Genetherapy

FDA expands approval of first gene therapy for rare form of muscular dystrophy – KDRV

June 25th, 2024

(CNN) The US Food and Drug Administration has given the green light for the first gene therapy that treats a rare form of muscular dystrophy to be used in most people who have the disease and a certain genetic mutation.

Last year, the drug Elevidys, from the biotech company Sarepta Therapeutics was approved to treat only children ages 4 and 5 with Duchenne muscular dystrophy, one of the most severe forms of inherited muscular dystrophies, who have a confirmed mutation in a gene called DMD that is associated with muscle strength.

The FDA announced Thursday that it had given traditional approval for Elevidys for ambulatory people 4 and older with a confirmed mutation in the DMD gene and accelerated approval for non-ambulatory people 4 and older with this mutation. Theres not enough data on safety to support its use in children under 4, the agency says.

Elevidys, given as a one-time intravenous infusion, costs about $3.2 million per patient, making it among the most expensive drugs in the world. Although eye-popping, such aprice tagisnt out of step with other one-time gene therapies, which have topped$3 million to 4 millionper patient in recent years.

Elevidys was previously approved under the FDAs accelerated approval pathway, which clears medicines for diseases where theyre urgently needed based on data suggesting that theyre likely to confer clinical benefits. The drug has been closely monitored since that approval, and in October, Sarepta Therapeutics released results from a confirmatory trial showing that the therapy missed its primary goal a measure of how well kids can move but was successful on a number of secondary measures.

The approval addressed an urgent unmet medical need and is an important advancement in the treatment of Duchenne muscular dystrophy, a devastating condition with limited treatment options, that leads to a progressive deterioration of an individuals health over time, Dr. Peter Marks, director of the FDAs Center for Biologics Evaluation and Research, said in a news release at the time.

It was the first time a therapy of this nature a one-time treatment that delivers a working copy of a gene to make up for one that leads to disease had been cleared under the accelerated approval framework. The move came after emotionaltestimonialsfrom families at an FDA advisory committee meeting.

Duchenne muscular dystrophy causes progressive muscle weakness that can rob children of their ability to walk by the time theyre teenagers, and many dont live well into their 30s. It primarily affects boys because of the way its inherited, affecting an estimated 1 in 3,300 boys.

The Muscular Dystrophy Association trusts the decision of the FDA, which weighs the risks and benefits of the drug, said Dr. Sharon Hesterlee, chief researcher at the association.

Ultimately, what we want is whats best for our patient community and thats balancing that risk-benefit ratio appropriately, she said.

Potential risks of Elevidys include increases in certain liver enzyme levels and acute serious liver injury. The most common side effects of the drug include vomiting, nausea, increased liver function tests and fever.

Yet a major benefit is that the gene therapy provides another option for people with Duchenne muscular dystrophy, and its administered just once.

There is no cure for Duchenne muscular dystrophy, and outside of Elevidys, treatments are limited. Otherapproachesmay include steroid medications,certaindrugs that change how the muscle cells read the mutated gene, physical therapy or surgery to correct spinal curvature, Hesterlee said.

Right now, themainstandard of care for Duchenne is corticosteroids, like prednisone,although there are some newer drugs available. These kids arestilloften on chronic doses ofsteroidsfor many, many years, she said, adding that the side effects of corticosteroids such as weight gain, behavioral issues and increased risk of bone breakage are not ideal.

Duchenne muscular dystrophy can be difficult to treat, she said, and having more treatment options that are proven to be effective remains important.

Muscle makes up a significant amount of your body mass. So when you have a disease like this, its really impacting a lot of tissue. So anything you do, youre looking at trying to bring back or stop a disease process thats really throughout the body, and its a disease thats progressive, so you lose more and more muscle over time, Hesterlee said.

Thats made it pretty challenging, but weve certainly learned a lot, she said. You cant overlook the fact that these boys are living so much longer and doing so much better. Even 20 years ago, they were dying in their teens, and many of them are now living into their 30s. Theyre going to college; they have girlfriends; some of them have gotten married. These are things that werent happening years ago. So weve made a tremendous amount of progress.

The-CNN-Wire

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Lentiviral Vector In Gene Therapy Market Forecasts, Market Trends and Impact Analysis (2024 – 2031) – openPR

June 25th, 2024

Market Overview and Report Coverage

Lentiviral vectors are a type of viral vector used in gene therapy to deliver genetic material into target cells. They are derived from lentiviruses, which are a type of retrovirus known for their ability to integrate their genetic material into the host cell's genome. This integration allows for stable and long-lasting gene expression, making lentiviral vectors an attractive option for gene therapy applications.

The Lentiviral Vector In Gene Therapy Market is expected to grow at a CAGR of 12.30% during the forecasted period. The current outlook for this market is promising, with increasing research and development activities in the field of gene therapy driving the demand for lentiviral vectors. Advances in genetic engineering and gene editing technologies have also expanded the potential applications of lentiviral vectors in treating a wide range of genetic disorders, cancers, and other diseases.

Moreover, the growing globalization of the pharmaceutical and biotechnology industries, along with increasing partnerships and collaborations between companies and research institutions, are further fueling the growth of the Lentiviral Vector In Gene Therapy Market. With ongoing technological advancements and a supportive regulatory environment, the future of lentiviral vectors in gene therapy looks bright, offering hope for patients with currently incurable genetic diseases.

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Market Segmentation 2024 to 2031

The Lentiviral Vector In Gene Therapy Market Analysis by types is segmented into:

Retrovirus (RV) Adenovirus (AdV) Adeno-associated Virus (AAV)

Lentiviral vectors are commonly used in gene therapy due to their ability to efficiently deliver genetic material into target cells. Retrovirus (RV) vectors are derived from retroviruses and integrate their genetic material into the host cell genome. Adenovirus (AdV) vectors are based on adenoviruses and provide high levels of gene expression in target cells. Adeno-associated Virus (AAV) vectors are derived from adeno-associated viruses and are known for their safety and ability to infect a wide range of cell types. These vectors play a crucial role in the gene therapy market for various applications.

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The Lentiviral Vector In Gene Therapy Market Industry Research by Application is segmented into:

Hospital Clinic Research Institution Others

The Lentiviral Vector in Gene Therapy market application is utilized in various sectors including hospitals, clinics, research institutions, and other medical facilities. This technology is being increasingly used in gene therapy to treat genetic disorders and other diseases. Hospitals and clinics are incorporating Lentiviral Vector technology to provide advanced treatment options to their patients. Research institutions are utilizing these vectors in their studies to explore potential therapeutic applications. Other markets also benefit from Lentiviral Vectors for various research and medical purposes.

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In terms of Region, the Lentiviral Vector In Gene Therapy Market Players available by Region are:

North America: United States Canada

Europe: Germany France U.K. Italy Russia

Asia-Pacific: China Japan South Korea India Australia China Taiwan Indonesia Thailand Malaysia

Latin America: Mexico Brazil Argentina Korea Colombia

Middle East & Africa: Turkey Saudi Arabia UAE Korea

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What are the Emerging Trends in the Global Lentiviral Vector In Gene Therapy market?

- CRISPR/Cas9 technology: Lentiviral vectors are being used in conjunction with CRISPR/Cas9 gene editing technology to more precisely target and edit genes for therapeutic purposes.

- Cell-specific targeting: Researchers are developing lentiviral vectors that can target specific cell types, improving the efficiency and safety of gene therapy treatments.

- Non-viral gene delivery systems: Emerging non-viral gene delivery systems are being developed as alternatives to lentiviral vectors, potentially disrupting the market.

- Personalized medicine: Increased focus on personalized medicine is driving the development of lentiviral vectors tailored to individual patient needs.

- Regulatory advancements: Regulatory agencies are working to streamline the approval process for gene therapy products, spurring growth in the lentiviral vector market. These trends collectively indicate a positive growth trajectory for the Lentiviral Vector In Gene Therapy market as it continues to evolve and innovate.

Lentiviral Vector In Gene Therapy Market Competitive Analysis

One of the key players in the competitive Lentiviral Vector in Gene Therapy market is Thermo Fisher Scientific. Thermo Fisher Scientific is a global biotechnology company that offers a wide range of products and services for the life sciences industry. The company has a strong presence in the gene therapy market, offering high-quality Lentiviral vectors for gene delivery. Thermo Fisher Scientific has a proven track record of innovation and expertise in the development of gene therapy products.

Another major player in the market is Vigene Biosciences, a leading provider of viral vector products and services for gene therapy applications. Vigene Biosciences has a strong focus on quality and innovation, which has helped the company to establish itself as a key player in the gene therapy market. Vigene Biosciences has experienced significant growth in recent years, driven by the increasing demand for Lentiviral vectors in gene therapy research and applications.

OriGene Technologies is also a prominent player in the Lentiviral Vector in Gene Therapy market, offering a wide range of Lentiviral vectors and other gene therapy products. OriGene Technologies has a strong presence in the market, backed by its extensive experience and expertise in gene therapy research and development. The company has witnessed substantial market growth and has been able to capture a significant market share in the gene therapy market.

In terms of sales revenue, companies like Thermo Fisher Scientific and Vigene Biosciences have reported strong financial performance in recent years, reflecting the growing demand for Lentiviral vectors in gene therapy applications. These companies have continued to invest in research and development to expand their product offerings and stay ahead of the competition in the gene therapy market.

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Roche, Ascidian to develop gene therapies for neurological diseases – LabPulse

June 25th, 2024

Roche has announced a research collaboration and licensing agreement with biotech firm Ascidian Therapeutics to develop gene therapies for neurological diseases.

According to the terms of their agreement, Roche will pay Ascidian $42 million upfront for exclusive, target-specific rights to use Ascidian's RNA exon-editing technology to develop therapeutics for undisclosed neurological diseases, the firms said in a statement. Furthermore, Roche will pay Ascidian up to $1.8 billion in total as research, clinical, and commercial milestones are reached. Ascidian is also eligible to receive royalties on commercial sales worldwide for any therapies that are developed under the collaboration.

Under their arrangement, Ascidian will be responsible for conducting discovery and certain preclinical activities in collaboration with Roche, and Roche will be responsible for certain other preclinical activities, as well as further clinical development, manufacturing, and commercialization, Ascidian said. While Roche will have exclusive rights to the technology for the targeted diseases, Ascidian can pursue other disease targets outside of its agreement with Roche.

Boston-based Ascidian's exon-editing technology is designed to correct the RNA produced by damaged exons, the regions of DNA containing the blueprints to make proteins. Correcting the RNA produced by damaged exons greatly mitigates the risks associated with direct DNA editing and gene replacement, such as off-target edits, Ascidian said.

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Medical Breakthroughs: Using genetic testing to improve treatment outcomes – KRGV

June 25th, 2024

A simple blood draw or saliva sample can identify opportunities for prevention, single out the best clinical trials, and improve treatment outcomes.

This type of genetic testing can cost hundreds of dollars, and is sometimes not covered by insurance.

We actually recognize that it's going to be the most cost-effective care as well, Stephen Gruber, chair of the Center for Precision Medicine at City of Hope, said.

City of Hope is one of the first cancer centers in the world to offer free genetic testing to every single patient, and possibly their immediate families.

Someone I recently spoke to was identified to have a genetic change that increased her risk for breast and ovarian cancer, and we got those results in just before she was about to start chemotherapy, City of Hope genetic counselor manager Bita Nehoray said. It actually changed things for her, and we were able to offer her a more appropriate and better line of therapy."

The panel tests 189 genes related to the risk of cancer and other inherited diseases.

It's been a tremendous game changer, as it relates to prevention in families, but also in really personalizing the most appropriate treatment plan, Nehoray said.

Taking part in the genetic testing is completely free to the patients. City of Hope will soon begin offering the inspire study testing nationwide in their locations in Los Angeles, Atlanta, Chicago, and Phoenix.

Watch the video above for the full story.

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Precision Diagnostics Market Size to Reach USD 270.31 Billion by 2033 – BioSpace

June 25th, 2024

According to the latest report the global precision diagnostics market size was USD 76.19 billion in 2023, calculated at USD 86.48 billion in 2024, and is expected to reach around USD 270.31 billion by 2033, expanding at a CAGR of 13.5% from 2024 to 2033. North America dominated the market with the largest revenue share of 49.19% in 2023.

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The precision diagnostics market refers to the segment of the healthcare industry that focuses on the development and application of diagnostic tests and tools designed to accurately detect and characterize diseases at a molecular or genetic level. Precision diagnostics aim to provide tailored and precise information that can guide personalized treatment decisions, improve patient outcomes, and reduce healthcare costs. These diagnostics encompass a wide range of technologies including genetic testing, molecular diagnostics, companion diagnostics, next-generation sequencing (NGS), biomarker analysis, and advanced imaging techniques.

Growth factors

Precision Diagnostics Market Key Takeaways

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Market dynamics

Driver

Rising demand for early detection of diseases

Precision diagnostics provide the ability to detect diseases at an early stage, improving the chances of successful treatment and reducing healthcare costs by avoiding late-stage interventions. Focused on offering Multiple countries with the support of government fundings and private investments are focusing on early detection of diseases, this acts as a major driver for the market. The expanding field of precision medicine, which relies heavily on precision diagnostics for patient stratification and treatment selection, propels the demand for advanced diagnostic tools.

Restraint

Complexity in data interpretation

The high cost of advanced diagnostic tests and technologies can limit their accessibility and affordability, particularly in low- and middle-income countries. The complexity of interpreting genetic and molecular data requires specialized expertise and infrastructure, which can be a barrier to widespread adoption in clinical settings. Stringent regulatory requirements and varying regulations across different regions can pose challenges for the approval and commercialization of precision diagnostics.

Opportunity

Growing healthcare infrastructure and increasing investments in emerging markets present significant opportunities for the expansion of precision diagnostics in regions such as Asia-Pacific and Latin America. The integration of precision diagnostics with digital health technologies, such as telemedicine and health informatics, can improve patient management and facilitate remote monitoring and diagnosis. Thereby, the integration of digital health is observed to act as an opportunity for the market.

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U.S. Precision Diagnostics Market Size and Growth 2024 to 2033

The U.S. precision diagnostics market size was estimated at USD 26.23 billion in 2023 and is projected to hit around USD 97.19 billion by 2033, growing at a CAGR of 12.73% during the forecast period from 2024 to 2033.

North America dominated the precision diagnostics market with the largest revenue share of 49.19% in 2023, mainly the U.S., which is known for its advanced healthcare infrastructure and robust biotechnology research sectors. Continuous investments and developments in these areas have led to innovations in personalized diagnostics technologies, making them more efficient and reliable. Government initiatives in North America aimed at improving healthcare quality and accessibility, along with funding for research and development in the field of diagnostics, have significantly contributed to the market growth.

U.S. Precision Diagnostics Market Trends

The precision diagnostics market in the U.S. is expected to grow at the fastest CAGR over the forecast period, driven by advancements in genomic medicine, increased awareness of personalized healthcare, the integration ofartificial intelligence (AI)in diagnostic processes, and rising demand for early and more accurate disease detection. Precision diagnostics, which includesgenetic testing, molecular diagnostics, and companion diagnostics, among others, focus on identifying unique genetic and biomolecular characteristics to guide more tailored treatment strategies.

The U.S. government and private sectors have supported research and initiatives related toprecision medicineand diagnostics. Programs such as the Precision Medicine Initiative (PMI) aim to revolutionize how diseases are treated and prevented by considering individual differences in peoples genes, environments, and lifestyles.

Europe Precision Diagnostics Market Trends

The precision diagnostics market in Europe was identified as a lucrative region in this industry. The Europe market is experiencing significant growth. This growth can be attributed to advancements in technologies, increasing healthcare expenditures, the rising prevalence of chronic diseases, and the growing emphasis onpersonalized medicine. The regulatory environment in Europe is also adapting to the advancements in precision diagnostics, with efforts to streamline approval processes for new diagnostic technologies. In addition, collaborations between diagnostic companies, research institutions, and healthcare providers are fostering innovation and accelerating the development of new diagnostic solutions.

The UK precision diagnostics market held a significant share in 2023.There is a growing emphasis on personalized healthcare in the UK. Treatments and diagnostics are tailored to individual genetic profiles, improving patient outcomes and treatment efficacy. The UK government and healthcare system are supportive of precision medicine initiatives. For instance, the NHS has launched the 100,000 Genomes Project and continues to invest in genomic medicine, creating a conducive environment for the growth of precision diagnostics.

The precision diagnostics market in France is expected to grow at a remarkable CAGR over the forecast period,driven by the increasing incidence of chronic diseases, such as cancer, cardiovascular diseases, and diabetes, which has heightened the demand for early and accurate diagnostic solutions. This need is critical in managing these conditions effectively, leading to a push for advancements in diagnostic technologies. France has an aging population. This demographic trend results in a higher prevalence of various diseases, necessitating the development and implementation of advanced diagnostic tools to cater to the growing healthcare needs of this segment of the population.

The Germany precision diagnostics market is anticipated to grow at a significant CAGR over the forecast period.The Germany market is characterized by a strong focus on innovation and quality, reflecting the country's leading position in healthcare and medical technology. With a robust healthcare system and a high level of spending on healthcare relative to GDP, Germany presents a productive ground for the growth and adoption of personalized diagnostics technologies. Regulatory frameworks in Germany are designed to ensure patient safety while promoting technological advancements. The Federal Institute for Drugs and Medical Devices (BfArM) and the Paul-Ehrlich-Institute (PEI) are key regulatory bodies that oversee the approval and market surveillance of diagnostic products. These agencies work to balance innovation with strict safety standards, ensuring that new diagnostic technologies entering the market are effective and reliable.

Asia Pacific Precision Diagnostics Market Trends

The precision diagnostics market in Asia Pacific is anticipated to grow at the fastest CAGR of 12.8% over the forecast period. The increasing prevalence of chronic diseases, such as cancer and diabetes, in this region drives the demand for advanced diagnostic methods that can provide personalized treatment options. The growing awareness and acceptance of precision diagnostics among healthcare professionals and patients contribute to this rapid growth. Improvements in healthcare infrastructure, mainly in emerging economies such as China and India, along with government initiatives aimed at incorporating advanced healthcare technologies, further bolster the market expansion. The rising investment in healthcare research and development, coupled with collaborations between public and private sectors in the field of precision medicine, are also significant contributors.

The China precision diagnostics market is expected to grow at a rapid CAGR over the forecast period. China has seen rapid advancements in healthcare infrastructure and technology. The government and private sector have invested robustly in healthcare innovation, particularly in precision medicine, which includesgenomicsand personalized healthcare solutions. This focus aligns with the global trend toward more personalized and precise medical interventions based on individual genetic and molecular profiles.

The precision diagnostics market in Japan has one of the highest proportions of elderly citizens in the world. This demographic trend increases the demand for healthcare services, including precision diagnostics, as older populations typically have higher incidences of chronic diseases such as cancer, cardiovascular diseases, and neurological disorders. The Japanese government actively promotes healthcare innovation through funding, research programs, and regulatory reforms designed to facilitate the development and adoption of new medical technologies. Initiatives such as the Japan Health Sciences Foundation and the Japan Agency for Medical Research and Development (AMED) support research in precision medicine and diagnostics.

Middle East & Africa Precision Diagnostics Market Trends

The precision diagnostics market in Middle East & Africa is expected to grow at a exponential CAGR over the forecast period. Countries across the MEA are significantly investing in healthcare infrastructure and services. This includes the development of state-of-the-art medical facilities and hospitals, which are essential for implementing advanced diagnostic technologies. The MEA region is witnessing a surge in chronic diseases such as diabetes, cardiovascular diseases, and cancer. Precision diagnostics play a crucial role in the early detection and management of these conditions, making them important in regional healthcare.

The Saudi Arabia precision diagnostics market is expected to grow at the fastest CAGR over the forecast period. The Saudi Arabian government has been actively investing in healthcare infrastructure and digital health technologies as part of its Vision 2030 program. This includes initiatives aimed at enhancing the precision diagnostics sector, such as funding for research and development and the establishment of state-of-the-art medical facilities equipped with the latest diagnostic technologies. There has been an increase in the prevalence of chronic diseases such as diabetes, cardiovascular diseases, and cancer in Saudi Arabia. Precision diagnostics play a crucial role in the early detection and management of these conditions, driving demand for advanced diagnostic services.

The precision diagnostics market in Kuwait is anticipated to grow at a significant CAGR over the forecast period. Kuwait is witnessing a substantial adoption of digital health technologies. The use of artificial intelligence (AI) andmachine learningfor data analysis in healthcare is becoming more common. These technologies are improving the accuracy and efficiency of disease diagnosis and treatment plans, thus boosting the capabilities of precision diagnostics. There's a focus on ensuring that healthcare professionals in Kuwait are up-to-date with the latest diagnostic technologies and techniques. Education and training programs are critical for equipping the healthcare workforce with the necessary skills to utilize precision diagnostics tools effectively.

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Precision Diagnostics Market By Type Insights

Based on type, the genetic tests segment led the market with the largest revenue share of 45.15% in 2023. The dominance of genetic tests in the market can be attributed to technological advancements, a better understanding of genetic disorders, the rise of personalized medicine, an increase in chronic diseases and cancer, consumer interest, and a supportive regulatory environment. Furthermore, the sector has witnessed significant investments and collaborations between diagnostic companies, pharmaceutical companies, and academic institutions. These partnerships aim to develop new genetic tests and integrate them into clinical practice, further driving market growth. For instance, in January 2024, DNAnexus, Inc. and TMA Precision Health announced a collaboration to enhance diagnostic processes and treatment alternatives for rare diseases. This partnership is focused on developing more accurate and efficient diagnostic tools that can lead to better personalized treatment plans for individuals suffering from rare conditions.

