of organs including brain, lungs, or liver.117 For example, EVs containing Tspan8 in complex with integrin alpha4 were shown to be preferentially taken up by pancreatic cells.298 Similarly, the lipid composition of EVs influences the cellular uptake of EVs by macrophages.299 EVs derived from dendritic cell achieved targeted knockdown by fusion between expression of Lamp2b and neuron-specific RVG peptide by using siRNA in neuronal cell.45 EVs loaded with Cre recombinase protein were able to deliver functional CreFRB to recipient cells through active and passive mechanisms in the presence of endosomal escape, enhancing the compounds chloroquine and UNC10217832A.300 EVs from cardiosphere-derived cells achieved targeted delivery by fusion of the N-terminus of Lamp2b to a cardiomyocyte-specific peptide (CMP).301 RVG-exosomes were used to deliver anti-alpha-synuclein shRNA minicircle (shRNA-MC) therapy to the alpha-synuclein preformed-fibril-induced mouse model of parkinsonism. This therapy decreased alpha-synuclein aggregation, reduced the loss of dopaminergic neurons, and improved clinical symptoms. RVG exosome-mediated therapy prolonged the effectiveness and was specifically delivered into the brain.302 Zhang et al evaluated the effects of umbilical cord-derived macrophage exosomes loaded with cisplatin on the growth and drug resistance of ovarian cancer cells. High loading efficiency of cisplatin was achieved by membrane disruption of exosomes by sonication.303 Incorporation of cisplatin into umbilical cord blood-derived M1 macrophage exosomes increased cytotoxicity 3.3-fold in drug-resistant A2780/DDP cells and 1.4-fold in drug-sensitive A2780 cells, compared to chemotherapy alone. Loading of cisplatin into M2 exosomes increased cytotoxicity by nearly 1.7-fold in drug-resistant A2780/DDP cells and 1.4-fold in drug-sensitive A2780 cells. The findings suggest that cisplatin-loaded M1 exosomes are potentially powerful tools for the delivery of chemotherapeutics to treat cancers regardless of drug resistance. Shandilya et al developed a chemical-free and non-mechanical method for the encapsulation and intercellular delivery of siRNA using milk-derived exosomes through conjugation between bovine lactoferrin with poly-L-lysine, wherein lactoferrin as a ligand was captured by the GAPDH present in exosomes, loading siRNA in an effortless manner.304 Targeted drug delivery was achieved with low immunogenicity and toxicity using exosomes derived from immature dendritic cells (imDCs) from BALB/c mice by expressing the fusion protein RGD. Recombinant methioninase (rMETase) was loaded into tumor-targeting iRGD-Exos. The findings suggest that the iRGD-Exos-rMETase group exhibited significant antitumor activity compared to the rMETase group.305 Several diseases show high inflammatory responses; therefore, amelioration of inflammatory responses is a critical factor. The inflammatory responses in various disease models can be attenuated through introduction of super-repressor IB (srIB), which is the dominant active form of IB, and can inhibit translocation of nuclear factor B into the nucleus. Intraperitoneal injection of purified srIB-loaded exosomes (Exo-srIBs) showed diminished mortality and systemic inflammation in septic mouse models.306 Systemic administration of macrophage-derived exosomes modified with azide and conjugated with dibenzocyclooctyne-modified antibodies of CD47 and SIRP (aCD47 and aSIRP) through pH-sensitive linkers can actively and specifically target tumors through distinguishing between aCD47 and CD47 on the tumor cell surface.307 SPION-decorated exosomes prepared using fusion proteins of cell-penetrating peptides (CPP) and TNF- (CTNF-)-anchored exosomes coupled with superparamagnetic iron oxide nanoparticles (CTNF--exosome-SPIONs) significantly enhanced tumor cell growth inhibition via induction of the TNFR I-mediated apoptotic pathway. Furthermore, in vivo studies in murine melanoma subcutaneous cancer models showed that TNF--loaded exosome-based vehicle delivery enhanced cancer targeting under an external magnetic field and suppressed tumor growth with mitigating toxicity.308 Yu et al309 developed a formulation of erastin-loaded exosomes labeled with folate (FA) to form FA-vectorized exosomes loaded with erastin (erastin@FA-exo) to target triple-negative breast cancer (TNBC) cells with overexpression of FA receptors. Erastin@FA-exo increased the uptake efficiency of erastin and also significantly inhibited the proliferation and migration of MDA-MB-231 cells compared with erastin@exo and free erastin. Interestingly, erastin@FA-exo promoted ferroptosis with intracellular depletion of glutathione and ROS generation. Plasma exosomes (Exo) loaded with quercetin (Exo-Que) improved the drug bioavailability, enhanced the brain targeting of Que and potently ameliorated cognitive dysfunction in okadaic acid (OA)-induced AD mice compared to free quercetin by inhibiting phosphorylated tau-mediated neurofibrillary tangles.310 Spinal cord injury (SCI) causes paralysis of the limbs. To determine the role of resveratrol in SCI, exosomes derived from resveratrol-treated primary microglia were used as carriers which are able to enhance the solubility of resveratrol and enhance penetration of the drug through the BBB, thereby increasing its concentration in the CNS. The findings demonstrated that Exo + Res are highly effective at crossing the BBB with good stability, suggesting they have potential for enhancing targeted drug delivery and recovering neuronal function in SCI therapy, and is likely associated with the induction of autophagy and inhibition of apoptosis via the PI3K signaling pathway.311 Delivery of miR-204-5p by exosomes inhibits cancer cell proliferation and tumor growth, and induces apoptosis and chemoresistance by specifically suppressing the target genes of miR-204-5p in human cancer cells.312 Engineered exosomes with RVG peptide on the surface for neuron targeting and NGF-loaded exosomes (NGF@ExoRVG) were efficiently delivered into ischemic cortex, with a burst release of encapsulated NGF protein and de novo NGF protein translated from the delivered mRNA. The delivered NGF protein showed high stability and a long retention time, and also reduced inflammation by reshaping microglia polarization, promoted cell survival, and increased the population of double cortin-positive cells, a neuroblast marker.313 Intranasal delivery of mesenchymal stem cell-derived extracellular vesicles exerts immunomodulatory and neuroprotective effects in a 3xTg model of AD by activation of microglia cells and increased dendritic spine density.314 Exosome-encapsulated paclitaxel showed efficacy in the treatment of multi-drug resistant cancer cells and it overcomes MDR in cancer cells.315,316 Saari et al found that the loading of Paclitaxel to autologous prostate cancer cell-derived EVs increased its cytotoxic effect.316 Exosome loaded doxorubicin (exoDOX) avoids undesired and unnecessary heart toxicity by partially limiting the crossing of DOX through the myocardial endothelial cells.317 Studies from in vitro and in vivo demonstrate that exosome loaded doxorubicin showed that exosomes did not decrease the efficacy of DOX and there is no cardiotoxicity in DOX-treated mice.318

