A seventh person has essentially been cured of HIV after receiving a stem cell transplant nearly a decade ago, doctors announced Thursday.

The 60-year-old unidentified German man was suffering from acute myeloid leukemia when he underwent the risky procedure to replace his unhealthy bone marrow in October 2015.

He quit taking anti-retroviral drugs which stop HIV from reproducing in September 2018. He remains in viral remission and appears to be cancer-free.

A healthy person has many wishes, a sick person only one, the man, who wishes to remain anonymous, said of his progress.

Dr. Christian Gaebler, a physician-scientist at the Charit-Universittsmedizin Berlin, is slated to present the case next week at the 25thInternational AIDS Conference.

The longer we see these HIV remissions without any HIV therapy, the more confidence we can get that were probably seeing a case where we really have eradicated all competent HIV, Gaebler said.

At a news conference last week, International AIDS Society President Sharon Lewin cautioned against using the word cure.

Still, she said, being in remission for more than five years means he would be close to being considered cured.

There is one major difference between the German mans case and most of the rest.

Five of the other six patients received stem cells from donors with two copies of a rare genetic mutation that stops HIV from replicating.

The German patient is said to be the first to have received stem cells from a donor with just one copy of the mutated gene and he had a copy of the gene himself.

About1% of Caucasians have two copies of thedefective gene, while 10% to 18% of people with European heritage are estimated to have one copy of the gene, thus expanding the potential donor pool.

Some 39 million people around the world are living with HIV, the virus that causes AIDS. Very few will be able to access this treatment, as it is reserved for those with HIV and aggressive leukemia.

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7th person likely cured of HIV in a remarkable case - New York Post

Recommendation and review posted by Bethany Smith

As a hematologist-oncologist in Miami, Mikkael Sekeres always hopes his patients will find a perfect match for the bone marrow transplant they need to save their lives but he doesnt expect it. Most of his patients are Latino or African American, and rates of perfect matches are much lower for racial or ethnic minorities.

That gloomy picture could soon change. A study published Wednesday in the Journal of Clinical Oncology found that certain unmatched donors, or people whose bone marrow does not as closely resemble that of the patients, provided similar outcomes to matched donors so long as patients receive a key drug called cyclophosphamide to prevent dangerous complications. That suggests that patients who need a transplant might be able to safely consider both matched and some unmatched donors, vastly expanding the pool of potential acceptable donors for all patients, though particularly those of African, Latino, or Asian ancestry.

Its much harder to find a match for most of my patients. Looking to people who are donor unrelated and arent a perfect match for my patients has become the norm, said Sekeres, who is the chief of hematology at Sylvester Cancer Center at the University of Miami and did not work on the study. Thats why this study really resonated with me. The classic teaching is you want a perfect match as opposed to less than perfect. What this study suggests is, if you use the right drugs after transplant, it may not be as big of a deal.

If so, up to roughly 84% of African American patients might have a potential donor in the national registry. Currently, less than 30% of African American patients have a potential match in the NMDP registry, previously called the National Marrow Donor Program.

Bone marrow transplants, also called hematopoietic cell or blood stem cell transplants, are essentially immune system transplants, and often represent a patients last chance for a cure for blood cancers like leukemia and lymphoma. Oncologists give chemotherapy first to put the cancer in remission, but the chemotherapy also does substantial damage to healthy bone marrow, where stem cells that give rise to blood and immune cells reside. The transplanted immune system would then replenish the lost stem cells as well as attack any remaining cancer in the patient.

The trouble is that the grafted immune system can also reject its new home, attacking healthy tissues in a potentially fatal complication known as graft versus host disease. Your native immune system avoids this by using a system of proteins called HLAs or human leukocyte antigens. Every cell carries these proteins like a security badge, identifying itself as part of your own body to patrolling immune cells. A matched donor would thus carry the same eight major HLA markers as the recipient or be an eight of eight match to make it more likely the transplanted immune system will settle into the new host without much fuss.

For many years, it was known having a donor whose immune system is matched to yours conferred a better outcome. Back when I was a fellow, outcomes were dismal when patients got an unmatched donor, said Brian Shaffer, a bone marrow transplant physician at Memorial Sloan Kettering Cancer Center and the lead author on the study.