The Direct-to-Consumer Tests (DTC)segment is anticipated to register at the fastest CAGR from 2024 to 2033. There's a growing awareness among consumers about the importance of early disease detection and personalized health information. DTC tests provide a convenient way for individuals to access health information directly without necessarily going through a healthcare provider. Advancements in genomic sequencing technologies and bioinformatics have made it easier and more cost-effective to offer these tests directly to consumers. This has led to an increase in the variety and accuracy of tests available, from genetic predisposition to certain conditions to personalized nutrition and fitness advice. Regulatory bodies in some regions have started providing clearer frameworks and guidelines for DTC genetic testing, which has helped companies navigate the approval process more efficiently and bring their products to market.

Precision Diagnostics Market By Application Insights

Based on application, the oncology segment led the market with the largest revenue share of 25.7%in 2023. This is primarily due to the increasing prevalence of cancer worldwide and the need for early detection and monitoring of this disease. According to the American Cancer Society, approximately 1.96 million new cases of cancer were diagnosed in 2023. This high prevalence demands more personalized and accurate diagnostic methods to identify specific cancer types and their genetic makeup, facilitating targeted treatment approaches. In addition, government investment in this segment is expected to boost the market in the forecast years. For instance, in the U.S., the National Cancer Institute (NCI) received USD 7.8 billion from the government and a USD 500 million increase from the Fiscal Year 2023 budget to support personalized medicine.

The genetic diseases application segment is expected to grow at the fastest CAGR during the forecast period. The rising incidence of genetic disorders worldwide is driving the demand for personalized diagnostic solutions. Conditions such as cystic fibrosis, sickle cell anemia, and various forms of cancer have genetic roots, necessitating advanced diagnostics for early detection and management. The advent of next-generation sequencing (NGS) and other high-throughput technologies has revolutionized genetic testing. These advancements have made it possible to analyze and interpret large volumes of genetic data quickly and cost-effectively, thereby accelerating the growth of precision diagnostics in identifying genetic diseases.

Precision Diagnostics Market By End-use Insights

Based on end-use, the clinical laboratories segment led the market with the largest revenue share of 48.11% in 2023.Clinical laboratories play a key role in the market, primarily due to their extensive use of advanced diagnostic technologies for accurate disease detection and monitoring. Precision diagnostics often requires the interpretation of complex data, such as genetic mutations or biomarker levels. Clinical laboratories have the expertise and personnel, such as pathologists and geneticists, to interpret these results accurately, making them a crucial end-use segment. Furthermore,clinical laboratories offer a wide range of diagnostic services, from routine blood tests to complex genetic testing. This flexibility attracts a broad patient base, further driving the demand for personalized diagnostics.

The hospital segment is anticipated to grow at a significant CAGR during the forecast period. Hospitals are adopting precision diagnostic technologies, driven by the need for more accurate and individualized patient care. This adoption is facilitated by advancements in diagnostic technologies, such as next-generation sequencing (NGS), PCR (polymerase chain reaction), and liquid biopsy, which are becoming more accessible and integrated into hospital settings. In addition, rising investment and collaborations by private players in the market are expected to support market growth. For instance, in January 2024, Qlucore Insights, a software development company for precision diagnostics, signed an agreement with Sahlgrenska University Hospital in Sweden. Through the agreement, the hospital will use the Qlucore Insights software to improve the diagnosis of acute lymphoblastic leukemia in children.

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Precision Diagnostics Market Recent Developments

Key Precision Diagnostics Company Insights

The market players operating in the global market are adopting product approval to increase the reach of their products in the market and improve the availability of their products in diverse geographical areas, along with expansion as a strategy to enhance production/research activities. In addition, several market players are acquiring smaller players to strengthen their market position. This strategy enables companies to increase their capabilities, expand their product portfolios, and improve their competencies.

The following are the leading companies in the precision diagnostics market. These companies collectively hold the largest market share and dictate industry trends.

Precision Diagnostics Market Report Segmentation

This report forecasts revenue growth at country levels and provides an analysis of the latest industry trends in each of the sub-segments from 2021 to 2033. For this study, Nova one advisor, Inc. has segmented the Precision Diagnostics market.

By Type

By Application

By End-use

By Region

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Precision Diagnostics Market Size to Reach USD 270.31 Billion by 2033 - BioSpace

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Color Health uses OpenAI to develop cancer screening copilot for doctors – Healthcare IT News

June 25th, 2024

Color Health, a genetic testing company, is using OpenAI's newest, less expensive, large language model to equip doctors with pretreatment workup expertise that could speed up prior authorization requests for cancer screening diagnostics and get patients into treatment faster.

The company has also partnered with the University of California San Francisco to study how the cancer copilot tool performs in surfacing early warning signs, seemingly incongruous red flags and other pertinent details that may be deeply dispersed throughout electronic health records and other patient information.

WHY IT MATTERS

While decision factors for different types of cancers vary, a trial of the technology helped providers analyze patient records in five minutes, according to the company.

"Primary care doctors dont tend to either have the time or sometimes even the expertise, to risk-adjust peoples screening guidelines," Othman Laraki, cofounder and chief executive of Color Health, said in aWall Street JournalreportMonday.

The UCSF Helen Diller Family Comprehensive Cancer Center is testing Colors copilot for cancer pretreatment diagnostic work-ups by comparing it to retrospective analyses of cancer patient charts.

Though that study is in the early stages, according to a Color Spokesperson, if AI can ultimately reduce wait times for cancer treatment by connecting the dots, that's a patient care win.

In Color'sannouncementMonday, Laraki said the company designed the tool to address the supply gap in oncology expertise to decide on a pre-treatment workup for a patient with a confirmed malignancy.

The goal is to offer primary care doctors and other clinicians an AI service that can determine what tests are needed to inform the patient's cancer treatment, without waiting for the patient to see an oncologist before pretreatment diagnostics are ordered and the prior authorization process is initiated, he explained.

"That way, by the time the patient meets her oncologist for the first time, she has a much higher chance of being ready to initiate treatment and, we hope, save weeks of precious time."

Laraki also stressed the clinician's role in decision-making when using the tool.

"One of the most important design decisions behind our work is that the tools were built from the ground up to be based on a human-in-the-loop model," he said.

The company said it will share the results of the first use case tested which focuses on automating the analysis of a persons background risk factors and then applying the guidelines that adjust their screening plan first with individuals in its cancer program, and then give primary care doctors a chance to review the information.

Color estimated that physicians using the cancer copilot will have supported more than 200,000 patient cases in generating AI personalized care plans by the end of the year.

THE LARGER TREND

Before focusing on tools to help doctors improve cancer patient outcomes, Color launched its model of patient-initiated proactive testing in 2015. The tests focused on genes known to increase an individuals cancer risk, such as BRCA1 and BRCA2 for breast, ovarian cancer and pancreatic.

Within a few years, theunicorn, along with 23andMe and other companies, shattered patient barriers to cancer screening not previously possible by offering low-cost, over-the-counter home test kits that could illuminate key genetic risk factors.

Using AI for a new decision support service that empowers PCPs to get their patients with cancer into treatment faster is a budding area in healthcare AI where automating physician note-taking and reducing clinical administrative burden have made up the majority of mainstream LLM use cases.

However, applying machine learning to health data is amajor opportunityto enhance health outcomes for individuals and populations.

AI could be instrumental in disease management, said Xin Wang, assistant professor in the University at Albany department of epidemiology and biostatistics.

"By analyzing patient data over time, AI algorithms can predict individual patient risks, suggest personalized treatment plans and even alert healthcare providers to early signs of complications," he toldHealthcare IT Newsin January.

"This proactive approach can lead to earlier interventions, better disease management and, ultimately, improved health outcomes."

ON THE RECORD

"We see a perfect fit for AI technology, for language models," Brad Lightcap, OpenAIs chief operating officer, said in theWSJstory. "They can give clinicians more tools to understand medical records, to understand data, to understand labs and diagnostics."

Andrea Fox is senior editor of Healthcare IT News. Email:afox@himss.org Healthcare IT News is a HIMSS Media publication.

The HIMSS AI in Healthcare Forum is scheduled to take place September 5-6 in Boston.Learn more and register.

Continue reading here:
Color Health uses OpenAI to develop cancer screening copilot for doctors - Healthcare IT News

Recommendation and review posted by Bethany Smith

Bone marrow transplantation reduces FGF-23 levels and restores bone formation in myelodysplastic neoplasms … – Nature.com

June 25th, 2024

Myelodysplastic neoplasms (MDS) are hematopoietic stem cell disorders characterized by ineffective hematopoiesis and dysplastic cells in the bone marrow (BM) [1]. In addition, patients with MDS display an increased susceptibility to osteoporosis [2]. Evidence points towards dysregulation in the BM niche that concurrently impairs bone turnover and hematopoiesis. We identified fibroblast growth factor (FGF)-23 as a critical regulator of bone mineralization and erythropoiesis. FGF-23 serum levels were higher in both patients and mice with MDS, and its neutralization resulted in improved erythropoiesis and bone mineralization in NUP98/HOXD13 (NHD13) mice [3]. FGF-23 is mainly produced by osteoblasts/osteocytes [4] and exerts phosphaturic effects leading to poor bone mineralization [5]. However, in NHD13 mice, intact FGF-23 (iFGF-23) and C-terminal FGF-23 (cFGF-23; produced by the cleavage of the intact form) protein levels were unchanged in the bone tissue, but erythroid progenitors secreted more FGF-23 compared to littermate wild-type (WT) controls (Fig.S1A, B).

Here, we tested the hypothesis that erythroid precursors contribute to increased FGF-23 production/cleavage in MDS as a cause for impaired erythropoiesis and bone mineralization. To that end, we used BM transplantation as a first approach to substitute myelodysplastic erythroblasts with healthy ones in NHD13 mice. Four months after the BM transplantation, all mice that received the NHD13 BM showed MDS-like symptoms. In WT recipients, a reduction in hemoglobin levels [32%; p<0.001], platelets [20%; p<0.05], and lymphocytes [71%; p<0.001], but not in neutrophils or monocytes was observed compared to WT controls (transplanted with WT BM), showing a similar MDS status as NHD13 controls. In turn, NHD13 mice transplanted with WT BM did not develop MDS during the observation period. Compared to NHD13 controls, blood count reached normal levels [hemoglobin: +22%; p<0.001; platelets: +26%; p<0.05; lymphocytes: +6.5-fold; p<0.001; neutrophils: +2-fold; p<0.001] (Fig.1AE). This confirms that the MDS blood phenotype is transferable via hematopoietic cells. In line with NHD13 mice only showing increased cFGF-23 levels, but normal serum levels of iFGF-23 [3], the transplantation of WT or NHD13 BM into either WT or NHD13 recipient mice did not alter iFGF-23 (Fig.1F). In contrast, cFGF-23 was increased in all recipients of NHD13 BM [WT: +3.5-fold; p<0.05; NHD13: +2.1-fold; p<0.01] compared to the corresponding mice with WT BM (Fig.1G). Because of the transferable FGF-23 status, we hypothesized that WT mice receiving NHD13 BM would exhibit a bone phenotype mimicking the NHD13 controls. That was the case regarding the increased bone formation parameters usually observed in NHD13 mice. Similar to NHD13 mice, WT mice receiving NHD13 BM showed an increased number of osteoblasts [+95%; p<0.001] concomitant with elevated levels of the bone formation marker procollagen type I N-propeptide [+45%; p<0.05] and an increased bone formation rate [+87%; p<0.01] (Fig.1HJ). Also, the osteoid surface per bone surface tended to be increased [+44%; p=0.056] (Fig.1K). Importantly, transplanting WT BM to NHD13 mice normalized their bone formation parameters (Fig.1HK), indicating that hematopoietic cell signals control bone formation in NHD13 mice.

Eigth-week-old male wild-type (WT) and NUP98/HOXD13 (NHD13) mice were lethally irradiated one day before 2106 total bone marrow cells of age-matched WT (WT BM) or NHD13 (NHD13 BM) donor mice were transplanted by intravenous injection. After 16 weeks all mice were sacrificed and analyzed. The blood count, (A) hemoglobin levels (WT BMWT: n=9; NHD13 BMWT: n=9; WT BMNHD13: n=14; NHD13 BMNHD13: n=8), (B) platelet number (WT BMWT: n=8; NHD13 BMWT: n=8; WT BMNHD13: n=14; NHD13 BMNHD13: n=7) as well as the number of (C) neutrophils, (D) lymphocytes (WT BMWT: n=8; NHD13 BMWT: n=8; WT BMNHD13: n=14; NHD13 BMNHD13: n=8), and (E) monocytes (WT BMWT: n=8; NHD13 BMWT: n=7; WT BMNHD13: n=15; NHD13 BMNHD13: n=7) were received using the Sysmex XN-100 (Sysmex, Norderstedt, Germany). After collecting the serum, (F) the intact (WT BMWT: n=9; NHD13 BMWT: n=8; WT BMNHD13: n=14; NHD13 BMNHD13: n=9) as well as (G) C-terminal fibroblast growth factor (FGF)-23 (WT BMWT: n=8; NHD13 BMWT: n=6; WT BMNHD13: n=13; NHD13 BMNHD13: n=8) were measured by ELISA. (H) The osteoblasts per bone perimeter were evaluated in TRAP-stained vertebral bone slices (WT BMWT: n=9; NHD13 BMWT: n=9; WT BMNHD13: n=14; NHD13 BMNHD13: n=9) and (I) the osteoblast activity was assessed by procollagen type I N-propeptide (P1NP) using ELISA (WT BMWT: n=8; NHD13 BMWT: n=9; WT BMNHD13: n=14; NHD13 BMNHD13: n=9). J To determine the bone formation rate in vertebrae, mice received intraperitoneal calcein injection 5 and 2 days before sacrifice for the double labeling analysis (WT BMWT: n=9; NHD13 BMWT: n=6; WT BMNHD13: n=13; NHD13 BMNHD13: n=6). K Embedded vertebrae were stained with von Kossa/van Gieson to determine the osteoid surface per bone surface (WT BMWT: n=6; NHD13 BMWT: n=8; WT BMNHD13: n=14; NHD13 BMNHD13: n=5). Data are shown as meanSD of five independent experiments. Statistical analysis was performed by two-sided Students t test. *p<0.05; **p<0.01; ***p<0.001.

To address whether stem cell transplantation (SCT) leads to similar changes in FGF-23 in patients with MDS, we employed samples from the BoHemE study, in which we previously confirmed the high plasma iFGF-23 and cFGF-23 levels in patients with MDS [3]. Within this cohort, we identified 10 patients with MDS (3 women, 7 men; median age: 64 years; without renal disease) who had undergone SCT. We analyzed their hematological and bone-specific parameters before (range: 16 months) and after SCT (range: 511 months). SCT led to a higher number of red blood cells in 9/10 patients, neutrophils in 9/10 patients, and lymphocytes in 6/10 patients with normal monocyte counts. Platelet counts were below the reference range in 8/10 patients and higher in 1/10 patients before SCT, but only 4 patients had persistent thrombocytopenia after SCT (Figs.2A, S2AD). Before SCT, 5 patients showed elevated cFGF-23 plasma levels, which were normalized after SCT (Fig.2B). Elevated iFGF-23 levels were observed in 2 patients before SCT, with levels decreasing post-SCT. However, after SCT, iFGF-23 levels slightly increased in all patients with normal baseline levels (Fig.2C). Additionally, 7/10 patients had reduced osteocalcin levels (bone formation) before SCT, though this did not result in abnormal bone mineral density (BMD) (Fig.2D, TableS1). Given that bone mineralization is impaired in MDS [3], we also analyzed albumin-adjusted calcium, phosphate, and bone-specific alkaline phosphatase (BSAP). Calcium levels were reduced in 2/5 patients with elevated cFGF-23 and normalized after SCT (Fig.2E). All patients with normal cFGF-23 had calcium levels within the reference range, with only one showing reduced levels of phosphate, which were corrected by the SCT. Whereas 3/5 patients with high cFGF-23 had mild to moderate hypophosphatemia before SCT, only one remained hypophosphatemic after SCT (Fig.2F). In line with the increase of serum phosphate, BSAP levels, the major regulator of bone mineralization, also increased after SCT with high cFGF-23 (determined in 3/5 patients only, Fig.S2E). In addition, we analyzed 10 BM plasma samples regarding cFGF-23 and iFGF-23 levels in a separate set of patients with MDS (4 women, 6 men; median age: 57 years; TableS2). Since the samples were collected relatively shortly after SCT (range: 28 months), it is not surprising that the number of red blood cells was equal or decreased after SCT in 4/9 patients (data from one patient are not evaluable) compared to the basal levels (Fig.2G). In line with our previous observations, before SCT 5/10 patients had elevated cFGF-23 levels, which normalized after SCT. In patients with normal baseline cFGF-23, levels were either slightly increased (1/5 patients) or decreased (2/5) after SCT (Fig.2H). Before SCT, all patients had normal iFGF-23 levels. The SCT led to an increase in 6/10 patients and a decrease in 4/10 patients independently of the basal iFGF-23 levels (Fig.2I). Overall, the regulation of cFGF-23 in blood and BM plasma samples from patients with MDS after SCT suggests that BM cells are a source for cFGF-23 in MDS. This is supported by the transplantation of NHD13 BM cells, which causes the increase of cFGF-23 levels leading to impaired erythropoiesis and bone mineralization. Only erythroid precursors of NHD13 mice show a high Fgf23 expression, but myeloid cells and megakaryocytes do not (Fig.S1C, D). The question remains why and how cFGF-23 levels are increased in MDS. The expression of Galnt3 and Fam20c, which stabilize or mark FGF-23 for cleavage [6, 7], was normal in NHD13 erythroid precursors (Fig.S1E, F), indicating that these cells do not directly contribute to the increased cleavage of erythroid-derived FGF-23. Therefore, other signals or cells within the bone microenvironment or beyond may participate in this regulation. In line with this, it has been shown that FGF-23 production/cleavage can be triggered by erythropoietin, iron deficiency, anemia, and inflammation [8,9,10], factors that also play a role in MDS [11, 12]. While iron serum levels are unchanged in NHD13 mice, erythropoietin is upregulated. Since erythropoietin can affect FGF-23 production/cleavage in WT erythroid cells [8], this may be a possible regulator also in NHD13 mice. The whole inflammatory status of NHD13 mice has not been described yet, suggesting that inflammation and/or anemia might be drivers of cFGF-23 in NHD13 mice as well. The production of cFGF-23 is increased by inflammation, inhibits hepcidin induction in the liver, and increases iron bioavailability independent of the functions of iFGF-23 [10]. This scenario may hold true for MDS as it is also characterized by inflammation (and anemia) and may require high levels of cFGF-23 to provide enough iron for erythropoiesis. In our human cohorts, not all patients with MDS showed elevated cFGF-23 levels, and not all patients with elevated cFGF-23 showed dysregulations of iron or inflammation (TableS1). All patients with elevated cFGF-23 however did have anemia. MDS is a heterogeneous group of disorders. As NHD13 mice mimic a severe form of MDS with a high percentage of blasts in the bone marrow and a high propensity to transformation towards acute leukemia [13], we included patients with intermediate to very high-risk MDS in our cohorts and indicated their mutations. Analyzing the mutational landscape in patients with MDS might further allow assumptions on the underlying mechanisms leading to increased cFGF-23 levels. Mutations like TET2, DNMT3A, ASXL1, RUNX1, SF3B1, and SRSF2 are linked to increased responses to inflammatory stimuli [12, 14], and Tet2 or Dnmt3a deficiency causes bone loss in mice due to increased osteoclastogenesis [15]. In our blood plasma cohort, 4/5 patients with elevated cFGF-23 carried a mutation in at least one of these genes. However, 2/5 patients with normal cFGF-23 also had these mutations, but they received the MDS diagnosis a month earlier only. It is conceivable that the cFGF-23 levels increase after some time. Future research is needed to determine whether any of these mutations contribute to high cFGF-23 levels. In summary, we show that the high serum cFGF-23 levels in MDS originate from the BM and that BM transplantation/SCT can reduce cFGF-23 levels and its associated negative effects on erythropoiesis and bone mineralization. Future studies need to validate these findings in humans and address why cFGF-23 levels are increased in MDS.

The hematological and plasma parameters of patients with MDS were analyzed before and after allogeneic stem cell transplantation (SCT) in blood (AF) and bone marrow samples (GI). A, G The number of red blood cells was determined by the Sysmex XN-100 (Sysmex, Norderstedt, Germany). B, H C-terminal fibroblast growth factor (FGF)-23, (C, I) intact FGF-23, as well as (D) osteocalcin, were determined in plasma samples and in serum (E) albumin-adjusted calcium levels, as well as (F) phosphate levels, were measured by ELISA. n=10 except (G) n=9. The grey boxes in the graphs mark the reference range of healthy individuals. In all graphs, each dot represents a patient with MDS, and the values from the same patient are connected by a line (normal C-terminal FGF-23 before SCT, n=5) or dotted line (high C-terminal FGF-23 before SCT, n=5).