The intrinsic properties of exosomes have been exploited to control various types of diseases, including neurodegenerative conditions and cancer, through promoting or restraining the delivery of proteins, metabolites, and nucleic acids into recipient cells effectively, eventually altering their biological response. Furthermore, exosomes can be engineered to deliver diverse therapeutic payloads to the target site, including siRNAs, antisense oligonucleotides, chemotherapeutic agents, and immune modulators. The natural lipid and protein composition of exosomes increases bioavailability and minimizes undesirable side effects to the recipients. Due to the availability of exosomes in biological fluid, they can be easily used as potential biomarkers for diagnosis of diseases. Exosomes are naturally decorated with numerous ligands on the surface that can be beneficial for preferential tumor targeting.282 Due to their unique properties, including superior targeting capabilities and safety profile, exosomes are the subject of clinical trials as cancer therapeutic agents.284 Exosomes derived from DCs loaded with tumor antigens have been used to vaccinate cancer patients with the goal of enhancing anti-tumor immune responses.284,319,320

Due to the potential level of various types of cargoes and salient features, exosomes are involved in intercellular messaging and disease diagnosis. As a result of dedicated studies, exosomes have been identified as natural drug delivery vehicles. However, we still face challenges regarding the purity of exosomes due to the lack of standardized techniques for their isolation and purification, inefficient separation methods, difficulties in characterization, and lack of specific biomarkers.321 The first challenge is the use of conventional methods, which are laborious for isolation and purification, time consuming, and vulnerable to contamination by other impurities, which will affect drug delivery processes. The second challenge is the various cellular origins of exosomes, which could affect specific applications. For example, in the application of exosomes in cancer therapy, we should avoid the use of exosomes derived from cancer cells, due to their oncogenic properties. Finally, exosomes have variable properties due to extraction from different types of cell and different cell culture techniques. Therefore, there is a necessity to address and overcome the challenges. There is also a need for an exosome consortium to develop common protocols for the development of rapid and precise methods of exosome isolation, and to assist the selection of sources that are dependent upon the specific therapeutic application. The most important challenge of exosome biology is the clinical translation of exosome-based research using different cell sources. Further characterization studies based on therapeutic applications are needed. Finally, important steps need to be taken to purify exosomes in a feasible, rapid, cost-effective, and scalable manner, which are free from downstream processing and have minimal processing times, that are specifically targeted to therapeutic applications and clinical settings.