Then, several years ago, scientists at Johns Hopkins University showed that cyclophosphamide could lower the risk of these complications for half-matched first-degree relative donors. Blood stem cells are resistant to this particular chemotherapy, but not so much immune cells like T and B cells that drive graft versus host disease. These immune cells are particularly vulnerable to the toxin if theyre activated and in the process of proliferating, Shaffer said.

That means when the transplanted immune system goes into the patient, some of these T and B cells will recognize theyre in the wrong body and begin lashing out against the recipient, but make themselves more vulnerable to cyclophosphamide in doing so. That means the drug can selectively delete the immune cells that are most likely to cause dangerous complications.

Other T cells will remain quiet, because theyre happy with the host, Shaffer said. These angry T cells will go into cell division, and theyre more exposed to cyclophosphamide.

Some of the first indications that this strategy would work to ease even unrelated and unmatched immune systems into patients came in 2021. A team of researchers saw favorable outcomes in the overall survival of about 80 patients who received either an unmatched unrelated transplant after one year. This study expands those findings with data collected from approximately 10,000 patients treated for acute leukemia or myelodysplastic syndromes.

The study was possible partly because so many patients, particularly those with non-European ancestry, cannot find an 8/8 match in the registry. So, their only option is to go down to a 7/8 or lower mismatched donor. Some centers were already using cyclophosphamide to prevent graft versus host disease, though others use another drug called a calcineurin inhibitor. Shaffer and his colleagues used data from 153 centers comparing patients who received either an 8/8 or 7/8 match and either cyclophosphamide or a calcineurin inhibitor.

The major finding is that the patients who had post-transplant cyclophosphamide had no differences in survival or any other sort of key clinical outcome, freedom from graft versus host disease and other complications, from matched or mismatched donors, Shaffer said. That wasnt true for the patients who received calcineurin inhibitors. These patients also had worse survival, relapse occurrence, and graft versus host disease compared to those who received cyclophosphamide.

I was pleased to read this article, said Warren Fingrut, a transplant and cell therapy physician and MD Anderson Cancer Center who did not work on the study. Allowing seven of eight mismatched unrelated donors will extend access to many more patients, especially those from racial, ethnic minority groups to receive transplantation.

While the study was specifically on patients with acute leukemia or myelodysplastic syndromes, the findings are of great interest for patients who have other hematologic malignancies and nonmalignant conditions who also receive transplants, Fingrut said. Though, he added, it may still be important to replicate the work in other indications.

According to the analysis, broadening the pool of bone marrow donors to include 7/8 mismatched transplants increases the potential match rate for Asians and Hispanics from less than 50% to close to 90%. The potential match rate for African Americans rises to 84%. The potential match rate for white Americans also goes up from about 79% to 99%.

Those are enormous gains and would likely help substantially in reducing health disparities in these cancers, Fingrut said, though it wouldnt solve all the disparities in transplant access. One problem is even if a potential donor exists in the registry for a patient, many of these donors cannot actually donate. That might be because their contact information changed and arent reachable, they have new health conditions that preclude them from donating, or they may no longer be interested.

About half of donors are unavailable overall for confirmatory typing. When you zoom in on African ancestry, its less than one third that are available, Fingrut said. Thats not improving over time, and its not just due to the Covid-19 pandemic.

This study opens an avenue to getting around that problem, Fingrut said. Transplant doctors could consider 7/8 unmatched donors alongside matched donors for patients who have worse chances of finding a match in the registry. If you go after the few unrelated donors that never show up, and only then you switch to mismatched donors or alternatives like cord blood donors, it in fact impacts overall survival, Fingrut said. These patients cannot wait months and months for a donor that never materializes.

Dropping down to a four, five, or six out of eight match would further increase the match rate to nearly 100% for all patients, although its still unclear if using more heavily mismatched donors would worsen outcomes. Everyone is eagerly awaiting that data, Fingrut said.

But there is also another way to improve the match rate without resorting to more heavily mismatched donors, he pointed out. More people could join the donor registry.

An earlier version of this article incorrectly described a 2021 study. Participants in that trial received only unmatched, unrelated transplants.