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Bone marrow transplantation reduces FGF-23 levels and restores bone formation in myelodysplastic neoplasms ... - Nature.com

Recommendation and review posted by Bethany Smith

Allogeneic HSCT for Myelofibrosis: What to Know as More Patients Receive Treatment – Physician’s Weekly

June 25th, 2024

Photo Credit: Wildpixel

Authors of a recent review provide updates on stem cell transplants for myelofibrosis, with an emphasis on managing graft versus host disease and relapse.

Due to new transplant approaches, allogeneic hematopoietic stem cell transplant (HSCT) is now perceived as a safer therapeutic option in patients with myelofibrosis, even among older patients. Authors of a review published in the American Journal of Hematology emphasized the crucial role of early consideration and implementation of HSCT in improving clinical outcomes in this patient population.

Despite the approval of new therapies and various other exciting non-transplant treatments in development, allogeneic HSCT remains at present the only curative therapy for patients with myelofibrosis, wrote coauthors Haris Ali, MD, and Andrea Bacigalupo, MD.

The challenges associated with treating myelofibrosis include transplant-related mortality and the risk for relapse after HSCT. The authors aimed to provide a comprehensive review of current clinical data, new transplant platforms, and clinical updates, which can enhance patient outcomes.

The number of patients undergoing an allogeneic HSCT annually is steadily increasing, Dr. Ali and Dr. Bacigalupo wrote. This reflects the fact that HSCT has become safer with the reduction in non-relapse mortality over the years, making the choice of an HSCT more attractive among hematologists caring for [patients with myeloproliferative neoplasms].

Prior to HSCT, clinicians should conduct an in-depth assessment of organ functions, including cardiac, pulmonary, hepatic, and renal functions, as established by their institutions predefined criteria. This evaluation ensures that patients can withstand the possible physiological stresses of the transplant process, such as toxicity of the conditioning regimen, increased risk of infection, graft versus host disease (GVHD), and cytopenia. Patients should also undergo a detailed psychosocial assessment, which is an integral component of this process.

Following a thorough physical examination, we need to assess whether the patients disease justifies the risk from an allogeneic HSCT. Several prognostic scoring systems have been developed over the past years to identify patients who are likely to progress and are therefore at higher risk of morbidity and mortality, the authors explained.

The dynamic international prognostic scoring system is the most widely used prognostic tool for patients with myelofibrosis. Clinicians should account for patient age, as there are limited outcomes data regarding HSCT in patients with myelofibrosis who are aged 70 years or older.

The review offered information about approaches to managing splenomegaly and pretransplant treatment, recommended conditioning regimens, post-transplant outcome prediction models, recommendations for sourcing stem cells (eg, bone marrow, peripheral blood, cord blood), and criteria for selecting stem cell donors.

The authors provided protocol recommendations for preventing GVHD, managing patients with blast and accelerated phase myelofibrosis, and monitoring for disease markers. They also recommended monitoring driver mutations and early clinical intervention with cellular therapy to treat relapse. They also provided guidance for cases of hematologic reconstitution and graft failure.

The treatment is different according to the degree of donor chimerism: in patients who show mixed donor or only host-derived cells, the graft has failed completely, and the only solution is an early second transplant. On the other hand, if complete donor chimerism is present, then a boost of CD34 positive cells from the same donor, without conditioning regimen, can rescue over 70% of patients, Dr. Ali and Dr. Bacigalupo explained.

Myelofibrosis is a nuanced disease that often bears a significant transfusion burden and an unfavorable marrow environment, and early selection of patients for HSCT is critical to enhancing transplant outcomes.

HSCT in myelofibrosis is becoming safer due to new transplant strategies and is even offered in older patients. Early consideration of HSCT in patients with myelofibrosis is the key to the success of the transplant, Dr. Ali and Dr. Bacigalupo concluded.

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Allogeneic HSCT for Myelofibrosis: What to Know as More Patients Receive Treatment - Physician's Weekly

Recommendation and review posted by Bethany Smith

Life After Sickle Cell: A Seven-Year-Old Was Cured Of The Disease Thanks To Her Younger Sister – Essence

June 25th, 2024

Today is World Sickle Cell Disease Day. The international awareness day is observed annually to increase public knowledge and an understanding of sickle cell disease and the challenges experienced by patients, their families, and caregivers. According to the CDC, Sickle cell disease (SCD) affects about 100,000 people in the United States; more than 90% are non-Hispanic Black or African Americans. The estimated life expectancy of those with SCD in the United States is more than 20 years shorter than the average expected. Sickle cell disease is an inherited blood disorder that affects red blood cells. People with sickle cell disease have red blood cells that contain mostly hemoglobin S, an abnormal type of hemoglobin.

Sometimes, these red blood cells become sickle-shaped (crescent-shaped) and have difficulty passing through small blood vessels. When sickle-shaped cells block small blood vessels, less blood can reach that body part. The tissue that does not receive normal blood flow eventually becomes damaged. However, the FDA approved a new sickle cell disease treatment in December 2023. The treatment is called Casgevy, the first medicine approved in the United States that uses CRISPR, a gene editing tool from Vertex Pharmaceuticals and CRISPR Therapeutics. In May 2024, a 12-year-old Black boy, Kendric Cromer, who suffered debilitating pain because of sickle cell disease, became the first patient in the United States to undergo a newly approved gene therapy.

Sickle cell disease has no specific age and affects children like Cali Cole, who was born with the disease and was miraculously cured at four years old, thanks to the help of her younger sister, who is now four. Kendra Cole shared with ESSENCE that her daughter Cali was born with sickle cell disease and received a bone marrow transplant on April 1, 2021, at four years old, curing her of sickle cell disease, thanks to a stem cell donation from her 18-month-old sister Reign (who we had through a year-long process of in-vitro fertilization). The family of five, Kendra, her husband, Lord Cole, and her three children (Cali, Reign, and Valor), bonded to brave through a timeline of medical events relating to sickle cell disease. In 2016, Kendra and Lord began family planning, knowing they wanted to grow their family. Through family planning, they decided to participate in genetic testing, where Kendra learned she had sickle cell trait.

In 2017, their first child, Cali, was born, and the familys medical team at Lurie Childrens Hospital in Chicago, Illinois, informed them that Cali had sickle cell disease, which was determined through newborn screening. From 2017-2021, Cali experienced the following complications due to sickle cell include: Splenic sequestration, Multiple pain crises, Dactylitis, Acute chest syndrome, Extreme constipation, Kidney damage, and Abnormal TCD brain scan results. At the end of 2017, the Cole family feverishly checked the Be the Match bone marrow registry for a potential match and did not find one, so they decided to try another child via IVF to see if it could be a bone marrow match. In 2018, Kendra began the IVF process again, and Reign was born in 2019. In 2021, the Cole family decided to move forward with the bone marrow transplant via stem cell donation of Reign. While Reign and Valor dont have sickle cell disease, they are susceptible to the trait.

Although now Cali is three years post-transplant with no complications and is living a happy, healthy life, sickle cell-free, her family remembers the toll sickle cell disease had on all of them. We spoke with Kendra to understand sickle cell diseases impact on her, her husband, and her children.

ESSENCE: Can you speak to your experience as a caregiver?

Kendra Cole: There were so many moments where there were high highs and lows. Any person who any parent who has a child, you know, they love them with every ounce of your being. At the same time, I felt immense guilt for not knowing my trait status. I often thought to myself, how could I have decided to bring a child into the world and have her experience so much pain early on in her life? I think there were many times throughout those first four years of her life that I felt like I was almost operating in survival mode a little bit. I wouldnt allow myself to be fully vulnerable with my daughter as her mother because I genuinely was just so afraid. But there were so many hospital days where I had to put on a brave face, be calm, and make these tough decisions within an emotionally charged atmosphere.

How can we be more of sickle cell disease in our community?

Sickle cell disease is an inherited blood disorder, so its not something that you can see. And pain is often subjective, right? So its painful to one person and may or may not be that painful to someone else.

Can you speak to the importance of Gene therapy?

Ive been excited about many new developments, specifically gene therapy. Gene therapy is a great advancement in sickle cell disease care and curative options, and there just hasnt been much movement on that in years.

How are you continuing to spread awareness?

Im still active in my local Sickle Cell Disease Association of Illinois chapter, whether through the parent group or our annual awareness walk. Ive also been in contact with several parents whose children want to undergo the bone marrow transplant process. Ive connected with many families and just offered them our story, support, and checking in with them.

Read the original here:
Life After Sickle Cell: A Seven-Year-Old Was Cured Of The Disease Thanks To Her Younger Sister - Essence

Recommendation and review posted by Bethany Smith

Hematopoietic stem cell transplantation (HSCT) Market Future Growth Trends, Upcoming Opportunities and … – openPR

June 25th, 2024

Latest Report, titled "Hematopoietic stem cell transplantation (HSCT) Market" Trends, Share, Size, Growth, Opportunity and Forecast 2024-2031, by Coherent Market Insights offers a comprehensive analysis of the industry, which comprises insights on the market analysis. The report also includes competitor and regional analysis, and contemporary advancements in the market.

The report features a comprehensive table of contents, figures, tables, and charts, as well as insightful analysis. The keyword market has been expanding significantly in recent years, driven by various key factors like increased demand for its products, expanding customer base, and technological advancements. This report provides a comprehensive analysis of the Hematopoietic stem cell transplantation (HSCT) market, including market size, trends, drivers and constraints, competitive aspects, and prospects for future growth.

The report sheds light on the competitive landscape, segmentation, geographical expansion, revenue, production, and consumption growth of the Hematopoietic stem cell transplantation (HSCT) market. The keyword Market Size, Growth Analysis, Industry Trend, and Forecast provides details of the factors influencing the business scope. This report provides future products, joint ventures, marketing strategy, developments, mergers and acquisitions, marketing, promotions, revenue, import, export, CAGR values, the industry as a whole, and the particular competitors faced are also studied in the large-scale market.

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Key Players Covered In This Report:

Pluristem Therapeutics Inc. CellGenix GmbH Regen Biopharma Inc. Lonza Group Kiadis Pharma Taiga Biotechnologies Inc. Takeda Pharmaceutical Company Limited Escape Therapeutics Inc. Bluebird Bio Inc. Talaris Therapeutics Inc. Marker Therapeutics Inc. Stempeutics Research Pvt Ltd. CBR Systems Inc. Priothera Ltd. Eurobio Scientific Group Otsuka America Pharmaceutical Inc. Pfizer Inc. Sanofi FUJIFILM Holdings Corporation

This Report includes a company overview, company financials, revenue generated, market potential, investment in research and development, new market initiatives, production sites and facilities, company strengths and weaknesses, product launch, product trials pipelines, product approvals, patents, product width and breath, application dominance, technology lifeline curve. The data points provided are only related to the company's focus related to Hematopoietic stem cell transplantation (HSCT) markets. Leading global Hematopoietic stem cell transplantation (HSCT) market players and manufacturers are studied to give a brief idea about competitions.

Market Segmentation:

By Transplant Type: Allogeneic, Autologous By Indication: Acute Myeloid Leukemia (AML), Acute Lymphoblastic Leukemia (ALL), Hodgkin lymphoma (HL), Non-Hodgkin Lymphoma (NHL), Multiple Myeloma (MM), Others By Application: Bone Marrow Transplant (BMT), Peripheral Blood Stem Cells Transplant (PBSCT), Cord Blood Transplant (CBT) By End User: Hospitals, Specialty Clinics, Others

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This report is centred around the Hematopoietic stem cell transplantation (HSCT) in the worldwide market, with a specific focus on North America, Europe, Asia-Pacific, South America, Middle East, and Africa. The report classifies the market by manufacturers, regions, type, and application. It presents a comprehensive view of the current market situation, encompassing historical and projected market size in terms of value and volume. Additionally, the report covers technological advancements and considers macroeconomic and governing factors influencing the market.

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Questions Answered by the Report:

(1) Which are the dominant players of the Hematopoietic stem cell transplantation (HSCT) Market? (2) What will be the size of the Hematopoietic stem cell transplantation (HSCT) Market in the coming years? (3) Which segment will lead the Hematopoietic stem cell transplantation (HSCT) Market? (4) How will the market development trends change in the next five years? (5) What is the nature of the competitive landscape of the Hematopoietic stem cell transplantation (HSCT) Market? (6) What are the go-to strategies adopted in the Hematopoietic stem cell transplantation (HSCT) Market?

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Ravina Pandya, Content Writer, has a strong foothold in the market research industry. She specializes in writing well-researched articles from different industries, including food and beverages, information and technology, healthcare, chemical and materials, etc. (https://www.linkedin.com/in/ravina-pandya-1a3984191)

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Hematopoietic stem cell transplantation (HSCT) Market Future Growth Trends, Upcoming Opportunities and ... - openPR

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‘General Hospital’ star John J York returns to work after ‘aggressive’ cancer treatment – Yahoo Entertainment

June 25th, 2024

"General Hospital" star John J. York got emotional while recounting his long cancer battle.

York, who announced his hiatus from the hit soap opera in September, was a guest on "Good Morning America" and explained that a number of people signed up to donate bone marrow after he announced his cancer diagnosis.

"Everybody has been very welcoming, very supportive," York said before beginning to cry. "And here I go already right off the top cause I cant tell you how nice its been, the support that Ive gotten."

'GENERAL HOSPITAL' ACTOR JOHNNY WACTOR'S KILLER AT LARGE, LAPD SHARES NEW DETAILS ABOUT THREE SUSPECTS

After a routine check-up in December 2022, York was diagnosed with two types of blood and bone marrow cancer: myelodysplastic syndrome and smoldering multiple myeloma.

According to the Mayo Clinic, myelodysplastic syndrome is "a group of disorders caused by blood cells that are poorly formed or don't work properly. Myelodysplastic syndromes result from something amiss in the spongy material inside your bones where blood cells are made (bone marrow)."

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The Mayo Clinic describes smoldering multiple myeloma as a form of multiple myeloma that does not always cause symptoms, explaining "If the myeloma is at an early stage and is growing slowly, you might have regular checkups to monitor the cancer."

"I made the announcement and it has helped. And so many people have joined the registry, just to help to save someone's life," York said, taking a pause in the middle of the statement as he continued to get emotional.

Due to both of York's diagnoses, he required a bone marrow transplant.

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The actor had to undergo seven days of chemotherapy at Vanderbilt University in Tennessee before he was allowed to get on a flight to Los Angeles to film "General Hospital." His first episode back will air on June 19.

After York was told he would have "3-5 years" if he did not undergo treatment, he decided to go the most "aggressive" route by getting a bone marrow transplant and chemotherapy.

"My philosophy was always, One day at a time, lets just get through today,'" he said. "I made the announcement, and it has helped and so many people have joined the registry just to help save someones life."

It took some time for York to find a stem cell donor. He recalled on "Good Morning America" the moment he found a donor.

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"She said we found an exact match and I just couldnt talk," York said. "Its just a little bag of blood and fluid, and they put it in my body, 40 minutes later, and now Im this person."

York explained that his cells are "now fighting each other and battling each other and getting to know each other."

"And here we are, back to work," he added. John has appeared on "General Hospital" since 1991.

York's hiatus from the show didn't feel very long to him, but rather felt like he "had a little break."

Original article source: 'General Hospital' star John J York returns to work after 'aggressive' cancer treatment

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'General Hospital' star John J York returns to work after 'aggressive' cancer treatment - Yahoo Entertainment

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Takeaways from AP’s report on access to gene therapies for rare diseases – Yahoo News Canada

June 25th, 2024

The promise of gene therapy looms large for families dealing with rare, genetic disorders. Such treatments offer the possibility of one-time cures.

But families and researchers worry such therapies will remain out of reach.

Collectively, about 350 million people worldwide suffer from rare diseases, most of which are genetic. But each of the 7,000 individual disorders affects perhaps a few in a million people or less. So theres little commercial incentive to develop or bring to market these one-time therapies to fix faulty genes or replace them with healthy ones.

The Associated Press examined what this means for families, scientists and the nascent field of gene therapy.

Here are key takeaways from AP's report.

Families are frustrated, and some try to raise their own funds.

Camden Alderman was diagnosed as a baby with a rare disease called Wiskott-Aldrich syndrome, which is caused by a mutated gene on the X chromosome. It primarily affects boys up to 10 out of every million and can cause frequent infections, eczema and excessive bleeding.

When he was a toddler, doctors removed his spleen because of uncontrolled bleeding. As a young boy, he wound up in the hospital many times and was told he couldnt play baseball.

His mother Robin Alderman recalls one doctor saying: Basically, your sons only chance at a cure is going to be gene therapy.

He also told her researchers werent then accepting U.S. residents into a clinical trial for the treatment, which just kind of broke my heart, she said. There's still no clinical trial he can join, and London-based Orchard Therapeutics stopped investing in an experimental treatment for the condition in 2022.

Lacey Hendersons daughter, 5-year-old Estella, has alternating hemiplegia of childhood, a neurological condition that affects 300 people in the U.S. Estella is cognitively delayed, has limited use of her hands and suffers episodes that temporarily paralyze part or all of her body, Henderson said. Medications can curb symptoms, but theres no cure.

Her Iowa family raises money through a GoFundMe and a website to develop a gene therapy. Theyve brought in around $200,000.

We have three different projects with various researchers, Henderson said. But the problem is everything is underfunded.

Financial disincentives can plague the process.

The amount of work it takes to get from a lab to human testing and through the drug approval process is incredibly expensive, said Dr. Donald Kohn, professor of microbiology, immunology and molecular genetics at the University of California, Los Angeles.

In the last couple of years, he said, investment in gene therapy has largely dried up.

If you have to spend $20 million or $30 million to get approval and you have five or 10 patients a year, its hard to get a return on investment, Kohn said. So we have successful, safe therapies, but its more the financial, economic elements that are limiting them from becoming approved drugs."

Ultimately, most biotechnology companies become public and must focus on shareholder profit, said Francois Vigneault, CEO of the Seattle biotech Shape Therapeutics.

The board is the thing that gets in the way; theyre trying to maximize gain, said Vigneault, whose company is privately held. Thats just greed. Thats just incentive misaligned between corporate company structure and what we should do thats good for the world.

Scientists, nonprofits and patient groups are working toward solutions.

In the U.S., for example, The Bespoke Gene Therapy Consortium was organized by the Foundation for the National Institutes of Health and includes the FDA, various NIH institutes and several drug companies and nonprofits. Its goals include supporting a handful of clinical trials and streamlining regulatory processes.

Researchers are trying to address the problem scientifically. Dr. Anna Greka said the Broad Institute of MIT and Harvard has launched an effort to look at the commonalities behind various conditions or nodes, which can be likened to branches meeting at a tree trunk. Fixing the nodes with gene therapies or other treatments, rather than particular misspellings in DNA responsible for one disorder, could potentially address multiple diseases simultaneously.

What this does is it increases the number of patients who can benefit from the therapy, said Greka, a Broad member.

Still, scientists say these efforts dont negate the larger financial quandary surrounding therapies for rare diseases, and it may be a while before such gene therapies are available to patients worldwide.

This is a massive challenge, and Im not entirely sure were going to be able to overcome it, said Claire Booth of University College London. But we have to give it a go because weve spent decades and millions making these transformative treatments. And if we dont try, then it feels like the end of an era.

___

The Associated Press Health and Science Department receives support from the Howard Hughes Medical Institutes Science and Educational Media Group. The AP is solely responsible for all content.

Laura Ungar, The Associated Press

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Tunable translation-level CRISPR interference by dCas13 and engineered gRNA in bacteria – Nature.com

June 25th, 2024

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U.S. CRISPR And Cas Genes Market Size to Hit USD 8.59 Billion by 2033 – BioSpace

June 25th, 2024

According to latest report, the U.S. CRISPR and cas genes market size was estimated at USD 1.85 billion in 2023 and is projected to hit around USD 8.59 billion by 2033, growing at a CAGR of 16.6% during the forecast period from 2024 to 2033.

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Therapeutic applications of CRISPR and Cas genes, rising significance for gene editing, and the introduction of anti-CRISPR proteins are boosting market growth. Moreover, CRISPR and Cas genes provide growth prospects for developing novel cancer therapies that boost market expansion.

U.S. CRISPR and Cas genes market accounted for a 63.0% share in the global CRISPR and Cas genes market in 2023. CRISPR technology is preferred for treating various diseases, including cancer and inflammatory and infectious diseases, making it favorable for future biomedical therapeutics. It revolutionizes cancer treatment by enhancing Chimeric Antigen Receptor T-cell (CAR-T) immunotherapy. Unlike traditional methods, the next generation of CAR-T therapies utilizes CRISPR to improve the precision and efficiency of therapeutic and manufacturing processes. This advancement allows for accurate delivery of CAR genes into T-cell DNA, a significant improvement over viral vectors that randomly insert genes. These features of CRISPR-Cas increase its demand in the market.

Furthermore, the increasing investment from government bodies, funding agencies, and biotechnology companies in genomic research is poised to impact the CRISPR market significantly. International funding organizations such as the NIH and Wellcome Trust play a crucial role by providing financial support for genetic studies. This substantial funding is expected to drive the utilization of genetic editing tools in the country, shaping the landscape of the CRISPR market. Furthermore, a report published in June 2022 stated that the U.S. government granted USD 639.5 million to Human Genome Research Institute for R&D in 2022. The institute further requested USD 629.6 million as funding for 2023.