The achievement of exosome therapy is based on success rate of clinical trials. Exosomes with size ranges from 60 to 200nm have been used as an active pharmaceutical ingredient or drug carrier in disease treatment. Exosomes derived from human and plant-derived exosomes are registered in clinical trials, but more complete reports are available for humanderived exosomes.322 There are two major exosomes from DCs and MSCs are frequently used in clinical trials, which potentially induce inflammation response and inflammation treatment. The more crucial aspect of exosomes in clinical trials needs to comply with good manufacturing practice (GMP) including upstream, downstream and quality control. Recently, France and USA conducted clinical trials using EVs containing MHCpeptide complexes derived from dendritic could alter tumor growth in immune competent mice and a Phase I anti-non-small cell lung cancer319,320 and several other clinical trial studies are shown in Table 1. Recent clinical case shows promising results with MSC-EVs derived from unrelated bone marrow donors for the treatment of a steroid-refractory graft-vs-host disease patient.279 Similarly, exosomes were used for the treatment of various types of diseases such as melanoma, non-small-cell-lung cancer, colon cancer and chronic kidney disease.284,319,320,323,324

Table 1 Summary of the Exosome Used in Clinical Trials (Source: clinicaltrials.com)

Exosomes are nano-sized membrane vesicles released by the fusion of an organelle of the endocytic pathway, a multivesicular body, with the plasma membrane. Since the last decade, exosomes have played a critical role in nanomedicine and studies related to exosome biology have increased immensely. Exosomes are secreted by almost all cell types and they are found in almost all types of body fluids. They function as mediators of cell-cell communications and play a significant role in both physiological and pathological processes. Exosomes carry a wide range of cargoes including proteins, lipids, RNAs, and DNA, which mediate signaling to recipient cells or tissues, making them a promising diagnostic biomarker and therapeutic tool for the treatment of cancers and other pathologies. In this review, we summarized what is known to date about the factors involved in exosome biogenesis and the role of exosomes in intercellular signaling and cell-cell communications, immune responses, cellular homeostasis, autophagy, and infectious diseases. Further, we reviewed the role of exosomes as diagnostic markers, and their therapeutic and clinical implications. Furthermore, we highlighted the challenges and outstanding developments in exosome research. The clinical application of exosomes is inevitable and they represent multicomponent biomarkers for several diseases including cancer and neurological diseases, etc. Recently, the mortality rate due to various types of cancers has increased. Therefore, therapies are essential to reduce mortality rates. At this juncture, we need sensitive, rapid, cost-effective, and large-scale production of exosomes to use as cancer biomarkers in diagnosis, prognosis, and surveillance. Furthermore, novel technologies are required for further tailoring exosomes as drug delivery vesicles with high drug pay loads, high specificity and low immunogenicity, and free of toxicity undesired side-effects. In addition, standardized and uniform protocols are necessary to isolate and purify exosomes for clinical applications, and more precise isolation and characterization procedures are required to increase understanding of the heterogeneity of exosomes, their cargo, and functions. There is an urgent need for information regarding the composition and mechanisms of action of the various substances in exosomes and to determine how to obtain highly purified exosomes at the right dosage for their clinical use. Currently, exosomes represent a promising tool in the field of nanomedicine and may provide solutions to a variety of todays medical mysteries.