The rest is here:
Bone marrow donors neednt be perfect match, study says, paving way for more equitable access - STAT

Recommendation and review posted by Bethany Smith

Alexandra Gomez Arteaga, MD, hematologist/oncologist in the bone marrow transplant and cellular therapy program at Weill Cornell Medicine in New York, New York, discusses the rationale behind a retrospective study comparing Orca-T with posttransplant cyclophosphamide-based hematopoietic cell transplantation using data from existing studies that involved similar patient populations.

Arteaga also discusses the mechanism of action of Orca-T, a novel cell therapy under investigation. The agent works by leveraging regulatory T cells from allogeneic donors to control graft-vs-host disease (GVHD).

Transcription:

0:09 | Our field in allogeneic stem cell transplantation is changing, and we now have new ways of doing GVHD prophylaxis. The posttransplant cyclophosphamide studies and the platform have shown significant reduction in chronic GVHD. There might be other ways that we can improve outcomes by reducing other important things such as toxicities and relapse.

0:31 | Orca-T is a high precision immunotherapy that is a more organized fashion to create immune reconstitution. Based on the new changes in post transplant cyclophosphamide, we wanted to compare Orca-T [with] posttransplant cyclophosphamide since we currently are doing a study with Orca-T against the standard of care.

0:52 | With the current allografts, there are over 50 cell types that are infused together, and we have no control over how these cells interact for engraftment. Orca-T immune reconstitution, on the other hand, is the high-precision immunotherapy where the cells are in manufacture and divided into 3 main components. The first component is hematopoietic stem cells. The second component is highly purified T regulatory cells. The third component is the conventional cells.

1:20 | With this high precision immunotherapy, we can give the patient the exact number of cells at the exact time. On day 0, the patients get the stem cells from the T regulatory cells and these the regulatory cells are going to have an optimal immunomodulatory environment so that there's less GVHD. There is more organization of how the immune reconstitution happens.

Read this article:
Advancements in Stem Cell Transplantation: Comparing Orca-T With PTCy - Targeted Oncology

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See more here:
Hemostasis and complement in allogeneic hematopoietic stem cell transplantation: clinical significance of two interactive systems - Nature.com

Recommendation and review posted by Bethany Smith

Study approval

All experiments were performed in accordance with protocols approved by the University of North Carolina Institutional Animal Care and Use Committee (application number 14-001). Prior to sample collection, all human patients signed informed consent under Duke University IRB study protocol Pro00110250. Healthy donor control cells were purchased from Memorial Blood Center (St. Paul, MN) where all commercially available products are collected with IRB approval or exemption.

C57BL/6 (strain 0000664) and C57BL/6JDBA/2 F1 (B6D2, strain 100006) mice were purchased from The Jackson Laboratory. The generation of enhanced GFP-expressing C57BL/6 mice has been described previously26. Donor and recipient mice were age-matched males between 8 and 16 weeks. Animals were housed under specific pathogen-free (SPF) conditions on a 12-h dark/light cycle at 2122C and 3070% humidity. Where applicable in all mouse studies, animals were euthanized via CO2-compressed carbon dioxide gas in cylinders followed by physical cervical dislocation to ensure death.

Eight- to 16-week-old B6 mice were given 0.4g recombinant mouse IL-17E/IL-25 (R&D Systems) by i.p. injection for 4 days. On day 5, cells were isolated from the mesenteric lymph nodes and peritoneum by peritoneal lavage using RPMI-1640 supplemented with 10% FBS, 2mM L-glutamine, 12mM HEPES, 0.1mM non-essential amino acids, 1mM sodium pyruvate, 1% Pen/Strep, and 50M 2-mercaptoethanol (complete media). ILC2s were isolated by negative selection with a MACS column using the following antibodies (anti-CD8 [clone 53-6.7], anti-CD4 [RM 4.4], anti-CD3 [clone 145-2C11], anti-TCR [UC7-13DS], anti-TER119 [TER-119], anti-B220 [RA3-6B2], anti-CD11b [M1/70], anti-NK1.1 [PK136], eBioscience; anti-CD11c [N418], anti-CD19 [MB19-1], anti-Ly6G [1A8], and anti-CD49b [DX5], BioLegend) and Streptavidin Microbeads (Miltenyi 130-048-101). Cells were expanded in culture at 2.25x105 cells/mL in 24 well flat bottom TC-treated plates or flasks (Corning) as described below.