U.S. CRISPR And Cas Genes Market Key Takeaways

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Global CRISPR & Cas Genes Market Size and share 2024 to 2033

The global CRISPR And Cas Genes market size was USD 3.11 billion in 2023, calculated at USD 3.64 billion in 2024 and is expected to reach around USD 15.15 billion by 2033, expanding at a CAGR of 17.16% from 2024 to 2033. North America dominated the market and accounted for the highest revenue share of 39.17% in 2023.

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What is CRISPR, the powerful genome-editing tool?

CRISPR-Cas9 is a simple yet powerful tool for editing genomes. It enables researchers to easily alter DNA sequences and modify gene function.

CRISPR is a powerful tool for editing genomes, meaning it allows researchers to easily alter DNA sequences and modify gene function. It has many potential applications, including correcting genetic defects, treating and preventing the spread of diseases, and improving the growth and resilience of crops. However, despite its promise, the technology also raises ethical concerns.

In popular usage, "CRISPR" (pronounced "crisper") is shorthand for "CRISPR-Cas9." CRISPRs are specialized stretches of DNA, and the protein Cas9 where Cas stands for "CRISPR-associated" is an enzyme that acts like a pair of molecular scissors, capable of cutting strands of DNA.

CRISPR technology was adapted from the natural defense mechanisms of bacteria and archaea, a domain of relatively simple single-celled microorganisms. These organisms use CRISPR-derived RNA, a molecular cousin to DNA, and various Cas proteins to foil attacks by viruses. To foil attacks, the organisms chop up the DNA of viruses and then stow bits of that DNA in their own genome, to be used as a weapon against the foreign invaders should those viruses attack again. When the components of CRISPR are transferred into other, more complex, organisms, those components can then manipulate genes, a process called "gene editing."

U.S. CRISPR And Cas Genes Market Concentration & Characteristics

The presence of several companies in the U.S. CRISPR And CAS Genes market contributed to its fragmented landscape. Moreover, companies are leveraging CRISPR editing in the human genome, offering growth opportunities in academic and pharmaceutical research.

By introducing innovative CRISPR-based therapies, companies have the potential to attract customers, drive revenue growth, and enhance patient outcomes significantly. Utilizing CRISPR technology in the development of advanced therapies can assist companies in differentiating themselves in the market, meet patients' evolving requirements, and contribute to personalized medicine. This offers a promising path for using cutting-edge therapies and advancement in personalized medicine.

Companies like CRISPR Therapeutics, Vertex Pharmaceuticals, Intellia Therapeutics, and Regeneron Pharmaceuticals have engaged in strategic partnerships to drive innovation in precision medicine. These collaborations involve sharing resources, expertise, and technologies to develop novel treatments that target genetic disorders at their root cause. Numerous biotechnological and pharmaceutical companies focus on M&A activities that showcase crucial aspects of strategic management that enable companies to facilitate growth, restructuring, and enhancing competitive positions within the industry

Various biotechnology and CRISPR-based therapeutics companies focus on providing services such as cell line engineering and design tools that help in research activities undertaken by institutions and other companies. This approach increases their customer base and enables them to sustain their position in the industry.

Increasing focus on regional expansion by key manufacturers serves a wide range of customers and capitalizes on geographical industry growth opportunities. This approach allows companies to strengthen their presence in different regions, adapt to local market needs, and enhance their market share by targeting diverse customer segments.

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By Product & Service Insights

In 2023, the product segment held the largest market share of 79.11%. This growth was fueled by the efforts of institutions and key companies to increase research and development activities. This comprises kits& enzymes such as CAS9, CRISPR libraries, antibodies, design tools, and more. Moreover, Vector-based CAS9 products facilitate research experiments, signifying the use of CRISPR/Cas for gene editing. Such applications shift the focus of manufacturers to develop these products, further expanding market growth. Epic Bio unveiled the GEMS (Gene Expression Modulation System) platform in 2022, which offers precise gene expression modification. The GEMS platform contains a vast library of newly discovered modulators combined with advanced functional and computational genomics capabilities. It enables the rapid design of guide RNAs highly targeted to specific genes.

From 2024 to 2033, the services segment is expected to experience the most rapid compound annual growth rate. This growth is fueled by the rising number of licensing agreements with biotech firms, which offer services ranging from cell line engineering and beyond. Moreover, CRISPR-based gene editing companies focus on offering advanced services to fulfill the unmet demand for this market. For instance, in August 2022, Creative Biogene introduced one-stop microbial genome editing services for knock-in, knockout, and foreign gene insertion using a variety of bacteria. These microbial genome editing services maximize customers microbial gene sequence efficiency and minimize off-target effects using the advanced CRISPR/Cas 9 platform.

By Application Insights

The biomedical application segment held the largest share of 92.25% in 2023, owing to the increasing popularity of CRISPR/Cas9 genome editing technology in several areas of biomedical sciences. The market is experiencing profitable growth opportunities thanks to the emergence of different CRISPR-based therapies to treat chronic conditions such as cancer, diabetes, blood disorders, and infectious diseases. Moreover, regulatory approval of these therapies is driving the segments growth. For instance, in December 2023, the US FDA approved Casgevy therapy for sickle cell anemia. Casgevy is the first FDA-approved therapy utilizing CRISPR/Cas9, a genome editing technology.

The agriculture segment will exhibit the quickest compound annual growth rate (CAGR) between 2024 and 2033. The rise in awareness of CRISPR-based gene editing in the agriculture sector has led to increasing adoption improvement in crop production. There is an increase in research studies on agriculture products using CRISPR technology. This trend will expand the growth trajectory of this segment.

By End-use Insights

The biotechnology and pharmaceutical companies segment dominated the market with a share of 50.19% in 2023, owing to the increasing development of CRISPR-based products by major biotechnology and pharmaceutical companies for drug and therapy development. The growing adoption of CRISPR technology in these sectors significantly influences the market landscape and drives revenue growth. Additionally, the rise in the number of companies offering gene and gene-editing products and services in recent years is further fueling the revenue growth within this segment.

The academic and government research institutes are anticipated to grow at a CAGR of 16.1% over the forecast period. The increased research and numerous genomics and gene editing studies in academic and government institutes have increased the demand for CRISPR-Cas9. This surge in research activities focusing on gene engineering and its applications is anticipated to drive rapid growth in the forecast period.

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U.S. Gene Synthesis Market: The U.S. Gene Synthesis market size was valued at USD 700.90 million in 2023 and is projected to surpass around USD 3,118.73 million by 2033, registering a CAGR of 16.1% over the forecast period of 2024 to 2033.

U.S. Clinical Trials Market : The U.S. clinical trials market size was valued at USD 25.81 billion in 2023 and is projected to surpass around USD 41.57 billion by 2033, registering a CAGR of 4.88% over the forecast period of 2024 to 2033.

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U.S. CRISPR And Cas Genes Market Size to Hit USD 8.59 Billion by 2033 - BioSpace

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Seven CRISPR companies to watch in 2024 – Labiotech.eu

June 25th, 2024

CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) is a gene-editing technology that allows scientists to modify DNA with unprecedented precision. Discovered in the early 2010s, CRISPR technology leverages a natural defense mechanism used by bacteria to protect against viral infections. The system uses a guide RNA to direct the Cas9 enzyme to a specific location in the genome, where it creates a double-strand break. This break can then be repaired by the cells natural mechanisms, allowing for the addition, deletion, or modification of genetic material. CRISPR companies are seeing more and more success in the clinic and the market is growing.

CRISPR has rapidly become one of the most powerful tools in genetic engineering, enabling precise changes to the DNA. Its applications are not limited to medicine, which will be our focus in this article, as it also allows the creation of crops with desirable traits in agriculture for instance.

In recent years, the field of CRISPR technology has improved and different forms of the technology are now being leveraged by biotech companies. Prime editing and base editing are innovative CRISPR-related technologies aiming to improve the versatility and precision of therapies.

After CRISPR Therapeutics and Vertex Pharmaceuticals collaborative success leading to CASGEVYs approval by the U.S. Food and Drug Administration (FDA) and Editas Medicines promising efforts to treat blindness, here are eight companies keeping the CRISPR field dynamic.

Beam Therapeutics was founded in 2017, and is headquartered in Cambridge, Massachusetts. The CRISPR technology company develops precision genetic medicines using its proprietary base editing technology.

The company went public on NASDAQ in February 2020 and has raised a total of $689 million since its creation according to Crunchbase.

Beams base editing technology distinguishes itself by focusing on single-base alterations, which can correct mutations at the nucleotide level. This precision reduces the risk of off-target effects and enhances the potential for treating a wide range of genetic disorders. The companys base editing platform includes the REPAIR (adenosine to inosine) and RESCUE (cytosine to uracil) systems for RNA editing, enabling targeted genetic modifications.

Beam Therapeutics has several key candidates in various stages of development:

Eligo Bioscience is a French company founded in 2014. The company focuses on precision gene editing of the microbiome to treat diseases driven by bacterial genes. Eligo Bioscience leverages its proprietary Gene Editing of the Microbiome (GEM) platform to develop therapies that target and modify specific bacterial populations. Eligo Bioscience recently raised $30 million in a series B funding led by Sanofi Ventures.

The companys GEM platform uses engineered bacteriophages to deliver CRISPR-Cas systems directly to specific bacteria within the microbiome. This approach allows for the precise elimination of pathogenic bacteria or the correction of harmful bacterial genes without disrupting the overall balance of the microbiome. By targeting bacterial genes in vivo, Eligos technology aims to address various diseases associated with microbiome dysbiosis, including antibiotic-resistant infections and chronic diseases.

Unlike broad-spectrum antibiotics, which indiscriminately kill bacteria and disrupt the microbiome, Eligos technology selectively targets pathogenic bacteria or genes within the microbiome. This precision reduces collateral damage to beneficial bacteria which helps maintain a healthy microbiome.

In January, Xavier Duportet, chief executive officer (CEO) of the company, was our guest on the Beyond Biotech podcast to talk about its flagship product EB005 targeting acne vulgaris. This candidate is on track to reach the clinic and expand its application to oncology.

Founded in 2018 and headquartered in South San Francisco, California, Epic Bio is focused on developing therapies to modulate gene expression in vivo using its proprietary Gene Expression Modulation System (GEMS) platform. The company launched in 2022 with a $55 million series A round.

Epic Bios approach combines a miniature DNA-binding protein called CasMINI with customized guide RNAs and a wide array of modulator proteins. CasMINI, licensed from Stanford University, is the smallest Cas protein to date, less than half the size of Cas9 and Cas12a, allowing for efficient delivery using adeno-associated virus (AAV) vectors. This platform enables precise gene modulation, expanding the potential for treating a variety of genetic diseases.

The CasMINI protein is engineered to function effectively in cells and is small enough to be delivered in vivo using AAV vectors. This compact size and robust functionality make it possible to target a wide range of tissues and organs with high precision.

Epic Bios pipeline is still preclinical and targets a wide variety of diseases. The companys lead candidate targets facioscapulohumeral muscular dystrophy (FSHD), a genetic muscle disorder characterized by progressive muscle weakness and wasting. The company also develops candidates for heterozygous familial hypercholesterolemia (HeFH), a genetic disorder characterized by high cholesterol levels, and retinitis pigmentosa, a group of inherited disorders that cause progressive retinal degeneration, leading to vision loss.

Locus Biosciences is a biotechnology company founded in 2015 and headquartered in Morrisville, North Carolina. The company specializes in developing precision antibacterial therapies using CRISPR-Cas3-enhanced bacteriophage technology, known as crPhage. Locus Biosciences most recent funding is a $35 million series B round in 2022.

The company employs a CRISPR-Cas3 system for its antibacterial therapies. Unlike the more commonly used Cas9, Cas3 destroys the DNA of target bacteria irreversibly, making it highly effective against antibiotic-resistant strains. This technology is delivered using engineered bacteriophages, viruses that specifically target bacteria, allowing the preservation of the microbiome.

The CRISPR-Cas3 system sets Locus apart by offering a genetic chainsaw approach, which differs from the genetic scissors approach of CRISPR-Cas9. Cas3s ability to degrade large segments of DNA makes it particularly effective for combating multi-drug resistant bacteria.

Locus lead candidate LBP-EC01 is currently in phase 2/3 and targets Escherichia coli (E. coli) infections. E. coli is a type of bacteria commonly found in the intestines of humans and animals. While most strains are harmless and part of the normal gut flora, some can cause serious infections. E. coli infections can occur through the consumption of contaminated food or water or by contact with animals or person-to-person spread.

LBP-SA01, another candidate in the companys pipeline, targets staphylococcus aureus infections. While it often exists harmlessly, it can cause a wide range of infections if it enters the body through a cut or a wound.

Founded in 2017 and headquartered in Brisbane, California, the company leverages its proprietary CRISPR platform for therapeutics and diagnostics. Like Caribou Biosciences we mentioned last week, this CRISPR company was co-founded by Nobel laureate Jennifer Doudna.

Mammoth Biosciences has raised substantial funding, including a $150 million series D financing round in 2021, which has elevated its status to a unicorn with a valuation of over $1 billion.

Mammoth Biosciences focuses on the discovery and engineering of novel CRISPR systems, specifically the ultra-small Cas14 and Cas (phi) enzymes. These systems are smaller and have an increased temperature stability, and faster reaction, which enhance their effectiveness in in vivo genome editing and diagnostics.

The use of Cas14 and Cas enzymes allows Mammoth Biosciences to develop CRISPR-based solutions that are more efficient and versatile. The smaller size of these enzymes enables easier delivery into cells, especially for diseases that affect the central nervous system.

Mammoth Biosciences is developing both therapeutic and diagnostic products. The companys therapeutic pipeline is still in the preclinical and research stages, and the indications of its candidates are mostly undisclosed.

Additionally, Mammoth has its diagnostic platform, the DETECTR platform, which is a CRISPR-based detection system.

Prime Medicine was founded in 2019 and is headquartered in Cambridge, Massachusetts. The company focuses on developing gene editing therapies using its proprietary prime editing technology. Prime editing aims to address the root causes of genetic diseases by precisely correcting mutations at their source.

The company launched with $315 million in financing, comprising a $115 million series A round followed by a $200 million series B round.

Prime Medicine utilizes prime editing, a novel gene editing technology that acts like a DNA word processor to search and replace disease-causing genetic sequences. Unlike traditional CRISPR methods, prime editing does not create double-strand breaks in DNA, which reduces the risk of unintended modifications. This technology can correct a wide range of genetic mutations, making it an interesting and promising tool for developing therapies for genetic disorders.

The technology employs a fusion protein combining a Cas protein with a reverse transcriptase enzyme and a guide RNA (pegRNA) to direct the correction process. This approach allows for highly specific and predictable edits at the targeted genomic location, minimizing off-target effects.

Prime Medicine is advancing several preclinical programs targeting various genetic diseases: Wilsons disease, preventing the body from properly eliminating excess copper and leading to severe brain and liver issues, glycogen storage disease, and retinitis pigmentosa, among others.

Primes most advanced program, however, is an ex vivo therapy in phase 1/2 targeting chronic granulomatous disease, an inherited immunodeficiency disorder that affects the bodys ability to fight certain infections.

Scribe Therapeutics is a molecular engineering company founded in 2018 and headquartered in Alameda, California. The company focuses on developing advanced CRISPR-based genetic medicines and collaborates with industry leaders such as Biogen or Sanofi.

The company recently completed a $100 million Series B financing round led by Avoro Ventures and Avoro Capital Advisors.

Scribe Therapeutics leverages its CRISPR by design platform, which includes custom-engineered CRISPR enzymes. By optimizing the CRISPR enzymes for greater efficiency, Scribes XE technology can achieve more precise and robust gene edits.Scribes XE platform features advancements in delivery technologies, such as viral vectors and lipid nanoparticles, that are optimized for delivering CRISPR components into target cells and tissues in vivo.

The CRISPR company works on several therapeutic areas hand in hand with key players in the industry. Scribe is collaborating with Biogen to develop CRISPR-based therapies for amyotrophic lateral sclerosis (ALS). In partnership with Sanofi, Scribe is also working on genetically modifying natural killer (NK) cell therapies for cancer treatment. The XE platforms high specificity and efficacy make it ideal for engineering these cells to target and eliminate cancer cells effectively.

SNIPR Biome was founded in 2017 and is headquartered in Copenhagen, Denmark. The company specializes in developing CRISPR-based microbial gene therapies aimed at precisely targeting and eradicating pathogenic bacteria, including antibiotic-resistant strains.

SNIPR Biome has raised notable funding including one of Europes largest series A rounds, securing $50 million.

SNIPR Biomes primary technology involves CRISPR-Guided Vectors (CGV), which deliver CRISPR components into bacterial cells via engineered bacteriophages. These vectors create double-stranded breaks in the DNA of target bacteria, leading to rapid and specific bacterial killing. This approach is designed to preserve beneficial microbiota while targeting harmful pathogens, particularly those resistant to conventional antibiotics.

SNIPR001 is the companys lead candidate, a CRISPR therapy targeting E. coli, including antibiotic-resistant strains. SNIPR001 is designed to prevent bloodstream infections in patients undergoing hematopoietic stem cell transplants, who are particularly vulnerable to such infections. Positive interim results from phase 1 clinical trials showed that SNIPR001 was well-tolerated and effectively reduced gut E. coli levels in treated individuals.

The CRISPR technology market is experiencing robust growth and substantial investments. In 2024, the global market was valued at approximately $3.78 billion and is projected to reach around $9.34 billion by 2029, growing at a compound annual growth rate (CAGR) of 19.9%. This promising outlook for the CRISPR market is driven not only by the recent success of companies like Vertex and CRISPR Therapeutics but also by the emergence of more refined versions of the CRISPR technology.

While there is no doubt CRISPR has a bright future ahead, the market faces several challenges. The high costs associated with CRISPR technology are one of the main obstacles to its democratization in the future. Ethical concerns regarding genetic modifications and regulatory hurdles are also significant obstacles as ethics and law always move slower than technology.

More broadly, the gene editing and engineering scenes are moving fast, and technologies such as epigenetic editing and gene writing with companies such as Chroma Medicine and Tessera Therapeutics show significant potential.

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Seven CRISPR companies to watch in 2024 - Labiotech.eu

Recommendation and review posted by Bethany Smith

In vivo CRISPR screens reveal SCAF1 and USP15 as drivers of pancreatic cancer – Nature.com

June 25th, 2024

Direct in vivo CRISPR gene editing in the mouse pancreas

To functionally test putative PDAC cancer genes in vivo, we employed a multiplexed CRISPR/Cas9 genome editing approach to generate knock-out clones directly in the pancreatic epithelium of tumor-prone mice. We used conditional Lox-Stop-Lox-(LSL)-KrasG12D and LSL-Cas9-GFP mice crossed to the pancreas-specific PDX1-Cre driver line (termed KC mice) and injected an adeno-associated virus that expresses a sgRNA and the H2B-RFP fluorescent marker (AAV-sgRNA-RFP) (Fig.1a). Cre-mediated excision of Lox-Stop-Lox cassettes resulted in expression of oncogenic KrasG12D, Cas9 and GFP and formation of hundreds of cytokeratin19 positive (CK19) pancreatic intraepithelial neoplasia (PanIN) precursor lesions, which can be lineage-traced by virtue of red fluorescence (Supplementary Fig.1a, b). To validate the efficiency of CRISPR/Cas9-mediated mutagenesis, we injected sgRNAs targeting GFP, which revealed a knock-out efficacy of 786% (Supplementary Fig.1c).

A Experimental design of the in vivo PDAC CRISPR screen, showing gene selection from long-tail mutations, pancreatic injection of AAV libraries and tumor sequencing. B Tumor-free survival of Pdx1-Cre;LSL-KrasG12D;LSL-Cas9-GFP mice transduced with a sgRNA library targeting putative pancreatic cancer genes (n=23) or a control sgRNA library (n=13) C Representative whole-mount, H&E and immunofluorescent images of an H2B-RFP+ pancreatic PDAC-library tumor: Scale bar 2mm. H&E image: scale bar 250m. Representative immunofluorescence image shows H2B-RFP and CK19 expression. Scale bar 50m. Similar results were observed in all collected tumor. D Representative pie charts showing tumor suppressor genes with enriched sgRNAs in tumor DNA obtained from three different pancreatic tumors and a control-transduced pancreas with multifocal PanINs. E Bar graph showing putative tumor suppressor genes with enriched sgRNAs in tumor DNA obtained from the PDAC mouse model (sgRNA enriched per tumors are indicated by color).

KC mice exhibited rapid growth of pre-invasive PanINs precursor lesions but showed very slow progression to invasive PDAC with a median latency of 14 months (Fig.1b). Additional genetic alterations such as loss of transformation-related protein 53 (Trp53), p16Ink4a, Lkb1 or inactivation of TGF- signaling was previously shown to cooperate with KrasG12D and induces rapid PDAC development within 3-5 month16,17,18,19,20. To test whether our direct in vivo CRISPR approach can reveal genetic interactions, we recapitulated cooperation between oncogenic KrasG12D and loss of p53 (Trp53). Indeed, Cas9-mediated ablation of Trp53 in KC mice triggered rapid PDAC formation with a median latency of 14 weeks, while littermates transduced with scrambled control sgRNAs remained cancer-free for over 1 year (Supplementary Fig.1d). This is in line with previous efforts using CRISPR/Cas9 gene editing in KRasG12D mice21,22 and demonstrates that this approach can be used to test for genetic cooperation between PDAC genes.