The future direction of exosome research must focus on addressing the differential responses of communication between normal cells and cancer cells, how normal cells rapidly become cancerous, and how exosomes plays critical role in cancer progression via cell-cell communications. In vivo studies need to urgently address the critical factors such as biogenesis, trafficking, and cellular entry of exosomes originating from unmanipulated exosomes that control regulatory pathological functions. Further studies are required to decipher the mechanism of the cell-specific secretion and transport of exosomes, and the biological controls exerted by target cells. Exosomes represent a clinically significant nanoplatform. To substantiate this idea, numerous systematic in vivo studies are necessary to demonstrate the potency and toxicology of exosomes, which could help bring this novel idea a step closer to clinical reality. The most vital part of the system is to optimize the conditions for the engineering of exosomes that are non-toxic, for use in clinical trials. Furthermore, the translation of exosomes into clinical therapies requires their categorization as active drug components or drug delivery vehicles. Finally, future research should focus on the nanoengineering of exosomes that are tailored specifically for drug delivery and clinical efficacy.

Although we are the authors of this review, we would never have been able to complete it without the great many people who have contributed to the field of exosomes biogenesis, functions, therapeutic and clinical implications of exosomes aspects. We owe our gratitude to all those researchers who have made this review possible. We have cited as many references as permitted and apologize to the authors of those publications that we have not cited due to the limitation of references. We apologize to other authors who have worked on these aspects but whom we have unintentionally overlooked.

This study was supported by the KU-Research Professor Program of Konkuk University.

This work was supported by a grant from the Science Research Center (2015R1A5A1009701) of the National Research Foundation of Korea.

The authors report no conflicts of interest related to this work..

1. Raposo G, Stoorvogel W. Extracellular vesicles: exosomes, microvesicles, and friends. J Cell Biol. 2013;200(4):373383. doi:10.1083/jcb.201211138

2. Denzer K, Kleijmeer MJ, Heijnen HF, Stoorvogel W, Geuze HJ. Exosome: from internal vesicle of the multivesicular body to intercellular signaling device. J Cell Sci. 2000;113(Pt 19):33653374.

3. Yez-M M, Siljander PR, Andreu Z, et al. Biological properties of extracellular vesicles and their physiological functions. J Extracell Vesicles. 2015;4:27066. doi:10.3402/jev.v4.27066

4. Cocucci E, Meldolesi J. Ectosomes and exosomes: shedding the confusion between extracellular vesicles. Trends Cell Biol. 2015;25(6):364372. doi:10.1016/j.tcb.2015.01.004

5. Yamamoto T, Kosaka N, Ochiya T. Latest advances in extracellular vesicles: from bench to bedside. Sci Technol Adv Mater. 2019;20(1):746757. doi:10.1080/14686996.2019.1629835

6. Valadi H, Ekstrm K, Bossios A, Sjstrand M, Lee JJ, Ltvall JO. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol. 2007;9(6):654659. doi:10.1038/ncb1596

7. Kosaka N, Ochiya T. Unraveling the mystery of cancer by secretory microRNA: horizontal microRNA transfer between living cells. Front Genet. 2011;2:97. doi:10.3389/fgene.2011.00097

8. Takahashi A, Okada R, Nagao K, et al. Exosomes maintain cellular homeostasis by excreting harmful DNA from cells. Nat Commun. 2017;8:15287. doi:10.1038/ncomms15287

9. Gruenberg J, van der Goot FG. Mechanisms of pathogen entry through the endosomal compartments. Nat Rev Mol Cell Biol. 2006;7(7):495504. doi:10.1038/nrm1959

10. Zhang J, Li S, Li L, et al. Exosome and exosomal microRNA: trafficking, sorting, and function. Genomics Proteomics Bioinformatics. 2015;13(1):1724. doi:10.1016/j.gpb.2015.02.001

11. Pegtel DM, Gould SJ. Exosomes. Annu Rev Biochem. 2019;88:487514. doi:10.1146/annurev-biochem-013118-111902

12. Maia J, Caja S, Strano Moraes MC, Couto N, Costa-Silva B. Exosome-based cell-cell communication in the tumor microenvironment. Front Cell Dev Biol. 2018;6:18. doi:10.3389/fcell.2018.00018

13. Zhang Q, Higginbotham JN, Jeppesen DK, et al. Transfer of functional cargo in exomeres. Cell Rep. 2019;27(3):940954.e946. doi:10.1016/j.celrep.2019.01.009

14. Hessvik NP, Llorente A. Current knowledge on exosome biogenesis and release. Cell Mol Life Sci. 2018;75(2):193208. doi:10.1007/s00018-017-2595-9