ILC2s were cultured at 2.25x105 cells/mL for 6 days in complete media (RPMI-1640 supplemented with 10% FBS, 2mM L-glutamine, 12mM HEPES, 0.1mM non-essential amino acids, 1mM sodium pyruvate, 1% Pen/Strep, and 50M 2-mercaptoethanol) and supplemented with 10ng/ml rIL-7 and rIL-33 (PeproTech), with the media changed every 2 days. ILC2 activation was evaluated using flow cytometry on day 6 by surface and intracellular cytokine staining with antibodies against Lineage (eBioscience) and ST2 (Thermo Scientific). For experiments in which cells were generated via cytokine-mediated skewing (pcILC2s), cells were cultured at 2.25x105 cells/mL for 48h in complete media supplemented with 10ng/ml rIL-7 and rIL-33 (PeproTech). On Days 2 and 4, the media was replaced with complete R10 containing 10ng/ml rIL-7, 10ng/ml rIL-12, 10ng/ml rIL-1b, 10ng/ml rIL-15, 10ng/ml rIL-2, and 5ng/ml rIL-18.

Non-mobilized healthy donor peripheral blood (PB) leukapheresis products were purchased from Memorial Blood Center (St. Paul, MN), and human ILC2 cells were captured via the RosetteSep human ILC2 enrichment kit (STEMCELL Technologies), per the manufacturers instructions.

ILC2s were cultured at 2.25x105 cells/mL for 6 days in complete media (RPMI-1640 supplemented with 10% FBS, 2mM L-glutamine, 12mM HEPES, 0.1mM non-essential amino acids, 1mM sodium pyruvate, 1% Pen/Strep, and 50M 2-mercaptoethanol) and supplemented with 10ng/ml rIL-7 and rIL-33 (PeproTech), with the media changed every 2 days. ILC2 activation was evaluated using flow cytometry on day 6 by surface and intracellular cytokine staining with antibodies against Lineage (eBioscience) and ST2 (Thermo Scientific). For experiments in which cells were generated via cytokine-mediated skewing (pcILC2s), cells were cultured at 2.25x105 cells/mL for 48h in complete media supplemented with 10ng/ml rIL-7 and rIL-33 (PeproTech). On Days 2 and 4, the media was replaced with complete R10 containing 10ng/ml rIL-7, 10ng/ml rIL-12, 10ng/ml rIL-1b, 10ng/ml rIL-15, 10ng/ml rIL-2, and 5ng/ml rIL-18.

The phenotype and function of murine ILC2s were evaluated by flow cytometry with antibodies as listed in Supplementary Data2. Prior to transplantation T cells were evaluated by surface staining of CD4 (GK1.5) and CD8 (clone 53-6.7). Sample acquisition was performed using a BD LSRII or BD LSRFortessa (BD Bioscience) or a MACS Quant (Miltenyi Biotec), and data were analyzed by FlowJo v9/10 (TreeStar, BD) and Prism v10 (GraphPad).

Total T cells were isolated using a Cedarlane T cell recovery column kit (Cedarlane Laboratories), followed by antibody depletion using PE-conjugated anti-mouse B220 (RA3-B62) and anti-mouse CD25 (3C7) antibodies (eBioscience) and magnetic bead selection using anti-PE beads (130-0480801, Miltenyi Biotec). TCD bone marrow was prepared as described previously27. The day prior to transplantation, recipient mice received 950cGy of total body irradiation. Recipients were intravenously injected with 4106T cells and 3x106 TCD BM cells. For ILC2 treatment groups, B6D2 recipients also received 3 4x106 ILC2s, respectively. Recipients were monitored three times a week and scored for clinical GVHD symptoms (designated clinical score) using a semiquantitative scoring system as previously described28,29; animals were coded for these evaluations. The sample size was chosen for the effect size needed based on our previous experience with sample sizes needed to demonstrate a significant difference in GVHD scoring between control and treated groups. For the scoring evaluation experiments, the inclusion of 912 recipients provided a power of 90% to detect a difference of 14 days in the median GVHD score of 5 with an error of <0.05 between control and treated groups. For all experiments, a control group received TCD bone marrow alone without additional T cells, which controlled for the presence of T cells in the marrow inoculum and potential infectious complications during aplasia.