In pancreatic cancer, 125 genes show recurrent somatic mutations6,7. To assess these genes in vivo, we established a sgRNA library targeting the corresponding mouse orthologs (4 sgRNAs/gene; 500 sgRNAs) and a library of 420 non-targeting control sgRNAs (Supplementary Data1). Of note, we did not include sgRNAs targeting well-established PDAC driver genes such as Trp53 or Smad416,17,18,19,20.

Next, we optimized the parameters for an in vivo CRISPR screen. Using a mixture of AAV-GFP and AAV-RFP, we determined the viral titer that transduces the pancreatic epithelium at clonal density (MOI<1). Higher viral titers were associated with double infections, whereas a 15% overall transduction level minimized double infections while generating necessary clones sufficient to screen (Supplementary Fig.1e). Using multicolor Rosa26-Lox-Stop-Lox(R26-LSL)-Confetti Cre-reporter mice, we next determined the viral titer required to generate thousands of discrete clones within the pancreatic epithelium (Supplementary Fig.1f). Thus, at a transduction level of 15% and a pool of 500 sgRNAs, each sgRNA would be introduced into at least 50 CK19+ epithelial cells within a single pancreas.

To uncover long-tail genes that cooperate with oncogenic KRasG12D and accelerate PDAC development, we injected the experimental and the control AAV-sgRNA libraries into the pancreas of 23 and 13 KC mice, respectively. Next-generation sequencing confirmed efficient AAV transduction of all sgRNAs (Supplementary Fig.2a). Importantly, KC mice transduced with the long-tail PDAC sgRNA library developed pancreatic cancer significantly faster than littermates transduced with the control sgRNA library (31 versus 59 weeks; p<0.0001) (Fig.1b and c). In addition, 13/23 (56%) KC mice transduced with the long-tail PDAC sgRNA library developed liver and/or lung metastasis, while only 1/13 (~8%) littermate mice transduced with the control sgRNA library developed metastasis (Supplementary Fig.2b-e), indicating the existence of strong tumor suppressors within the long-tail of PDAC associated genes.

To identify these PDAC driver genes, we examined the sgRNA representation in 151 tumors. 78% of tumors showed strong enrichment for single sgRNAs, indicating a clonal origin. In contrast, the pancreas of control-transduced mice with multifocal PanINs showed enrichment of several non-template control sgRNAs (Fig.1d). We prioritized genes that were targeted by 2 sgRNAs and knocked out in multiple tumors and/or metastatic foci, resulting in 8 candidate tumor suppressor genes (Fig.1e, Supplementary Data2). These candidates included well-known PDAC tumor suppressor genes, such as Cdkn2a23, Rnf4324, Fbxw725 or NF226, as well as genes with poorly understood function, such as Usp15 and Scaf1.

Pancreatitis is a risk factor for the development of PDAC in humans and cooperates with oncogenic KRas mutations to induce PDAC formation in mice23,27. Therefore, we repeated our screen and treated mice with chronic, low doses of cerulein to induce mild pancreatitis. As expected, cerulein treatment significantly accelerated PDAC development in KC mice transduced with the PDAC sgRNA library (17 versus 32 weeks median survival, p<0.0001), and a trend towards faster PDAC development in KC mice transduced with the control library (Supplementary Fig.2f). In line with the previous screen, Cdkn2a was the top-scoring gene followed by Rnf43 and the newly identified genes, Usp15 and Scaf1 (Supplementary Fig.2g), further supporting their function as strong suppressors of pancreatic cancer in KC mice.

The multi-domain deubiquitinase USP15 regulates diverse processes, such as the p53 tumor suppressor pathway28, MAPK signaling29, Wnt/beta-catenin signaling30, TGF- signaling31,32,33, NfKb signaling32,34,35 and chromosome integrity36,37, either through regulated de-ubiquitination of direct substrates such as MDM2, APC, SMADs or TGF- receptors, or de-ubiquitination-independent functions such as through protein-protein interactions38.

To validate the tumor suppressive function of Usp15, we first injected KC mice individually with one library or one newly designed sgRNA. All transduced mice developed highly proliferative pancreatic tumors with much shorter latencies compared to mice transduced with the non-targeting control sgRNAs (sgCrtl) (Fig.2a). In fact, age-matched control KC mice only exhibited PanINs at the time when USP15 knockout mice exhibit aggressive PDACs (Fig.2b). All tested tumors exhibited efficient CRISRP/Cas9-mediated mutagenesis of Usp15 (Supplementary Fig.3a and b).

A Tumor-free survival of Pdx1-Cre;LSL-KrasG12D;LSL-Cas9-GFP mice injected with CRISPR AAV-sgRNAs targeting the indicated gene or non-targeting control sgRNA (sgCtrl, n=6). Two independent sgRNAs were used (sgUsp15_1 n=9, sgUsp15_2 n=9). Log-Rank test (Mantel-Cox). B Representative H&E images showing multifocal PanINs in sgCtrl transduced pancreas and PADC tumors in sgUsp15 transduced pancreas. Scale bar 100m. C Tumor-free survival of Pdx1-Cre;LSL-KrasG12D mice with the indicated Usp15 genotype where + indicates the wildtype allele and indicates a conditionally deleted allele. KrasG12D +/- Usp15 +/+ (n=12); KrasG12D +/- Usp15 +/- (n=11); KrasG12D +/- Usp15 -/- (n=13). Log-Rank test (Mantel-Cox). D Representative H&E images of mice with the indicated genotype showing multifocal PanINs and PADC tumors. Scale bar 100m. E Cell proliferation curves of KC cells transduced with the indicated sgRNA obtained using the IncuCyte live-cell imaging. Cells were grown for five days and data are expressed as cell confluence percentage (%; meanSD, n=3 independent experiments, Two-way ANOVA (sgUsp15_1 p=3.43e-8: sgUsp15_2 p=4.89e-9), Dunnetts multiple comparison. F Cell proliferation curves of KC cells expressing ubiquitin variants inhibiting Usp15 (Ubv15.1a and Ubv15.1/d) or wildtype ubiquitin (Ubwt) as control. (%; meanSD, n=3 independent experiments, Two-way ANOVA (Ubv15.1a p=2.74e-6: Ubv15.1/d p=2.06e-7), Dunnetts multiple comparison. G Tumor-free survival of NSG (NOD Scid Gamma) mice after orthotopic injection sgCtrl (n=5) or sgUsp15_1/2 (n=5; n=5) KC cells. Two independent sgRNAs were used. Log-Rank test (Mantel-Cox). H Dose-response curves for KPC sgCtrl or sgUsp15 cells treated with the indicated concentration of Olaparib (meanSD, n=3 independent experiments). Two-way ANOVA (sgUsp15_1 p=0.0349: sgUsp15_2 p=0.0431), Dunnetts multiple comparison.

To further confirm the tumor suppressive role and rule out any confounding effect of Cas9 endonuclease expression, we generated conditional Usp15fl/fl; KRasG12D; Pdx1-Cre. This conventional knock-out approach recapitulated our CRISPR/Cas9 findings (Fig.2c and d), validating our in vivo CRISPR approach. Interestingly, Usp15fl/+ heterozygous mice also manifested significantly shorter disease-free survival (Fig.2c). To assess whether tumor development was due to Usp15 loss of heterozygosity, we used fluorescence-activated cell sorting (FACS) to isolate tumor cells from Usp15 homozygous, heterozygous and wild-type KRasG12D tumors. Western Blot analysis revealed Usp15 expression in Usp15 heterozygous tumor cells, albeit at a reduced level compared to control tumors (Supplementary Fig.3c), indicating Usp15 functions as a haploinsufficient tumor suppressor.

Next, we established primary PDAC cell lines from KC mice as well as KC mice with concomitant expression of the hotspot p53R270H mutant (KPC) and used CRISPR/Cas9 to knock-out Usp15 (Supplementary Fig.3d). Loss of Usp15 significantly increased proliferation of these KC cells (Fig.2e), while it did not affect KPC cells (Supplementary Fig.3e), presumably, because those cells are at the maximal proliferation rate. Similar results were obtained using ubiquitin variants (UbVs) that bind and block the catalytic domain of Usp1538, indicating that this tumor suppressive function is de-ubiquitination dependent (Fig.2f). Upon orthotopic injection, Usp15 knock-out KC cells also formed allograft tumor faster than non-targeting control cells (Fig.2g). Together, these data show that Usp15 regulates tumor cell proliferation in a cell-autonomous manner and loss of Usp15 increases a cells ability to form allograft tumors.

Consistent with a previous report36, we also found that loss of Usp15 sensitizes pancreatic cancer cells to Poly-(ADP-ribose) polymerase inhibition (PARPi) by Olaparib. This increased drug sensitivity was stronger in KPC cells than KC cells and was also seen in response to Gemcitabine, one of the most commonly used chemotherapies to treat pancreatic cancer (Fig.2h and Supplementary Fig3f, Fig.4a and b). KC cells were overall more sensitive to Gemcitabine likely due to the intact p53 response (Supplementary Fig3g). Importantly, loss of USP15 also sensitized allograft tumors in vivo towards Olaparib treatment (Supplementary Fig.4c). In addition, we found that Olaparib and Gemcitabine treatment significantly increases expression of Usp15 in KC and KPC cells (Supplementary Fig.4d). In line with its haploinsufficient tumorigenic effect, heterozygous loss of Usp15 also significantly increased proliferation and sensitized to Olaparib treatment, but not as pronounced as complete Usp15 loss (Supplementary Fig.4e and f). As such, Usp15 appears to function as a double-edged sword in pancreatic cancer, where the loss of Usp15 enhances tumor progression in the initial stages of tumorigenesis but sensitizes to certain treatment regimens in the later stages.

Given the wide range of USP15 substrates and USP15-regulated pathways with well-known functions in cancer, we set out to elucidate USP15s exact role in PDAC suppression. First, we transcriptionally profiled primary KC cells transduced with sgRNAs targeting Usp15 or non-template controls sgRNAs. Inactivation of Usp15 resulted in dramatic changes in gene expression compared to scrambled control KrasG12D tumor cells (794 differentially expressed genes (DEG), false discovery rate (FDR, Benjamini-Hochberg)<0.05 and absolute log2 fold-change > 1, Fig.3a and Supplementary Data3). Gene set enrichment analyses (GSEA) revealed significantly upregulated gene sets associated with xenobiotic detoxification, glutathione metabolism, anabolic processes, and oxidative phosphorylation (Fig.3b and Supplementary Data3). These findings are in line with USP15s known role in negatively regulating NRF239 (encoded by the NFE2L2 gene), the master regulator of glutathione metabolism and the redox balance of a cell. In addition, NRF2 expression is induced by oncogenic KRAS and known to stimulate proliferation and suppress senescence of PDAC cells40. Indeed, Usp15 knock-out cells exhibited significantly increased levels of Nrf2 (Supplementary Fig.5a).

A Volcano Blot showing differential expressed genes between Usp15-knockout compared to sgCtrl control KC cells. Wald test and Benjamini-Hochberg (BH)-adjusted P-value. Two independent sgRNAs, two biological duplicates. B Bar graph showing gene set enrichment analysis (GSEA) of Usp15-knockout compared to sgCtrl control KC cells. GSEA nominal p-values. Two independent sgRNAs, two biological duplicates. C GSEA plots and Heatmaps of log2 counts per million for selected differentially expressed pathways and genes in sgUsp15 versus sgCtrl control KC cells. GSEA nominal p-values. Two independent sgRNAs, two biological duplicates. D Expression levels of genes related to TNF signaling evaluated by RT-qPCR. Results were normalized with Gapdh and are expressed in fold change compared to Ctrl (meanSEM, n=3 independent experiments). Cells were incubated with 10ng/mL TNF-for 30min. Two-sided T-test, Rel-B p=0.043; TRAF-1 p=0.037/p=0.034; NFKB1 p=0.036; Rel-B p=0.042; TRAF-1 p=0.039; CXCL2 p=0.028; CXCL3 p=0.047/p=0.043; NFKB1 p=0.038/p=0.040; NFKB2 p=0.039/p=0.043.

GSEA also revealed depleted genes sets associated with inflammatory responses, TNF, TGF and p53 signaling (Fig.3b-d and Supplementary Fig.5b), all pathways with well-known tumor suppressive function in PDAC development17,41. Quantitative RT-PCR confirmed reduced expression of TNF and TGF responsive genes at baseline as well as TNF/TGF-stimulated conditions (Fig.3d and Supplementary Fig.5c). In addition, loss of USP15 reduced TNFinduced cell death and TGF-induced migration (Supplementary Fig.5d and e). Together, these data indicate that Usp15 functions as a strong haploinsufficient PDAC tumor suppressor potentially by regulating tumor suppressive cytokine signaling pathway.

Our second new hit, SCAF1 (SR-Related CTD Associated Factor 1), is a member of the human SR (Ser/Arg-rich) superfamily of pre-mRNA splicing factors. It interacts with the CTD domain of the RNA polymerase II (RNAPII) and is thought to be involved in pre-mRNA splicing42. Its close homologs SCAF4 and SCAF8 were recently shown to be essential for correct polyA site selection and RNAPII transcriptional termination in human cells43. SCAF1 was also one of the top-scoring hits in a screen for genes that can restore homologous recombination in BRCA1-deficient cells and thus conferred resistance to PARP inhibition44. However, the molecular function of SCAF1 remains completely elusive.

First, we validated the tumor suppressive function of Scaf1 by injecting KC mice individually with one library or one newly designed sgRNA. All transduced mice developed highly proliferative pancreatic cancer with much shorter latencies compared to mice transduced with the non-targeting control sgRNAs (Fig.4a, b). Of note, both Scaf1 sgRNAs induced high CRISPR/Cas9-mediated mutagenesis and resulted in significantly reduced Scaf1 mRNA expression (Supplementary Fig.6a, b). Similar to Usp15 knockout cells, we also found that primary Scaf1 knockout KC cells exhibited increased proliferation in culture and formed tumors faster when injected orthotopically into mice compared to scrambled control KC cells (Fig.4c and d). Scaf1 knockout cells also exhibited significantly increased sensitivity to Olaparib in vitro and in vivo (Fig.4e and Supplementary Fig.6c and d), again phenocopying Usp15 knockout cells.

A Tumor-free survival of Pdx1-Cre;LSL-KrasG12D;LSL-Cas9-GFP mice injected with CRISPR AAV targeting the indicated gene or non-targeting control sgRNA (sgCtrl n=6). Two independent sgRNAs were used (sgScaf1_1 n=8, sgScaf1_2 n=7). Log-Rank test (Mantel-Cox). B Representative H&E images showing multifocal PanINs in sgCtrl-transduced pancreas and PADC tumors in sgScaf1-transduced pancreas. Scale bar 100m. C Cell proliferation curves of KC sgCtrl and sgScaf1 cells were obtained using the IncuCyte live-cell imaging and data are expressed as cell confluence percentage (%; meanSD, n=3 independent experiments). Two-way ANOVA (sgScaf1_1 p=0.0039: sgScaf1_2 p=0.00042), Dunnetts multiple comparison. D Tumor-free survival of NSG mice orthotopically injected with sgCtrl (n=5) or sgScaf1_1/2 (n=5; n=5) KC cells. Two independent sgRNAs were used. Log-Rank test (Mantel-Cox). E Dose-response curves for KPC sgCtrl or sgScaf1 cells treated with the indicated concentration of Olaparib (meanSD, n=3 independent experiments). Two-way ANOVA (sgScaf1_1 p=0.0084: sgScaf1_2 p=0.0028), Dunnetts multiple comparisons. F Representative Western Blot of Usp15 in KC cells transduced with the indicated sgRNAs and treated as indicated. This experiment was repeated independently two times with similar results. G Cell growth curves of KC sgCtrl and sgScaf1cells expressing the listed isoform of USP15 or an empty vector (EV). Data are expressed as cell confluence percentage (%; meanSD, n=3 independent experiments); two-way ANOVA (sgScaf1+EV p=0.0342), Dunnetts multiple comparison. Dose-response curves for KC sgCtrl and sgScaf1 cells expressing the listed isoforms of USP15 or EV and treated with Olaparib. (%; meanSD, n=3 independent experiments; two-way ANOVA (sgScaf1+EV p=0.00129), Sidak multiple comparison H Tumor-free survival of NSG mice orthotopically injected with sgCtrl (n=5) or sgScaf1 KC cells expressing the listed isoforms of USP15 (n=5: n=5) or EV (n=5; n=5). Log-Rank test (Mantel-Cox).

Interestingly, we found a connection between Scaf1 and Usp15. Scaf1 knockout cells exhibited reduced expression of full-length Usp15 (molecular weight of ~125kDa) and showed expression of a 25kDa short Usp15 isoform under homeostatic as well as Olaparib and gemcitabine treatment (Fig.4f and Supplementary Fig.6e and f). SCAF1 KO tumors also exhibited lower levels of full-length USP15 (Supplementary Data Fig.6g). To examine a potential function of this truncated isoform, we cloned and transduced the long and the short isoforms into primary Usp15 knock-out KC cells (Supplementary Fig.6h). While full-length Usp15 was able to supress the hyperproliferative phenotype of Usp15 knock-out cells, the short isoform failed to suppress the cell proliferation (Supplementary Fig.7a). Similarly, re-expressing the full-length but not the short Usp15 isoform reversed the sensitivity of Usp15 knock-out KC cells to Olaparib and gemcitabine (Supplementary Fig.7b). In addition, overexpression of the full-length or the short Usp15 isoform did not alter proliferation of wildtype KC cells (Supplementary Fig.7c), indicating that the short isoform does not exhibit dominant negative functions. However, expression of the long but not the short Usp15 isoform or a catalytically-dead USP15 isoform suppressed the hyperproliferation and Olaparib sensitivity as well as the increased in vivo tumorigenesis of Scaf1 knock-out cells (Fig.4g and h and Supplementary Fig.7c-f). Together these data indicate that the short isoform has no tumor suppressive functions or alters the response to PARP inhibition and that Scaf1s tumor suppressive function is at least in part routed by regulating the expression of full-length Usp15.

To further elucidate the effects of Scaf1, we transcriptionally profiled Scaf1 knockout KC cells. Inactivation of Scaf1 resulted in 625 differentially expressed genes (DEG) (false discovery rate (FDR)<0.05 and absolute log2 fold-change > 1, Fig.5a and Supplementary Data3) compared to scrambled control KrasG12D tumor cells. GSEA revealed significantly upregulated gene sets associated with nucleotide metabolism, glutathione metabolism, microtubule polymerization, and oxidative phosphorylation as well as downregulation gene sets associated with TNF signaling, one-carbon metabolism, xenobiotic catabolic processes, mTorc1/mTOR signaling, hypoxia and p53 signaling (Fig.5b and Supplementary Fig.7g). In addition, we found a trend towards downregulated TGF signaling (Fig.5b and Supplementary Data3), reminiscent of the pathways altered in Usp15 knock-out cells.

A Volcano Blot showing differential expressed genes between Scaf1-knockout compared to control KC cells. Wald test and Benjamini-Hochberg (BH)-adjusted P-value. Two independent sgRNAs, two biological duplicates. B Bar graph showing gene set enrichment analysis of Scaf1-knockout compared to control KC cells. GSEA nominal p-values. Two independent sgRNAs, two biological duplicates. C Bar graph showing gene set enrichment analysis of Usp15-knockout and Scaf1-knockout compared to sgCtrl control KC cells treated with Olaparib (1M). GSEA nominal p-values. Two independent sgRNAs, two biological duplicates. D Expression levels of genes related to HH signaling evaluated by RT-qPCR in the indicated KC cell lines. Results were normalized with Gapdh and are expressed in fold change to CTRL (meanSEM, n=3 independent experiments). Cells were treated with 100nM Smoothened Agonist (SAG) and 1M Olaparib. Two-sided T-test, for sgUSP15: NRP2 p=0.021/p=0.018; PTCH1 p=0.037/p=0.033; GLI1 p=0.033; NRP2 p=0.042/p=0.037; for sgScaf1: PTCH1 p=0.046; PTCH2 p=0.040/p=0.042/p=0.033; GLI1 p=0.037/p=0.031; NRP2 p=0.042.

Lastly, we set out to elucidate how Usp15 and Scaf1 regulate the response of pancreatic cancer cells to PARP inhibition. Interestingly, transcriptional profiling and GSEA following Olaparib treatment revealed that both Usp15 and Scaf1 knock-out cells, exhibited downregulation of hedgehog signaling, TGF signaling and axon guidance by netrin as well as upregulation of glycolysis as the top dysregulated pathways compared to Olaparib-treated control KC cells (Fig.5c and Supplementary Data4). Together, this indicates a common mechanism leading to increased sensitivity to PARP inhibition shared between Usp15 and Scaf1 knock-out cells. Indeed, quantitative RT-PCR confirmed reduced expression of hedgehog target genes at baseline as well as upon sonic hedgehog stimulation (Fig.5d). Thus, Scaf1 and Usp15 knockout cells share several alterations such as upregulated TNF signaling and downregulated TGF, hedgehog and p53 signaling but also several distinct pathways.