15. Palanisamy V, Sharma S, Deshpande A, Zhou H, Gimzewski J, Wong DT. Nanostructural and transcriptomic analyses of human saliva derived exosomes. PLoS One. 2010;5(1):e8577. doi:10.1371/journal.pone.0008577

16. Kalluri R. The biology and function of exosomes in cancer. J Clin Invest. 2016;126(4):12081215. doi:10.1172/jci81135

17. Thry C, Zitvogel L, Amigorena S. Exosomes: composition, biogenesis and function. Nat Rev Immunol. 2002;2(8):569579. doi:10.1038/nri855

18. Thry C, Ostrowski M, Segura E. Membrane vesicles as conveyors of immune responses. Nat Rev Immunol. 2009;9(8):581593. doi:10.1038/nri2567

19. Janowska-Wieczorek A, Wysoczynski M, Kijowski J, et al. Microvesicles derived from activated platelets induce metastasis and angiogenesis in lung cancer. Int J Cancer. 2005;113(5):752760. doi:10.1002/ijc.20657

20. Lakkaraju A, Rodriguez-Boulan E. Itinerant exosomes: emerging roles in cell and tissue polarity. Trends Cell Biol. 2008;18(5):199209. doi:10.1016/j.tcb.2008.03.002

21. Ferguson SW, Nguyen J. Exosomes as therapeutics: the implications of molecular composition and exosomal heterogeneity. J Control Release. 2016;228:179190. doi:10.1016/j.jconrel.2016.02.037

22. Soung YH, Ford S, Zhang V, Chung J. Exosomes in cancer diagnostics. Cancers (Basel). 2017;9(12):8. doi:10.3390/cancers9010008

23. Meehan K, Vella LJ. The contribution of tumour-derived exosomes to the hallmarks of cancer. Crit Rev Clin Lab Sci. 2016;53(2):121131. doi:10.3109/10408363.2015.1092496

24. Quah BJ, ONeill HC. Maturation of function in dendritic cells for tolerance and immunity. J Cell Mol Med. 2005;9(3):643654. doi:10.1111/j.1582-4934.2005.tb00494.x

25. Bell BM, Kirk ID, Hiltbrunner S, Gabrielsson S, Bultema JJ. Designer exosomes as next-generation cancer immunotherapy. Nanomedicine. 2016;12(1):163169. doi:10.1016/j.nano.2015.09.011

26. Pegtel DM, Peferoen L, Amor S. Extracellular vesicles as modulators of cell-to-cell communication in the healthy and diseased brain. Philos Trans R Soc Lond B Biol Sci. 2014;369(1652):20130516. doi:10.1098/rstb.2013.0516

27. Xin H, Li Y, Buller B, et al. Exosome-mediated transfer of miR-133b from multipotent mesenchymal stromal cells to neural cells contributes to neurite outgrowth. Stem Cells. 2012;30(7):15561564. doi:10.1002/stem.1129

28. Rajendran L, Honsho M, Zahn TR, et al. Alzheimers disease beta-amyloid peptides are released in association with exosomes. Proc Natl Acad Sci U S A. 2006;103(30):1117211177. doi:10.1073/pnas.0603838103

29. Guo BB, Bellingham SA, Hill AF. The neutral sphingomyelinase pathway regulates packaging of the prion protein into exosomes. J Biol Chem. 2015;290(6):34553467. doi:10.1074/jbc.M114.605253

30. Simons M, Raposo G. Exosomesvesicular carriers for intercellular communication. Curr Opin Cell Biol. 2009;21(4):575581. doi:10.1016/j.ceb.2009.03.007

31. Natasha G, Gundogan B, Tan A, et al. Exosomes as immunotheranostic nanoparticles. Clin Ther. 2014;36(6):820829. doi:10.1016/j.clinthera.2014.04.019

32. Pascucci L, Cocc V, Bonomi A, et al. Paclitaxel is incorporated by mesenchymal stromal cells and released in exosomes that inhibit in vitro tumor growth: a new approach for drug delivery. J Control Release. 2014;192:262270. doi:10.1016/j.jconrel.2014.07.042

33. Haney MJ, Klyachko NL, Zhao Y, et al. Exosomes as drug delivery vehicles for Parkinsons disease therapy. J Control Release. 2015;207:1830. doi:10.1016/j.jconrel.2015.03.033