Animals were euthanized with CO2 followed by cervical dislocation,and spleen, liver, lungs, mesenteric lymph nodes (mLN), and lamina propria (LP) were excised. LP lymphocytes were isolated using the Miltenyi LP dissociation kit (catalog 130-097-410) as per the manufacturers instructions. Livers and lungs were digested in a solution of 1mg/ml collagenase A (Roche) and 75 U DNase I (Sigma-Aldrich) in RPMI 1640 with 5% newborn calf serum. Digested tissues were treated with ACK lysis buffer to remove RBCs and were passed through 100m cell strainers. Leukocytes were collected at the interface of a 40%:80% Percoll (Sigma-Aldrich) gradient in RPMI 1640 with 5% NCS. The pelleted cells were washed in 1x DPBS with 2% FBS. Spleens and mLN were teased apart, treated with ACK lysis buffer, and washed in 1 x DPBS with 2% FBS.

Animals were sacrificed, and lymphocytes were isolated from the SI, mLN, and IP lavage as described above. Single-cell suspensions were stained with an e450 Lineage antibody cocktail (Invitrogen, 88-7772-72) and BD Horizon AlexaFluor 700 Fixable Viability Stain (BD 564997). Cells were sorted based on GFP expression on a BD FACSAria II (BD Bioscience), and GFP+ cells were collected into cR10 prior to downstream processing.

Peripheral blood samples were collected from 12 adults who underwent HSCT at the Duke Adult Bone Marrow Transplant Clinic in Durham, NC between January 2015 and April 2017. All patients signed informed consent under Duke University IRB study protocol Pro00110250. Of the patients who remained stable after allo-HSCT, two out of three received myeloablative conditioning regiments while one underwent non-myeloablative conditioning. Similarly, of the patients who remained went on to experience an episode of acute GVHD in the first four months following their allo-HSCT, two out of three received myeloablative conditioning regiments while one underwent non-myeloablative conditioning. The average patient age at the time of HSCT was 56 years, and all included patients had a transplant indication of myelodysplastic syndrome. Sex and/or gender were not considered in the study design as specimen selection was limited to a small pool of experimentally eligible samples. All patients received calcineurin inhibition and short-course methotrexate for GvHD prophylaxis. We requested samples from 36 patients after alloHSCT with a diagnosis of acute graft-versus-host disease and 36 that were stable. In addition, we requested a pre-HSCT sample and then one drawn as close as possible to the time of the aGVHD diagnosis, as well as 3 months and 1 year where available.

2.55x106 cells were pelleted prior to fixation with and fixed with a 1% formaldehyde using the ChIP-IT High Sensitivity Kit (Active Motif). After quenching and washing, pellets were frozen at 80C. Upon thawing, cells were sheared using a chilled dounce homogenizer using with the ChIP-IT High Sensitivity Kit (Active Motif), and lysed cells were sonicated with nanodroplets for 60s with the Covaris Le220 prior to clarified by centrifuging at full speed for 15min. Input DNA was prepared with RNase A and Proteinase K prior to clean up and concentration with the Zymo Chip DNA Clean and Concentrate kit. 1030ug of ILC chromatin were treated with an anti-H3K4me3 antibody (Cell Signaling Technologies, rabbit mAb 9751, clone C42D8)+blocker mix along with a protease inhibitor cocktail prior to overnight end-to-end rotation at 4C. 30L of Protein G Dynabeads were added to each 240L immunoprecipitation reaction, and reactions were incubated for 3h. Samples were passed through a ChIP Filtration Column and then washed 5x with Wash Buffer AM1. After the removal of the residual wash buffer, samples were eluted in pre-warmed elution buffer AM4. De-crosslinking was carried out for 2.5h with Proteinase K prior to DNA extraction with the ChIP DNA Clean & Concentrator (Zymo Research) protocol. Chromatin immunoprecipitation quantitative real-time PCR (ChIP-qPCR) was performed using the QuantStudio 6K from Applied Biosystems.