To extend our findings from mouse to human cancers, we analyzed 295 PDAC samples from The Cancer Genome Atlas45,46,47. Mutations and homozygous deletion of USP15 and Scaf1 are rare as expected for long-tail mutation and were found in only 2.4% and 1.4% of PDAC samples, respectively. However, an additional 25% and 13% of PDAC cases showed shallow deletions of USP15 and SCAF1, respectively, indicative of heterozygous loss of these genes (Fig.6a). Focal USP15 and SCAF1 copy-number losses have been identified in independent large-scale genome studies48,49. In addition, allelic copy number loss also coincided with reduced expression of USP15 and SCAF1 and patients with deep or shallow USP15 or SCAF1 deletions showed a significant trend towards a shorter overall survival (Fig.6b and Supplementary Fig.8a). Given our genetic and biochemical data linking SCAF1 and USP15, we next considered patients with deep or shallow USP15 or SCAF1 deletions as a group (=37% of patients) and found a significantly shorter overall survival (Supplementary Fig.8b). This raises the possibility that USP15 and potentially also SCAF1 function in a haploinsufficient manner, which is in line with the increased tumorigenesis found in the Usp15fl/+; KRasG12D; Pdx1-Cre mice.

A Oncoprint of the indicated genes in PDAC samples (n=293, TCGA). B Kaplan-Meier survival analyses of PDAC patients with deep or shallow USP15 or SCAF1 deletion. (n=293, TCGA) Log-Rank test (Mantel-Cox). C Tumor-free survival of NSG mice orthotopically injected with sgCtrl (n=5), sgUsp15_1/2 (n=5; n=5) or sgSCAF1_1/2 (n=5; n=5) PANC-1 cells. Two independent sgRNAs were used. Log-Rank test (Mantel-Cox) D Dose-response curves for sgCtrl, sgUsp15 or sgSCAF1 PANC-1 cells treated with Olaparib. (%; meanSD, n=3 independent experiments) two-way ANOVA (sgUsp15_1 p=0.0242; sgUsp15_2 p=0.0387; sgScaf1_1 p=0.0281; sgScaf1_2 p=0.0371), Dunnetts multiple comparison. E sgUSP15 and sgOR2W5 PDO Competition Assay. sgUSP15 and control sgOR2W5 patient-derived organoids were disassociated into single cells and mixed in a 20:80% ratio. Organoid cultures were passaged, and a sample was collected every ~7 days. Percentage of DNA indels is tracked overtime by sanger-sequencing and TIDE analysis.

Next, we assessed the expression of USP15 in 4 human pancreatic cancer cell lines. While, PANC1 and HPAFII exhibited expression of the small as well as the long USP15 isoform, MiaPACA2 and BXPC3 cells only exhibited low-level expression of the long USP15 isoform, indicating that USP15 is also downregulated in some human pancreatic cancer cell lines (Supplementary Fig.8c).

To functionally test USP15 and SCAF1, we genetically ablated these genes in human PANC1 cells (Supplementary Fig.8d and e). Importantly, genetic ablation of SCAF1 resulted in increased expression of the short USP15 isoform, indicating that this mechanism is conserved from mouse to human cells (Supplementary Fig.8f). Similarly, to our autochthonous mouse experiments, we also found that loss of USP15 or SCAF1 in PANC1 cells resulted in accelerated tumorigenesis and increased sensitivity to Olaparib and Gemcitabine (Fig.6c, d and Supplementary Fig.8g). We also observed increased NRF2 protein levels in USP15 knockout PANC1 cells, which showed further elevated upon inhibition of TXNRD1/2 and antioxidant imbalance by auranofin treatment50 (Supplementary Fig.8h), akin to our findings in mouse KC cells. USP15 knockout PANC1 cells also exhibited increased sensitivity to auranofin treatment (Supplementary Fig.8i).

Lastly, we genetically ablated USP15 in patient-derived organoids (PDOs) from 3 different pancreatic cancer patients using Cas9 ribonucleotide particles. We set up competitive growth assays to assess the relative fitness of USP15 knockout PDOs compared to OR2W5 knockout PDOs. Of note, the OR2W5 olfactory receptor is not expressed in pancreatic PDOs and thus serves as control. We mixed the USP15 knockout and the OR2W5 knockout PDOs at a 1:4 ratio and followed their relative growth by quantifying the percent of USP15 and OR2W5 mutations over time using Sanger sequencing. Within ~10 passages, we observed that the PDO cultures were almost completely taken over by USP15 knockout cells (Fig.6e). Together, these data demonstrate the tumor suppressive function of USP15 and SCAF1 in pancreatic cancer by modulating several important signaling pathways and that loss of USP15 and SCAF1 sensitizes to Gemcitabine and Olaparib.

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In vivo CRISPR screens reveal SCAF1 and USP15 as drivers of pancreatic cancer - Nature.com

Recommendation and review posted by Bethany Smith

CRISPR-based paper test could improve influenza testing access, outbreak surveillance – LabPulse

June 25th, 2024

Researchers from the Broad Institute of MIT, Harvard, and Princeton University have developed a low-cost paper strip test that uses CRISPR to distinguish between the two main types of seasonal influenza, A and B, as well as subtypes H1N1 and H3N2.

Furthermore, the test can also identify strains that resist antiviral treatment and could potentially be adapted to detect swine and avian flu strains, including H5N1, currently causing an outbreak in cattle.

Results from the test, described in an article in The Journal of Molecular Diagnostics, show that the test, which was designed to be rapid, affordable, and easy to deploy at point-of-need is also accurate at distinguishing the types and subtypes of influenza, achieving results in 100% concordance with traditional polymerase chain reaction (PCR) assays.

The test is based on a technology called SHINE, which was developed in 2020 by the lab of co-author Pardis Sabeti, an institute member at the Broad and a professor at Harvard University and the Harvard T.H. Chan School of Public Health, as well as a Howard Hughes Medical Institute investigator. SHINE uses CRISPR enzymes to identify specific sequences of viral RNA in samples.

The teams aim was to create low-cost, rapid tests that could be deployed in clinics or in the field rather than in hospitals or diagnostic labs, and that didnt require expensive equipment to run. Accessible, efficient testing technology not only improves clinical care, but also may potentially improve outbreak management, making it easier for scientists to collect samples strategically to better monitor viral spread.

In contrast to typical diagnostic assays such as PCR which may require lengthy processing times, extensive training for personnel, and specialized equipment, SHINE testing can be performed in about 90 minutes at room temperature, and only requires an inexpensive heat block to warm the reaction.

The researchers first used SHINE to test for SARS-CoV-2, later adapting it to distinguish between the Delta and Omicron variants. They began adapting the assay to test for influenza viruses in 2022.

In the future, the team said in a story from the Broad Institute, the assay could be adapted to distinguish between different viruses with similar symptoms, such as influenza and SARS-CoV-2.

See more here:
CRISPR-based paper test could improve influenza testing access, outbreak surveillance - LabPulse

Recommendation and review posted by Bethany Smith

Scientists create gene-editing tool that may revolutionize DNA engineering – TweakTown

June 25th, 2024

A team of scientists created a new gene-editing tool that they claim is more accurate than the industry standard, CRISPR.

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Researchers from the University of Sydney, Australia, developed what is called SeekRNA, a new gene-editing tool that uses a programmable ribonucleic acid (RNA) strand capable of identifying and inserting itself into specific sites in genetic sequences. The team behind the project is being led by Dr. Sandro Ataide in the School of Life and Environmental Sciences, and their findings have already been published in Nature Communications.

The team explained that while CRISPR is the industry standard when it comes to genetic engineering, having revolutionized multiple industries such as medicine, agriculture, and biotechnology, it doesn't come without any problems. According to Dr. Ataide, SeekRNA differentiates itself from CRISPR in various ways, such as by not requiring any extra components to be cut and pasted into genetic sequences. SeekRNA is a stand-alone cut-and-paste tool that has higher accuracy.

Furthermore, CRISPR relies on creating a break in both strands of target DNA, which is the double-helix strand that commonly depicts a DNA sequence. While CRISPR is certainly impressive in its own right it requires the use of proteins or the DNA repair machinery to insert the new DNA sequence into its designated location. This process can produce errors in the code.

"SeekRNA can precisely cleave the target site and insert the new DNA sequence without the use of any other proteins. This allows for a much cleaner editing tool with higher accuracy and fewer errors," said Dr. Ataide

"We are tremendously excited by the potential for this technology. SeekRNA's ability to target selection with precision and flexibility sets the stage for a new era of genetic engineering, surpassing the limitations of current technologies," Dr Ataide said.

"With CRISPR you need extra components to have a 'cut-and-paste tool', whereas the promise of seekRNA is that it is a stand-alone 'cut-and-paste tool' with higher accuracy that can deliver a wide range of DNA sequences."

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Scientists create gene-editing tool that may revolutionize DNA engineering - TweakTown

Recommendation and review posted by Bethany Smith

The Potential of Induced Pluripotent Stem Cells to Test Gene Therapy Approaches for Neuromuscular and Motor … – Frontiers

June 25th, 2024

Introduction: iPSCs, an Invaluable Resource for Disease Modeling

The development of human induced pluripotent stem cells (iPSCs) (Takahashi et al., 2007) provided unprecedented opportunities to decipher pathophysiological mechanisms of diseases and to test therapeutic approaches in conditions that better translate to humans. This technology allows to obtain an unlimited number of cells from one patient thus representing an ideal model to study in vitro diseases developmental stages, onset and progression in specific human cells (Park et al., 2008a).

iPSCs are capable of indefinite self-renewal and can differentiate into any cell type under appropriate culture conditions (Takahashi et al., 2007; Yu et al., 2007). iPSCs are generated by reprogramming primary somatic cells, such as dermal fibroblasts or blood cells, using ectopic expression of selected embryonic transcription factors (e.g., Oct4, Sox2, Klf4, and c-Myc) (Takahashi et al., 2007). Over the years, several techniques have been refined to deliver the reprogramming cocktail for iPSCs generation. The first pioneering studies on iPSCs used integrating delivery systems, through retroviral or lentiviral vectors (Takahashi et al., 2007; Yu et al., 2007; Park et al., 2008b). To avoid any incorporation of the foreign genetic material and induction of genomic alterations (Nakagawa et al., 2008; Shao and Wu, 2010), novel delivery systems have been introduced, based on non-integrating vectors (such as the Sendai virus or episomal vectors), self-excising vectors (i.e., Cre-Lox, PiggyBac transposon), and non-viral vectors (i.e., combination of signaling molecules, small bioactive molecules, microRNAs, and other chemicals) (Liu et al., 2020). Interestingly, the delivery of synthetic mRNA expressing the reprogramming factors, was also exploited for the safe generation of iPSCs (Warren et al., 2010). It was also used for iPSCs differentiation (Warren et al., 2012; Mandal and Rossi, 2013; Yoshioka et al., 2013; Goparaju et al., 2017). This technology provides high in vitro transfection efficiency of complex mixtures, with transient expression and absence of genomic integration (Sahin et al., 2014).

iPSCs have the ability to retain the genetic mutation carried by the donor patient together with its genomic background, overcoming the limitations presented by the animal models and leading to a new era of disease modeling and clinical applications (Shi et al., 2017). Moreover, unlike the other unlimited sources of self-renewing cells, the embryonic stem cells (ESCs), which can only be obtained from early-stage blastocysts (45 days post fertilization), the iPSCs can be generated from adult patients, eliminating the ethical issues related to the generation of ESCs and leading to the opportunity for studying different stages of the disorders (Romano, 2008; Romito and Cobellis, 2016).

However, genetic background heterogeneity, lack of proper controls, as well as technical challenges in handling and standardizing the culture methods (Doss and Sachinidis, 2019; Volpato and Webber, 2020), contribute to the variability observed in the use of iPSCs as disease model (Hoekstra et al., 2017; Karagiannis et al., 2018; Volpato and Webber, 2020). To deal with genetic background influence on the expression of disease phenotype it is now possible to generate isogenic cell lines, introducing or repairing putative causative mutations through the clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9-mediated genomic editing technologies (Ben Jehuda et al., 2018). The use of such controls, when possible, reduces the observed variation in cellular phenotypes caused by the genomic milieu (Soldner and Jaenisch, 2012).

Thanks to the mentioned superior features, iPSCs were exploited to generate in vitro models of severe diseases affecting the neuromuscular system and/or the central nervous system, such as neuromuscular and motor neuron disorders (NMD and MND, respectively). While genetic corrected iPSCs are investigated in the complex field of cell replacement therapies, in which modified cells are reintroduced into patients (Tedesco et al., 2012; Barthlmy and Wein, 2018; Abdul Wahid et al., 2019), the iPSCs platform has already allowed the identification of drug candidates for some of these complex disorders (Ortiz-Vitali and Darabi, 2019; Pasteuning-Vuhman et al., 2020). Recently, the combination of iPSCs and gene targeting approaches is changing the face of modern medicine. In this review, we will thus briefly discuss the successes in the identification of drug candidates for NMD and MND and then we will focus on the efforts toward the validation of gene therapy approaches in iPSCs for muscular dystrophies, amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). Table 1 summarizes the research efforts in this direction mentioned in this review.

Table 1. Summary of the major findings of the cited articles in which iPSCs were used for therapeutic tests of neuromuscular and motor neuron disorders.

iPSCs are widely exploited in high-throughput drug screenings for genetic disorders. Thus far, the introduction of iPSCs into the drug development pipeline has allowed (i) physiologically improved modeling of disease-relevant phenotypes, (ii) a greater patient stratification, and (iii) discrimination between drug responders and non-responders (Pasteuning-Vuhman et al., 2020). In perspective, this will have an impact on the current limitations of the conventional drug discovery process and consequently improve the success of therapeutic target identification and clinical trial outcomes (Hosoya and Czysz, 2016).

Following their discovery, multiple research efforts focused on the generation of iPSCs for NMD and MND. As example, in 2008 Park and collaborators, established the first iPSCs line from skin fibroblasts from a patient affected by Duchenne muscular dystrophy (DMD), a fatal genetic disorder caused by mutations in the dystrophin (DMD) gene and characterized by progressive muscle wasting (Koenig et al., 1987; Park et al., 2008a; Gao and McNally, 2015). Since then, additional DMD-iPSC lines have been reported by other groups and several differentiation protocols were tested to refine the optimal methods for skeletal muscle and cardiac cell differentiation (reviewed by Danisovic et al., 2018; Piga et al., 2019). These attempts overcame some of the limitations of the commonly used human models of DMD, such as myoblasts obtained from patient biopsies, which are limited in number and phenotypically diverse (Blau et al., 1983; Renault et al., 2000; Sun et al., 2020). In contrast, patient-derived iPSCs allow the generation of large amount of mature skeletal muscle cells (Chal et al., 2016; Caputo et al., 2020) or cardiomyocytesrecapitulating the cardiomyopathy of dystrophic patients (Hashimoto et al., 2016), and can mimic different stages of the disorder (Xia et al., 2018). iPSCs were also converted to neuronal cells to study the impact on the central nervous system in NMD. For example, neuron-iPSCs were generated from patients affected by myotonic dystrophy 1 (DM1) (Du et al., 2013; Xia et al., 2013; Ueki et al., 2017), caused by an expansion of the CTG trinucleotide repeats in the 3 untranslated region of the dystrophia myotonica protein kinase (DMPK) gene (Brook et al., 1992). Altogether these studies highlight the versatility of iPSCs as model for the thorough study of gene mutations in the main affected tissues (i.e., skeletal and cardiac muscle for DMD) but also in other relevant cell types (such as neurons in DM1), which contribute to the disease manifestations. Furthermore, iPSCs are being exploited for the development of therapies for muscular dystrophies which is usually carried out in mouse models unable to fully recapitulate all the human disease features (Wells, 2018; Ortiz-Vitali and Darabi, 2019; van Putten et al., 2020). Recently, Sun and colleagues developed a platform based on DMD-iPSCderived myoblasts for drug screening and among 1524 compounds analyzed, they identified 2 promising small molecules with in vivo efficacy (Sun et al., 2020). Further efforts in this direction will likely improve the search for reliable drug candidates and eventually increase the success rate in clinical trials for these severe disorders.

While animal models remain the preferred choice also for modeling and drug testing for MND (Picher-Martel et al., 2016; Dawson et al., 2018; Giorgio et al., 2019), the large genetic variability of these disorders set the ground for the wide use of patient-derived cells. Since 2008, when Eggans group (Dimos et al., 2008) used for the first time iPSCs to produce patient-specific motor neurons and glia from skin cells of an 82-year-old female patient diagnosed with ALSthe most common adult onset MNDseveral groups have designed and validated protocols for spinal motor neurons (MN) (Son et al., 2011; Amoroso et al., 2013; Demestre et al., 2015; Maury et al., 2015; Toli et al., 2015; Sances et al., 2016; Fujimori et al., 2018) and astrocyte differentiation (Madill et al., 2017; Birger et al., 2019; Zhao et al., 2020). The studies performed in ALS-iPSCs with different genetic mutations, facilitated the identification of common pathological features to the various disease forms, such as endoplasmic reticulum stress (Kiskinis et al., 2014; Dafinca et al., 2016), mitochondrial abnormalities (Dafinca et al., 2020; Hor et al., 2020), and impaired excitability (Wainger et al., 2014), but also characteristics related to specific mutations, like protein aggregation or mislocalization (Liu et al., 2015).

Drug screenings using ALS-derived iPSCs additionally allowed the identification of three drugs that are currently explored as therapeutic options in clinical trials.

- The first one, ROPI, a dopamine receptor agonist, was identified from a panel of 1232 Food and Drug Administration (FDA)-approved drugs in a drug screening analysis conducted at Keio University, which examined Fused in sarcoma (FUS)- and TAR-DNA-Binding Protein 43 (TDP-43)-ALS iPSC-derived MN for suppression of ALS-related phenotypes in vitro, such as mislocalization of FUS/TDP43, stress granule formation, MN death/damage, and neurite retraction (Fujimori et al., 2018). This drug is now tested in the ROPALS trial (UMIN000034954 and JMA-IIA00397) as continuation of the Phase I/IIa clinical trial (Morimoto et al., 2019).

- Retigabine (known as an antiepileptic) was identified as a potential suppressor of the hyperexcitability of ALS iPSC-derived MNs based on electrophysiological analysis (Wainger et al., 2014). It is a voltage-gated potassium channel activator (Kv7) able to both block hyperexcitability and improve MN survival in vitro when tested in ALS cases carrying the most common genetic mutations (Wainger et al., 2014). A Phase II Pharmacodynamic Trial of Ezogabine (Retigabine) on neuronal excitability in ALS (NCT02450552) was conducted from 2015 to 2019 showing a decrease of cortical and spinal MN excitability in participants with ALS. These data suggest that such neurophysiological metrics may be used as pharmacodynamic biomarkers in multisite clinical trials (Wainger et al., 2020).

- The third drug is Bosutinib, a proto-oncogene non-receptor protein tyrosine kinase (Src/c-Abl) inhibitor that promoted autophagy and rescued degeneration in iPSC-derived MN, inhibiting misfolded Superoxide Dismutase 1 (SOD1) aggregation and suppressing cell death in genetic and sporadic ALS (Imamura et al., 2017). A new Phase I clinical trial of the drug bosutinib for ALS (UMIN000036295) was initiated in Japan in March 2019.

These examples of drug discovery in iPSCs and their ongoing translation to patients affected by a yet uncurable disease, indicate that this could be a valid paradigm for clinical success in similar diseases, such as SMA. SMA is a MND caused by homozygous mutations in the survival of motor neuron gene (SMN1) leading to infant mortality and motor disabilities in young and adult patients (Lefebvre et al., 1995; Verhaart et al., 2017; Smeriglio et al., 2020). This gene has a paralog called SMN2 that is nearly identical to SMN1, with few nucleotide differences, which result in the exclusion of exon 7 and 90% production of a truncated non-functional survival of motor neuron (SMN) protein (Lefebvre et al., 1995). Several therapeutic strategies have been tested to restore SMN expression (Wirth, 2021). Histone deacetylase (HDAC) inhibitors were tested to induce transcriptional activation of SMN2 and consequent increased production of full length SMN, with successful outcomes in proof-of-concept studies and failure in clinical trials. With the aim to identify compounds with higher efficacy and specificity, Lai and colleagues performed a drug screening in neuron-iPSCs from SMA patients. This study identified novel HDAC inhibitors with therapeutic potential that could be further explored for SMA treatment (Lai et al., 2017). Interestingly, neuron-iPSC from SMA patients were also used to test the efficacy of the recent FDA approved small molecule EvrysdiTM (risdiplam) (Ratni et al., 2016; Ratni et al., 2018; Dhillon, 2020), which forces the inclusion of exon 7 and thus restore SMN protein levels (Poirier et al., 2018). Moreover, the drug called TEC-1 (2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-6-(4-methylpiperazin-1-yl)quinazolin-4(3H)-one) another SMN2 splicing modulator, was recently identified in a screening on SMA patient-derived fibroblasts. The drugs effects were then confirmed in SMA-MN-iPSCs (Ando et al., 2020).

As suggested by the reported examples, the combination of iPSCs modeling, together with high-throughput drug screening followed by animal tests will likely ensure the identification of effective and safe therapeutic candidates. How this pipeline can be adapted to the development and tests for precision medicine approaches, such as gene therapy, will be discussed in the following paragraphs and is exemplified in Figure 1.