34. Kalani A, Tyagi A, Tyagi N. Exosomes: mediators of neurodegeneration, neuroprotection and therapeutics. Mol Neurobiol. 2014;49(1):590600. doi:10.1007/s12035-013-8544-1

35. Minciacchi VR, Freeman MR, Di Vizio D. Extracellular vesicles in cancer: exosomes, microvesicles and the emerging role of large oncosomes. Semin Cell Dev Biol. 2015;40:4151. doi:10.1016/j.semcdb.2015.02.010

36. Colombo M, Moita C, van Niel G, et al. Analysis of ESCRT functions in exosome biogenesis, composition and secretion highlights the heterogeneity of extracellular vesicles. J Cell Sci. 2013;126(Pt 24):55535565. doi:10.1242/jcs.128868

37. Ghossoub R, Lembo F, Rubio A, et al. Syntenin-ALIX exosome biogenesis and budding into multivesicular bodies are controlled by ARF6 and PLD2. Nat Commun. 2014;5:3477. doi:10.1038/ncomms4477

38. Kowal J, Tkach M, Thry C. Biogenesis and secretion of exosomes. Curr Opin Cell Biol. 2014;29:116125. doi:10.1016/j.ceb.2014.05.004

39. Villarroya-Beltri C, Baixauli F, Gutirrez-Vzquez C, Snchez-Madrid F, Mittelbrunn M. Sorting it out: regulation of exosome loading. Semin Cancer Biol. 2014;28:313. doi:10.1016/j.semcancer.2014.04.009

40. Fader CM, Snchez DG, Mestre MB, Colombo MI. TI-VAMP/VAMP7 and VAMP3/cellubrevin: two v-SNARE proteins involved in specific steps of the autophagy/multivesicular body pathways. Biochim Biophys Acta. 2009;1793(12):19011916. doi:10.1016/j.bbamcr.2009.09.011

41. Ostrowski M, Carmo NB, Krumeich S, et al. Rab27a and Rab27b control different steps of the exosome secretion pathway. Nat Cell Biol. 2010;12(1):1930; sup pp 1113. doi:10.1038/ncb2000

42. Gross JC, Chaudhary V, Bartscherer K, Boutros M. Active Wnt proteins are secreted on exosomes. Nat Cell Biol. 2012;14(10):10361045. doi:10.1038/ncb2574

43. Hyenne V, Apaydin A, Rodriguez D, et al. RAL-1 controls multivesicular body biogenesis and exosome secretion. J Cell Biol. 2015;211(1):2737. doi:10.1083/jcb.201504136

44. Gudbergsson JM, Johnsen KB, Skov MN, Duroux M. Systematic review of factors influencing extracellular vesicle yield from cell cultures. Cytotechnology. 2016;68(4):579592. doi:10.1007/s10616-015-9913-6

45. Alvarez-Erviti L, Seow Y, Schapira AH, et al. Lysosomal dysfunction increases exosome-mediated alpha-synuclein release and transmission. Neurobiol Dis. 2011;42(3):360367. doi:10.1016/j.nbd.2011.01.029

46. Tian Y, Li S, Song J, et al. A doxorubicin delivery platform using engineered natural membrane vesicle exosomes for targeted tumor therapy. Biomaterials. 2014;35(7):23832390. doi:10.1016/j.biomaterials.2013.11.083

47. Chen TS, Arslan F, Yin Y, et al. Enabling a robust scalable manufacturing process for therapeutic exosomes through oncogenic immortalization of human ESC-derived MSCs. J Transl Med. 2011;9:47. doi:10.1186/1479-5876-9-47

48. Yeo RW, Lai RC, Zhang B, et al. Mesenchymal stem cell: an efficient mass producer of exosomes for drug delivery. Adv Drug Deliv Rev. 2013;65(3):336341. doi:10.1016/j.addr.2012.07.001

49. Zheng Y, Campbell EC, Lucocq J, Riches A, Powis SJ. Monitoring the Rab27 associated exosome pathway using nanoparticle tracking analysis. Exp Cell Res. 2013;319(12):17061713. doi:10.1016/j.yexcr.2012.10.006

50. Wang JS, Wang FB, Zhang QG, Shen ZZ, Shao ZM. Enhanced expression of Rab27A gene by breast cancer cells promoting invasiveness and the metastasis potential by secretion of insulin-like growth factor-II. Mol Cancer Res. 2008;6(3):372382. doi:10.1158/1541-7786.Mcr-07-0162

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