Figure 1. Test and development of gene targeting approaches using iPSCs. This drawing summarizes the steps of development for drugs and gene therapy approaches, using induced pluripotent stem cells (iPSCs). Somatic cells, such as fibroblasts or blood cells (peripheral blood mononuclear cells, PBMCs) are obtained from patients biopsies. After reprogramming, the patient-derived iPSCs can be differentiated into disease-relevant cell types, such as skeletal muscle cells, neural or glial cells for neuromuscular or motor neuron disorders. These cells are then subjected to the classical high-throughput drug screening and in perspective will be used to test novel therapeutic entities, based on gene targeting approaches. As example, antisense oligonucleotides (ASOs) or adeno-associated viral vectors (AAV)-based strategies. After validations in animal models and the pre-clinical development process, these novel therapies could enter into clinical trials for patients affected by rare disorders. The use of iPSCs and gene targeting strategies will likely foster the development of personalized medicine approaches. Created with BioRender.com.

Gene targeting approaches are based on the direct correction of the genetic defects (Wang and Gao, 2014; Cappella et al., 2019). For example, antisense oligonucleotides (ASOs) widely tested in pre-clinical and clinical settings, have been approved for SMA (Spinraza) (Aartsma-Rus, 2017) and DMD (i.e., Exondys 51) (Stein, 2016) patients, encouraging their use for the treatment of other monogenic disorders.

ASOs are synthetic single-stranded strings of nucleic acids that bind to RNA through standard WatsonCrick base pairing. After binding to the targeted RNA, the antisense drug can modulate the function of the targeted RNA by several mechanisms (Bennett and Swayze, 2010; Crooke et al., 2018), depending on the chemical modifications and the binding position on the target RNA (Wurster and Ludolph, 2018; Talbot and Wood, 2019; Ochoa and Milam, 2020). Briefly, ASOs can promote degradation of the targeted RNA, by mimicking DNA-RNA pairing and activating endogenous nucleases (i.e., RNase H1), or can modulate the processing of the RNA molecule, without inducing its degradation. This can be achieved through several mechanisms, such as by masking RNA splicing sites, as in the examples described below for DMD or SMA (Dick et al., 2013; Shoji et al., 2015; Osman et al., 2016; Ramirez et al., 2018). Other methods of action of ASOs have been previously reviewed (Bennett and Swayze, 2010; Crooke, 2017).

Several strategies, (Miller and Harris, 2016; Schoch and Miller, 2017), are currently investigated to increase ASOs stability, enhance binding affinity to the target RNA, improve tissue distribution and cellular uptake, while decreasing possible adverse effects (Bennett et al., 2017). Here we will focus on the use of iPSCs as model for testing the efficacy of these gene targeting approaches in NMD and MND.

Due to the large size of the DMD gene (Koenig et al., 1987), the restoration of the full-length dystrophin protein is challenging (Gao and McNally, 2015; Duan, 2018). One of the most promising approaches for gene targeting in DMD, is the use of ASOs binding to the pre-mRNA of the DMD gene to restore its reading frame and consequently producing a truncated but yet functional protein.

The ASO-mediated exon-skipping efficacy on exon 51 was tested in cardiomyocytes derived from iPSCs with DMD mutations, restoring dystrophin to nearly 30% of the normal level (Dick et al., 2013). Another similar study tested an ASO forcing exon 45 skipping of the DMD gene in myotubes derived from iPSCs, thus restoring dystrophin expression but also reducing calcium overflow (Shoji et al., 2015). These studies indicate that iPSCs can be used as platforms for therapeutic selection of ASO, based on the gene correction and prevention of skeletal muscle phenotype in DMD. The new frontier for the treatment of DMD patients is the development of mutation-specific ASOs (Schneider and Aartsma-Rus, 2020) and the use of iPSCs will likely speed the path to success of those strategies through the selection of the patient-specific and most efficient candidates.

ASOs were also proven effective in differentiated myotubes from DM1-iPSCs. A repeat-directed ASO treatment abolished RNA foci accumulation and rescued mis-splicing (Mondragon-Gonzalez and Perlingeiro, 2018) in vitro. These discoveries indicate that once established the proper conversion and differentiation protocols, together with valid disease read-outs, the test of ASOs in iPSCs could be likely applied to a larger spectrum of muscular dystrophies and diseases.

Therapeutic ASOs are currently tested in clinical trials for ALS patients harboring the chromosome 9 open reading frame 72 (C9ORF72) mutations (NCT03626012), SOD1 mutations (NCT03070119, NCT02623699) (recently reviewed by Cappella et al., 2021) or for sporadic ALS patients, with the Ataxin2-ASO (NCT04494256, Becker et al., 2017). Importantly, a splice switching ASO targeted to SMN2 (Spinraza) was approved for SMA patients in 2016.

To better characterize ASOs ability to rescue disease hallmarks, to dissect pathophysiological mechanisms and to test novel chemistries and molecular technologies, different research groups are studying ASOs in iPSCs for MND. For example, ASOs were proven effective in reducing the accumulation of sense RNA foci or toxic dipeptides in C9ORF72-iPSCs differentiated to neurons or MN (Donnelly et al., 2013; Sareen et al., 2013; Giorgio et al., 2019). More recently, Zhang et al. (2018) demonstrated that nucleocytoplasmic transport deficits and neurodegeneration were alleviated in C9ORF72-MN-iPSCs, after treatment with ASOs directed against the Ataxin 2, an RNA-binding protein. Nizzardo et al. (2016) treated ALS MN-iPSCs with ASOs designed to reduce the synthesis of human SOD1 and observed an increased survival and reduced expression of apoptotic markers in treated cells.

In SMA, iPSCs were used to test novel ASO sequences for their improved capacity of producing the full length SMN protein from splicing modulation of SMN2 and exon 7 inclusion (Osman et al., 2016; Ramirez et al., 2018). They were also used to test novel molecular strategies to restore SMN expression and correct neuropathological feature, namely an U1 small nuclear RNA-mediated splice switching approach and SMN transcription activation, via the Transcription Activator-Like Effector-Transcription Factor (TALE-TF) (Nizzardo et al., 2015). This report suggests that iPSCs could serve for the side-by-side comparison of different gene targeting strategies for monogenic disorders.

The use of adeno-associated viral vectors (AAV) for gene therapy of rare disorders recently became a clinical reality. The approval of Zolgensma (an AAV-mediated therapy) for the treatment of the most severe form of SMA, endorses the development of similar approaches for NMD and MND. Indeed, several pre-clinical studies report successes of these approaches in disease models (Biferi et al., 2017; Cappella et al., 2019; Crudele and Chamberlain, 2019) and their use in clinical trials (Bowles et al., 2012; Mendell et al., 2015; Mueller et al., 2020).

Some of the challenges associated to the translation of AAV-based therapies from animal models to patients, are linked to (i) the selection of the best AAV serotype for efficient transgene expression, (ii) cell/tissue specificity, as well as (iii) production of high vector titers, and (iv) reduction of immunoreactivity (Colella et al., 2017; Naso et al., 2017). To date, hundreds of natural AAV serotypes, variants and bio-engineered versions have been described (Hester et al., 2009; Choudhury et al., 2016; Deverman et al., 2016; Chan et al., 2017; Hanlon et al., 2019). Beside serotypes, research efforts are also focusing on the combination of the best serotype with the therapeutic and regulatory sequencessuch as promoters or enhancers (Colella et al., 2018; Besse et al., 2020; Nieuwenhuis et al., 2020), for efficient, safe and specific transgene expressions (Guilbaud et al., 2019; Hanlon et al., 2019). This will likely contribute to expedite the translational path from bench to clinic. In this context, iPSCs can be used to select the vector with best transduction properties for a specific cell type and/or to test the therapeutic sequences (recombinant transgene, oligonucleotides, antibodies, etc.). These techniques will be further refined to design patient-specific approaches. In perspective, when a therapeutic candidate will be established, iPSCs could be further used for analytical tests of approved gene therapies, such as potency assays.

AAV vectors were initially tested for genetic manipulation of ESCs or iPSCs in vitro, using natural human-derived AAV serotypes (from 1 to 9). After some unsuccessful attempts (Smith-Arica et al., 2003; Jang et al., 2011), some reports showed that natural AAV vector serotypes, such as AAV 2 and 3, were able to target iPSCs, although with limited efficacy (Mitsui et al., 2009; Khan et al., 2010). Through direct evolution, Asuri et al. (2012), derived a novel variant of AAV (AAV1.9) with a threefold higher gene delivery efficiency than AAV2 in iPSCs. These pioneer studies suggested that AAV vectors could be also used for stem cell correction and consequently studies of biological mechanisms in vitro and eventually for therapeutic purposes in cell therapy approaches.

Several studies reported method for AAV-mediated delivery of differentiated iPSCs. For example, Rapti et al. (2015) compared the transduction efficiency of different AAV (serotypes 1, 2, 6, and 9) in cardiomyocyte-iPSCs. Interestingly, they noticed that AAV vectors preferentially transduced differentiated cells and identified in serotypes 2 and 6 the best suited for cardiomyocyte-iPSCs transduction.

For modeling and therapeutic testing of central nervous system cells, AAV serotype 5 expressing the green fluorescent protein (GFP), was proven efficient in iPSCs-derived neuronal and glial cells, resulting in up to 90% of transduction (Martier et al., 2019a). Moreover, Duong et al. examined the level of AAV-GFP expression following the transduction of 11 AAV vectors in iPSCs differentiated into retinal pigment epithelium and cortical neurons (Duong et al., 2019). GFP-expressing cells were examined and compared across doses, time and cell type. They reported that retinal pigmented epithelium had the highest AAV-mediated GFP expression compared to cortical neurons-iPSCs and that AAV7m8 and AAV6 were the best performing, across vector concentrations and cell types. This study suggested that in addition to vector tropisms, cell type significantly affects transgene expression (Duong et al., 2019).

Overall, following optimizations, AAV vectors can be used to efficiently transduce patient-derived cells converted to neural or glial cells, likely facilitating studies for neurological diseases. Indeed, Martier and colleagues investigated the feasibility of a miRNA-based gene therapy to obtain long-term silencing of the repeat-containing transcripts of C9ORF72. Four AAV5 carrying miR candidates were tested in neuron-iPSC, resulting in sufficient transduction and expression of therapeutically relevant levels of the corresponding mature miRNA (Martier et al., 2019b). Two of the tested candidates were then proven efficient in reducing RNA foci accumulation in some brain regions of a disease mouse model (Martier et al., 2019a).

Novel methods are currently developed to select AAV for their fitness in vitro. For example, the group of Lisowski developed an AAV Testing Kit, as novel high-throughput approach based on next-generation sequencing, to study the performance of 30 published AAV variants in vitro, in vivo, and ex vivo. They tested AAV variants in primary cells, immortalized cell lines and iPSCs, showing that iPSCs were most efficiently transduced with bioengineered vectors, such as AAV 7m8, AAV LK03, and AAV DJ (Westhaus et al., 2020). This suggests that further methods for AAV optimization are necessary and will likely improve AAV transduction properties in vitro and in vivo.

Transduction properties of AAV serotypes in the human context have been recently tested in 3D structure iPSC-derived cerebral organoids. The transduction properties of two commonly used AAV serotypes (AAV5 and 9) were compared for transgene expression at the mRNA and protein levels, together with the presence of viral DNA. This study reported a higher transduction of the AAV5 compared to AAV9, in organoids and neural cells (Depla et al., 2020). This work set the ground for the use of iPSCs-derived human organoids as valid system for testing AAV properties and will be likely a valuable platform for holistic characterization of AAV properties in vitro and identification of the best therapeutic candidates.

Gene therapy treatments are revolutionizing the face of modern medicine opening treatment perspectives for patients affected by fatal conditions. Despite the growing success of these approaches, several aspects of gene therapy development need refinement and would benefit of the use of iPSCs. Indeed, together with their most known use, such as disease modeling for high-throughput drug screenings, they can be converted into a reliable platform for testing the novel therapeutic entities. Indeed, after the establishment of proper differentiation protocols and disease readouts, patient-derived models are being utilized to test gene targeting approaches. Here, we have summarized research efforts in testing drugs and gene therapy approaches in iPSCs from patient affected by neuromuscular and motor neuron diseases. We have presented some of the successes in candidate drug identification, such as risdiplam for the treatment of SMA and the research efforts in testing ASOs and AAV-mediated therapies. These studies set the ground for further developments, to select optimized therapeutic molecules and to identify powerful and safe AAV vectors.

In parallel to iPSCs development, research efforts are currently focused on the generation of even more advanced disease models. Indeed, despite iPSCs represent a reliable model for the understanding of pathological mechanisms and therapeutic development, they do not fully recapitulate the complexity of a tissue, with its architecture and interactions (Costamagna et al., 2019). In this direction, 3D culture methods are being implemented for NMD and MND, for example with the generation of artificial skeletal muscle for DMD (Maffioletti et al., 2018) or spinal cord organoids for SMA, which were used for drug test (Hor et al., 2018). Interestingly, the group of Pasa, has recently reported the generation of iPSC-derived 3D culture, in which cerebral cortex or hindbrain/spinal cord organoids were assembled with skeletal muscle spheroids (Andersen et al., 2020). These so-called 3D cortico-motor assembloids hold promise for the development of effective therapeutics for NMD and MND.

In conclusion, the advances in novel technologies, such as production of mature organoids, will endorse the development of efficient personalized medicine approaches.

MC and SE: writing of the manuscript draft. MB: conceptualization, writing, and review. All authors contributed to the article and approved the submitted version.

MC was supported by the ANR grant no. ANR-19-CE18-0014-01. MB and SE were supported by the Association Institut de Myologie (AIM)

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

We thank the Association Franaise contre les Myopathies (AFM), the Association Institut de Myologie (AIM), the Sorbonne Universit, the Institut National de la Sant et de la Recherche Mdicale (INSERM). We also thank Piera Smeriglio for critical reading of the manuscript.

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The Potential of Induced Pluripotent Stem Cells to Test Gene Therapy Approaches for Neuromuscular and Motor ... - Frontiers

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Creative Medical Technology Holdings Announces Evolutionary Development of its iPSCelz Program with the … – StockTitan

June 25th, 2024

Creative Medical Technology Holdings (NASDAQ: CELZ) has successfully generated human insulin-producing Islet Cells derived from induced pluripotent stem cells (iPSC) under its iPSCelz program. This development is validated by Greenstone Biosciences and utilized in several FDA-cleared clinical programs in the U.S. The creation of these cells marks a significant milestone for the company, potentially accelerating clinical applications and saving years of research and development. CEO Timothy Warbington highlighted the cost-efficiency and regulatory adherence of the company's multiple programs while maintaining a lower burn rate compared to peers.

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PHOENIX, June 24, 2024 (GLOBE NEWSWIRE) -- Creative Medical Technology Holdings, Inc. (Creative Medical Technology or the Company) (NASDAQ: CELZ), a leading commercial stage biotechnology company focused on a regenerative approach to immunotherapy, urology, neurology, and orthopedics, today announced that it has successfully generated human induced pluripotent stem cells (iPSC)-derived Islet Cells that produce human insulin.

The iPSC clinical line that generated these insulin producing Islet Cells is part of the Companys iPSCelz program, which is validated by Greenstone Biosciences Inc. (Greenstone). The iPSC clinical line, which is currently utilized in a number of our FDA cleared clinical programs in the U.S., has also been utilized to derive validated mesenchymal cells and T-regulatory cells.

Timothy Warbington, President and CEO of the Company, commented, The production of human insulin from islets derived from the IPSCelz program is a significant milestone for the Creative Medical Team and a reflection of the leadership role we have assumed in developing these therapies. It was only year ago that we confirmed the development of our iPSC. As we said then, we estimated that the development of this cell line would save the Company two to three years in research and development time along with associated expenses. Today, we are thrilled to be able to announce the evolution of this program with the creation of insulin producing Islet Cells derived from our iPSC. We believe that this development has the potential for not only clinical translation of the human Islet Cells, but also the stand-alone human insulin which is produced by these cells. We are currently in strategic discussions on next step collaborations to further these programs.

The Company continues to achieve significant milestones with its multiple programs in a cost-efficient manner without sacrificing quality and maintaining strict adherence to all regulatory requirements, Mr. Warbington continued. We are focused on allocating our resources in a prudent and effective manner which we believe is evidenced by our achievements and a slower burn rate than many companies in our space.

About IPSCelz iPSCelz, which is protected by trade secrets and published U.S. patents, utilizes the companies xeno-free human perinatal cell line derived from qualified human donors which are then converted into IPS cells.These cells are incubated with the Companys cell-free reprogramming cocktail to create the human islets and other cell types.

About Creative Medical Technology Holdings Creative Medical Technology Holdings, Inc. is a commercial stage biotechnology company specializing in stem cell technology in the fields of immunotherapy, urology, neurology, and orthopedics. For further information about the Company, please visit http://www.creativemedicaltechnology.com.

Forward Looking Statements This news release may contain forward-looking statements including but not limited to comments regarding the timing and content of upcoming clinical trials and laboratory results, marketing efforts, funding, etc. Forward-looking statements address future events and conditions and, therefore, involve inherent risks and uncertainties. Actual results may differ materially from those currently anticipated in such statements. See the periodic and other reports filed by Creative Medical Technology Holdings, Inc. with the Securities and Exchange Commission and available on the Commission's website at http://www.sec.gov.

Creative Medical Technology announced the successful generation of human insulin-producing Islet Cells derived from iPSCs under its iPSCelz program.

Creative Medical Technology announced this development on June 24, 2024.

The generation of insulin-producing Islet Cells marks a key milestone, potentially speeding up clinical applications and saving years of research and development time for CELZ.

The iPSCelz program is validated by Greenstone Biosciences.

The PR highlights cost-efficient program management, regulatory adherence, and a slower burn rate compared to peers, as financial benefits for CELZ.

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Creative Medical Technology Holdings Announces Evolutionary Development of its iPSCelz Program with the ... - StockTitan

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Harnessing benefits of stem cells for heart regeneration | ASU News – ASU News Now

June 25th, 2024

Mehdi Nikkhah, an associate professor of biomedical engineering in theIra A. Fulton Schools of Engineeringat Arizona State University, and his collaborators at Mayo Clinic in Arizona have been awarded a $2.7 million grant by the National Institutes of Health to research how stem cell engineering and tissue regeneration can aid in heart attack recovery.

The research will be conducted in collaboration withWuqiang Zhu, a cardiovascular researcher and professor of biomedical engineering atMayo Clinic.

Nikkhah and Zhu are exploring stem cell transplantation to repair and possibly regenerate damaged myocardium, or heart tissue. Their work is focused on the development of a new class of engineered heart tissues with the use of human-induced pluripotent stem cells, or hiPSCs, and has resulted in two published papers in ACS Biomaterials.

Aheart attack, medically termed as a myocardial infarction, occurs when a coronary artery that sends blood and oxygen to the heart becomes obstructed. This blockage is often the result of an accumulation of fatty cholesterol-containing deposits, known as plaques, within the hearts arteries.

When these plaques rupture, a cascade of events is initiated, leading to the formation of a blood clot. These blood clots can obstruct the artery, impeding blood flow to the heart muscle, thus triggering a heart attack.

When someone has a heart attack, a portion of muscle tissue on the left ventricle, which pumps the blood throughout the whole body, is damaged, Nikkhah says. Over time, the other parts of the heart have to take on more workload, consequently leading to catastrophic heart failure.

A team of biomedical engineers in theSchool of Biological and Health Systems Engineering, part of the Fulton Schools, and medical researchers at Mayo Clinic in Arizona are taking a novel step forward in using stem cell technology and regenerative medicine to aid in heart attack recovery.

Nikkhah is developing engineered heart tissues, or EHTs, with electrical properties to simulate the contraction function typically found within the native hearts tissue.

He is integrating the EHTs with gold nanorods to enhance electrical conductivity among stem cells. Gold is a suitable material because it is conductive and nontoxic to human cells, making the nanorods safe for medical research and translational studies.

In the lab, Nikkhahs team mixes the gold nanorods with a biocompatible hydrogel to form a tissue construct a patch of stem cells to rejuvenate damaged cardiac muscle tissue, offering a promising outcome for heart regeneration.

After we generate the patch, we get the engineered hiPSCs from Dr. Zhus lab at Mayo Clinic, Nikkhah says. They seed the cells on the patch and look at their biological characterization, including cell proliferation, cell viability and gene expression analysis, to see how the cells respond to the conductive hydrogel.

We have successfully used hiPSC-derived cardiomyocytes and cardiac fibroblasts to create beating heart tissues.

The successful integration and proliferation of these cells can lead to the formation of new, healthy heart tissue, potentially reversing the damage caused by the heart attack and enhancing the recovery process.

Reprogrammed human stem cells have nearly limitless potential because they can be differentiated into various cell types. That means hiPSCs can also be used to construct capillaries and blood vessels, which are essential for restoring adequate blood flow and oxygen supply to the damaged areas of the heart.

This process involves the differentiation of hiPSCs intoendothelial cells, which form the lining of blood vessels, thereby facilitating the reconstruction of the hearts vascular network.

Michelle Jang, a graduate student in Nikkhahs lab, is currently studying EHTs to improve cell maturation and observe its electrical properties.

My engagement in this project showed a deep interest in how biomedical engineering technology and biology intersect to create new therapeutic possibilities in the field of regenerative medicine, Jang says. Im excited to see how my current research will further evolve and potentially contribute valuable insights to biomedical research.

Using these techniques, Nikkhah and Zhu can observe the capacity of programmed cells to regenerate damaged heart tissue. With continued advancement in regenerative medicine, there is potential for significant positive impact on outcomes for patients suffering from heart attacks.

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Harnessing benefits of stem cells for heart regeneration | ASU News - ASU News Now

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Global ischemia induces stemness and dedifferentiation in human adult cardiomyocytes after cardiac arrest | Scientific … – Nature.com

June 25th, 2024

Animal models have shown that cardiomyocytes can indeed regenerate. However, animal studies are not always directly transferable to a human setting. Thus, it is essential to assess regenerative processes in human heart when possible. In this study, we evaluated the expression of several early cardiac stem cell- and proliferation- associated biomarkers in adult human cardiac tissue from the left ventricle (LV) and the potential stem cell niche region the atrioventricular junction (AVj)3,4,5. Specifically, we sought to investigate whether global ischemia, caused by cardiac arrest, activate regenerative processes such as cardiomyocyte remodeling and cell renewal in the adult human heart.

When damage occur in cardiac tissue, the result is often an increase in fibrosis, hypertrophy, adipose tissue infiltration, lipofuscin accumulation or nuclei fragmentation. We expected histological changes in the cardiac arrest group, but no clear difference was observed by the systematic analysis of the tissue. The time window, 24days between the cardiac arrest and organ donation, seems too short for a histological remodeling of the normal myocardium to be demonstrated.

To further investigate potential differences between the two groups, the expression of cTnT, a part of the sarcomeres of cardiomyocytes, was studied. As expected, an even distribution was found in LV from the control group. In contrast, after cardiac arrest individual cardiomyocytes with a decreased expression of cTnT were discovered. Moreover, our results show that these cardiomyocytes with low cTnT upregulated the expression of the stem cell associated biomarkers. This is an interesting similarity to transient cardiomyocyte dedifferentiation, which is characterized by structural remodelling of the sarcomeres including decreased levels of cTnT7,9. We have previously reported that MDR1, SSEA4 and WT1 are expressed in small immature myocytes in the suggested hypoxic stem cell niche in the human AVj but not in LV from the same hearts4. Upregulation of these early cardiac biomarkers in a subpopulation of LV cardiomyocytes post ischemia supports the idea of dedifferentiation in existing cardiomyocytes. Furthermore, a study using brief non-lethal myocardial ischemiareperfusion model in sheep reported that MDR1 was upregulated both after 3 and 48h following reperfusion23. The authors proposed MDR1 as an early biomarker whose activation plays a pivotal role for cell survival. The expression of MDR1 in human LV following reperfusion after cardiac arrest in our study is consistent with a prolonged expression in response to global ischemia.

In addition, we found expression of the early cardiac transcription factor NKX2.5 in the LV cardiomyocytes with reduced cTnT interpreted as a potential reprogramming of adult cardiomyocytes into a more immature phenotype. NKX2.5 expression was detected in dedifferentiating rat cardiomyocytes in culture9 and is known to lie upstream of many essential genes for heart development13. Furthermore, in zebrafish, it was shown that activation of NKX2.5 was required for not only adult myocardial repair but also to provoke the associated proteolytic pathways of sarcomere disassembly as well as the proliferative response for cardiomyocyte renewal24. In line with this background, we suggest that the increase in NKX2.5 in combination with a decrease in cTnT expression may signify a remodeling process. Collectively, a reduction in cTnT and upregulation of stem cell associated biomarkers after an episode of global ischemia followed by few days of oxygen supply indicate a remodeling of the LV cardiomyocytes.

Intriguingly, hypoxia has been shown to induce dedifferentiation of early committed cells into pluripotency25. The fact that no nuclear Hif1 expression was observed in the LV after cardiac arrest despite the increased MDR1 expression after 14days of reperfusion is likely due to the very short half-life (~58min) of Hif1 after return to normal oxygen levels26,27. Under normal conditions Hif1 is expressed in the cytoplasm18, but when the oxygen levels drop Hif1 is instead accumulated in the nuclei17. Beyond its function as a transcriptional regulator for the cellular response to hypoxia, Hif1 plays a role in the activation of genes related to tissue repair28. In contrast to the findings in LV, nuclear Hif1 expression was detected in non-cardiomyocytes in the AVj in both groups, as previously reported4,5. This indicates that the AVj region holds a lower oxygen level than other parts of the heart, strengthening the theory of hypoxic stem cell niche in adult human heart. A hypoxia-responsive element has been identified in the early cardiac transcription factor WT1 sequence that bounds to Hif1 which was required for activation of the WT1 promotor29. WT1 has been correlated to epicardial regeneration30 as well as expression by endothelial cells31. We have previously reported that WT1 is expressed in the human AVj but not in LV cardiomyocytes4. In the present study, the co-expression of WT1 was found in small SSEA4+/cTnT+ myocytes in AVj. The numbers of WT1+/cTnT+ cells increased in the AVj after cardiac arrest, interpreted as a regenerative response to global hypoxia in the niche region. Another observation was increased numbers of WT1+/cTnT cells in LV after cardiac arrest (data not shown) interpreted as an activation of non-myocytes.

It is common for cardiomyocytes to have more than one nucleus. The nuclei are separated from each other in cardiomyocytes. The analyses of PCM1 expression revealed twin nuclei in cardiomyocytes. A systematic quantification of multiple large images showed that the number of twin nuclei increased after cardiac arrest, in both locations. The highest numbers were counted in the LV. Donor 21 was an outlier showing highest number of twin nuclei after the longest period of hypoxia (75min) compared to the others (Suppl. Table 1). However, it is difficult to draw conclusions from only one case. Binucleation takes place during the fetal development32. The absence of Ki67 or PCNA expression in the twin nuclei in the LV suggest that the results represent binucleation rather that proliferation. However, it should be noted that the half-lives of these two proliferation markers are short (~1 and 8h respectively)20,21. Although we cannot solidly determine whether the twin nuclei represent ongoing cell division or binucleation, it is worth noting that both these processes reflect mitosis33,34. Furthermore, it has been shown that PCM1 is a centrosome protein which localizes to the nuclear membrane2 and more specifically to dense structures on the cytoplasmic site of the nuclear envelope35. Therefore, the appearance of the PCM1 staining in the twin nuclei with two visible nuclear envelopes (see Fig.5b2,c2,d) is in itself evidence which strongly suggests binucleation rather than polyploidy within a single nucleus. In line with our results, double nuclei were observed in dedifferentiating cardiomyocytes days after apical resection in newborn mice, whereas neighbouring myocytes which did not undergo dedifferentiation or associated sarcomeric disorganization only displayed single nuclei36. Thus, regardless of whether they were destined for cell division or binucleation, the twin nuclei are consistent with a remodeling process.

Neither of the proliferation markers were found in cardiomyocytes in the LV after cardiac arrest, not even in the cardiomyocytes with the low cTnT expression suggesting that remodeling is a longer process, and that proliferation has not been initiated 14days following cardiac arrest. Support for this can be found in the study by Meckert et al. who found 12% of the LV myocytes contained Ki67+ nuclei in 713days-old infarcts. Earlier (16days) and also later (1421days), the portion of Ki67+ myocytes was significantly lower37. The absence of Ki67+ nuclei in the LV in the present study (14days after cardiac arrest) therefore seems to be largely in agreement with these results.

In contrast to the LV, PCNA and Ki67 were co-expressed with cardiac specific nuclei marker PCM1 in AVj, which may indicate increased proliferation in small myocytes after a period of global hypoxia. Ki67 has a shorter half-time than PCNA20,21, which could be an explanation to why more of PCNA+/PCM1+ nuclei compared to Ki67+/PCM1+ nuclei were detected. Another possibility is that PCNA can also be involved in DNA repair, including in human cardiomyocytes37. As there were clear examples of PCNA+/PCM1+ as well as Ki67+/PCM1+ twin nuclei in AVj, it appears that at least some of the PCNA positivity was associated with nuclei which had entered the cell cycle. Previously, we reported increased numbers of BrdU+ proliferating cells in the AVj using physical exercise in the adult rats3. In addition we have shown expression of biomarkers related to hypoxia, cardiac stem cells, proliferation and migration in the left and right AVj4,5 indicating that this region is of importance to cardiomyocyte cell renewal in human. I the current study, the increased expression of proliferation markers in the AVj after cardiac arrest suggests that more cardiomyocytes might had entered the cell cycle.

What may be the ultimate fates of the PCM1+ cardiomyocytes in AVj that displayed cell cycle markers? Regarding some of the PCM1+ nuclei that displayed no clear PCM1+ nuclear envelopes (Fig.4a2,a3), these are admittedly difficult to interpret. However, there is evidence to suggest that the insoluble perinuclear matrix remains in most phases of the cell cycle but disassembles only in pro-metaphase and metaphase of mitosis, making it possible to visualize myocyte nuclei almost throughout the whole cell cycle38. It thus seems possible that some of the Ki67+/PCM1+ and PCNA+/PCM1+ nuclei in the AVj in the present study were in prometaphase and metaphase.

In a study on infarcted human hearts, a low number of Ki67+ myocytes in the periinfarct zone had appearances consistent with conventional mitosis37. Thus, there is a slight possibility that minor portion of the Ki67+/PCM1+ and PCNA+/PCM1+ nuclei in the AVj may represent conventional cell division. However, Meckert et al. reported evidence to suggest that in human infarcts, entrance of cardiomyocytes into the cell cycle is transient and that endomitosis, leading to polyploidy rather than mitosis, is the final fate of cycling cells37. Nevertheless, since cardiac arrest and myocardial infarction are different conditions, there is a clear need for further studies into these issues. A possible explanation behind the differences between the AVj and the LV in the present study may be that the cardiomyocytes in the AVj are younger and in a more immature stage and thus perhaps able to express proliferation markers early after global ischemia.

Some limitations of the present study should be acknowledged. Immunohistochemistry data shows only a snapshot in time but provide important insights on co-expression of biomarkers in human adult cardiomyocytes. The low number of individuals and the limited range of the reperfusion period after cardiac arrest, as well as the short half-life of the chosen proliferation markers, makes it challenging to ascertain whether the twin nuclei were destined for binucleation, polyploidization or cell division. Also, some of the Ki67 and PCNA positivity may have been reflective of polyploidization and/or DNA damage, both of which may have occurred to varying extents. The methods and markers that we used did not allow us to investigate whether this was indeed the case. The physiological significance of the increased number of twin-nuclei as well as the Ki67+/PCM1+ and PCNA+/PCM1+ nuclei in and the remodelling cardiomyocytes after cardiac arrest thus needs further investigation. Nevertheless, the material is highly unique and may provide important insights into cellular response to cardiac arrest in human heart and clues for therapies aimed at improving heart regeneration.

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Global ischemia induces stemness and dedifferentiation in human adult cardiomyocytes after cardiac arrest | Scientific ... - Nature.com

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Cardiac Disease Stem Cell Therapy Market 2024-2031: Emerging Trends, Growth Opportunities, Growth And Business … – openPR

June 25th, 2024

Cardiac Disease Stem Cell Therapy Market

Understanding the segments helps in identifying the importance of different factors that aid market growth. This report gives you a clear vision of how the research is derived through primary and secondary sources considering expert opinion, patent analysis, the latest market development activity, and other influencing factors. The report throws light on the competitive landscape, segmentation, geographical expansion, and revenue, production, and consumption growth of the Cardiac Disease Stem Cell Therapy market.

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Some of the key players profiled in the study are:

Cellino Biotech Mesoblast BioCardia Cedars-Sinai Stem Cells Transplant Institute CCTRN Help Therapeutics Co., Ltd. Beijing Cellapy biotechnology Co., LTD CardioCell

Cardiac Disease Stem Cell Therapy Market Segmentation:

By Types:

Autologous Allogeneic

By Applications:

Preclinical Clinical Phase 1,2

Research Methodology:

This includes the collection of information through analysts to have them studied and filtered thoroughly in an try to provide good-sized predictions approximately the marketplace over the evaluate length. The research method further consists of interviews with main market influencers, which makes the primary research applicable and realistic. The secondary methods give a direct peek into the demand and deliver the connection. The market methodologies followed within the record offer specific facts analysis and provide a tour of the whole marketplace.

Market Geography:

The Cardiac Disease Stem Cell Therapy Market provides a diverse geographical landscape, with several areas exhibiting unique market characteristics. While some locations see rapid growth due to factors like economic expansion and technical advancements, other regions may experience slower but more consistent market expansion. Market trends vary greatly throughout regions due to factors including cultural influences, legal frameworks, and population developments. Businesses looking to go global must understand these regional differences and adjust their strategy to take advantage of local opportunities.

North America (U.S., Canada, China)

Europe (Germany, U.K., France, Italy, Russia, Spain, Rest of Europe)

Asia-Pacific (Japan, South Korea, China Taiwan, Southeast Asia, India)

Middle East, Africa, Latin America (Brazil, Mexico, Turkey, Israel, GCC Countries)

Informational Takeaways from the Market Study:

The Cardiac Disease Stem Cell Therapy Market report matches the completely examined and evaluated data of the noticeable companies and their situation in the market considering the impact of Coronavirus. The measured tools including SWOT analysis, Porter's five analysis, and assumption return debt were utilized while separating the improvement of the key players performing in the market.

If you are involved in the Cardiac Disease Stem Cell Therapy market or aim to be, then this study will provide you inclusive point of view. You must keep your market knowledge up to date segmented by top players. If you have a different set of players/manufacturers according to regional or countrywide segmented report we can provide customization according to your requirements.

Objectives of the Report:

To carefully analyze and forecast the market size by value and volume. To estimate the market shares of major segments. To showcase the development of the market in regions. To analyze micro-markets in terms of their contributions to the Cardiac Disease Stem Cell Therapy market, their prospects, and individual growth trends. To offer precise and useful details about factors affecting the growth of the market. To provide a meticulous assessment of crucial business strategies used by leading companies operating in the Cardiac Disease Stem Cell Therapy market, which include research and development, collaborations, agreements, partnerships, acquisitions, mergers, new developments, and product launches.

Key Questions Answered with this Study:

1) What makes Cardiac Disease Stem Cell Therapy Market feasible for long-term investment? 2) Teritorry that may see a steep rise in CAGR & Y-O-Y growth? 3) Which regions would have better demand for products/services? 4) What opportunity emerging regions would offer to established and new entrants in the market? 5) Risk side analysis connected with service providers? 6) How influencing are factors driving the demand for Cardiac Disease Stem Cell Therapy in the next few years? 7) What is the impact analysis of various factors in the global market growth? 8) What strategies of big players help them acquire a share in a mature market?

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Reasons to Purchase Report:

This report provides an in-depth exploration of the trends, challenges, and opportunities within this dynamic market landscape. From enabling technological advancements to driving innovation and sustainability initiatives, the Cardiac Disease Stem Cell Therapy market plays a pivotal role in shaping the modern world economy. The report throws light on the competitive landscape, segmentation, geographical expansion, and revenue, production, and consumption growth of the Cardiac Disease Stem Cell Therapy market. This report provides future products, joint ventures, marketing strategy, developments, mergers and acquisitions, marketing, promotions, revenue, import, export, CAGR values, the industry as a whole, and the particular competitors faced are also studied in the large-scale market. The report also analyzes the different segments along with major geographies that have more market demand.

Thanks for reading this article; you can also get individual chapter-wise sections or region-wise report versions.

Author Bio:

Money Singh is a seasoned content writer with over four years of experience in the market research sector. Her expertise spans various industries, including food and beverages, biotechnology, chemical and materials, defense and aerospace, consumer goods, etc. (https://www.linkedin.com/in/money-singh-590844163)

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Cardiac Disease Stem Cell Therapy Market 2024-2031: Emerging Trends, Growth Opportunities, Growth And Business ... - openPR

Recommendation and review posted by Bethany Smith

Bonus Features June 16, 2024 40% of patients are willing to follow medical advice generated by AI, genetic testing … – Healthcare IT Today

June 17th, 2024

Welcome to the weekly edition of Healthcare IT Today Bonus Features. This article will be a weekly roundup of interesting stories, product announcements, new hires, partnerships, research studies, awards, sales, and more. Because theres so much happening out there in healthcare IT we arent able to cover in our full articles, we still want to make sure youre informed of all the latest news, announcements, and stories happening to help you better do your job.

Studies

Partnerships

Product and Company News

Sales

People

If you have news that youd like us to consider for a future edition ofHealthcare IT Today Bonus Features, please submit them onthis page. Please include any relevant links and let us know if news is under embargo. Note that submissions received after the close of business on Thursday may not be included in Bonus Features until the following week.

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Bonus Features June 16, 2024 40% of patients are willing to follow medical advice generated by AI, genetic testing ... - Healthcare IT Today

Recommendation and review posted by Bethany Smith

Genetic discoveries map out your health risks, if you can keep up with them – Star Tribune

June 17th, 2024

Genetics discoveries are rapidly identifying the people at greater risk for cancers and other diseases, but researchers at HealthPartners are concerned that they are happening too fast for doctors and patients to keep up.

The Bloomington-based health care provider is testing a new alert system to close that knowledge gap by identifying patients with inherited risks for diseases and automatically alerting their doctors of their need for testing. Screening guidelines changed three times in the past 18 months, just for breast and ovarian cancers, after researchers identified genetic variants that increased risks of those diseases, said Dr. Patrick O'Connor, a senior researcher with HealthPartners Institute.

"There is a risk of information overload," O'Connor said. "That's why we're creating a system to help organize these data in a way that's clear to patients so they can make informed decisions about treatment options that may be of benefit to them."

Using a $3.2 million federal grant announced earlier this week, HealthPartners hopes its alert system will hasten testing, which in turn will hasten diagnosis and treatment of diseases before they become severe or fatal. The goal is precision medicine tailoring treatments based on patients' unique circumstances but O'Connor said there are many examples in health care now when that approach is underused.

Research has identified numerous genetic variants that affect the course of type 2 diabetes, for instance, but those nuances aren't widely used right now to customize treatments, O'Connor said. Antidepressants are dispensed at a common starter dosage without consideration of the known variants that can dictate how well they will work, he added.

HealthPartners' study will identify patients at 40 clinics in Minnesota and western Wisconsin who haven't followed up on genetic testing results, even though they have one of seven variants linked to elevated risks of breast, colon or ovarian cancers. Doctors at 20 of those clinics will be prompted by the new alert system to talk with these patients about recommended tests or treatments. Researchers expect that these patients will receive more recommended screenings over the next three years than a comparison group of patients at the 20 other clinics that aren't receiving alerts.

Genes are chemical strands that program the body's cells based on hereditary information passed down from parents to children. Millions of variations alter how genes work in the body, but a much smaller portion has been linked through research so far to elevated rates of disease.

The Centers for Disease Control and Prevention recommends testing for 11 genetic variants that have proven links to cancer or heart disease, including the variants of the BRCA1 and BRCA2 genes that are closely tied to breast cancer. The American College of Medical Genetics and Genomics lists 81 variants that should be reported to doctors and patients because of their links to treatable conditions.

If HealthPartners' system works, it will be expanded to alert patients to other clinically important variants. Some only cause minute shifts in disease risks, while one known variation can increase lifetime risk of ovarian cancer from 1% to 70%. Another can identify smokers who have the best chance of reducing heart attack risks if they quit their habits.

"The difference can be gigantic in some cases," O'Connor said.

Deenya Craig, 52, of Maple Grove didn't hesitate when testing identified a BRCA2 mutation that increased her cancer risks and explained her family's tragic history with the disease. One cousin recently died from prostate cancer while another struggled with an aggressive breast cancer. The result "opened doors that previously had been closed," she said, including consultations with cancer specialists and insurance coverage of preventive treatments. She had a mastectomy last year to remove breast tissue that posed cancer risks, and had a gynecological procedure this month to reduce her risks for ovarian cancer.

Craig spread the word of her results, and now her sisters and three of her six children have been tested. Her whole genome testing of thousands of genes at once produced other interesting information about her susceptibility to caffeine and sleep disturbances, but mostly she said she felt empowered by the knowledge about her cancer risks.

"It gives the control back to you over your health instead of sitting and wondering what, if or when," Craig said.

Craig received free testing through HealthPartners' partnership with California-based Helix Inc. to gather genetic data from 100,000 volunteers. The myGenetics program is designed to alert volunteers to health risks but also amass genetic information for further identification of troublesome variants. Out of 40,000 volunteers, testing has found more than 600 with inherited risks for breast, colon or ovarian cancers.

Mayo Clinic will soon publish interim data from a similar project called Tapestry, which is recruiting 100,000 volunteers from its campuses in Minnesota, Arizona and Florida to identify those with any of the 11 CDC-identified variants. Results will show how many people with these variants wouldn't have qualified for screening under current insurance and health system guidelines, said Dr. Jewel Samadder, co-director of precision oncology at Mayo Clinic's cancer center in Arizona.

Mayo also will be following 15,000 of these patients over five years to compare their health and health care spending with patients who don't have any of the variants. Screening just for the breast cancer variants used to cost $5,000, but now tests of thousands of genes at once cost around $500. Samadder said health systems will need to expand to account for a new generation of patients who are acting on this affordable genetic information.

Some studies already estimate that the cost is low enough to warrant widespread testing because it will end up saving money by identifying cancers before they require high-cost treatments.

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Genetic discoveries map out your health risks, if you can keep up with them - Star Tribune

Recommendation and review posted by Bethany Smith