Cells of interest were prepared in suspension and nuclei were isolated by pelleting 25,000200,000 in a fixed-angle centrifuge. Cells were lysed with 10mM Tris-HCl (pH 7.4), 10mM NaCl, and 3mM MgCl2 prior to 30min of transposition with an in house Tn5 transposase (generated at UNC CICBDD with Addgene construct #60240 as adapted from Picelli et al., Genome Res, 2014)30 at 37C. Immediately following transposition, samples were purified with Zymo Conc & Clean (Genesee) and stored at 20C prior to library amplification. Fragments were amplified using 1 NEBnext PCR master mix (New England BioSciences) and custom Nextera PCR primers 1 and 2 (Illumina, Supplementary Data3). Full libraries were amplified for five cycles (Thermo Fisher), after which a test aliquot of each sample was taken to test 20 cycles to determine the additional number of cycles needed for the remaining 45L reaction (QuantStudio 6K, Applied Biosystems). After the additional cycles were complete (average of 515 additional cycles), libraries were purified using a Zymo Conc & Clean (Genesee) prior to a two-sided Ampure bead (Beckman Coulter) size selection to enrich nucleosome-free fragments. Fragment size and concentration were determined by TapeStation 2000 and Qubit 4 (Agilent). Following QAQC, samples were sequenced on the Illumina HiSeq4000 (75x paired-end HO).

Following FACS sorting, paired multiome Single Cell ATAC (scATAC) and Single Cell Gene Expression (scGEX) libraries were prepared using the 10x Chromium Single Cell Multiome ATAC+Gene Expression kit (CG000338) with the low cell input nuclei isolation protocol (CG000365 Rev C). Lysis buffer strength was 1X, and lysis time was 4min. Multiome ATAC libraries (50x8x24x9) and GEX libraries (28x8x24x9) were sequenced at a depth of 2550,000 read pairs per cell on either the Illumina NextSeq2000P2 or Illumina NovaSeq SP.

The expression of Type 1 and Type 2 lineage-defining and lineage-associated genes was assessed in ex vivo expanded ILC2s and pcILC2s via quantitative real-time polymerase chain reaction (qRT-PCR) was performed with the RT2 Profiler PCR Array system (Qiagen, Hilden, Germany). Briefly, ILC2 and pcILC2 cells were cultured as described above and RNA was extracted after 6 days of expansion with the RNeasy Mini Kit (Qiagen). cDNA synthesis and genomic DNA elimination were performed with the RT2 First Strand Kit (Qiagen). cDNA was applied to the RT Profiler PCR Array Mouse Th1 & Th2 Response kit (PAMM-034Z; Qiagen) and PCR amplification was performed using RT2 SYBR Green qPCR Mastermix (Qiagen). Raw CT values were uploaded to Qiagens web-based software GeneGlobe, wherenormalization was performed by comparing to the internal housekeeping gene panel, and relative mRNA expression in the ILC2s and pcILC2s was calculated via the CT method.

Adapter sequences were removed from reads using cutadapt (v. 1.12). Reads were quality filtered using FASTX-ToolKit (v0.0.12) passing options Q 33, -p 90, and q 20. Reads were aligned to the mm10 genome using STAR (v2.5.2b) with the options: --outFilterScoreMin 1, --outFilterMultimapNmax 1 --outFilterMismatchNmax 2, --chimJunctionOverhangMin 15, --outSAMtype BAM Unsorted, --outFilterType BySJout, --chimSegmentMin 1. Read per million (RPM) normalized H3K4me3 signal at gene (RefSeq) promoters was calculated using deepTools (v.3.5.2), with the promoter region being defined as +300bp from mm10 RefSeq TSS to 500bp. Published H3K4me3 fastq files were downloaded from a public repository (GEO: GSE85156)8 and were aligned to the mm10 genome as described above. H3K4me3 peaks were identified using MACS2 (v.2.1.2, using default parameters)9 for all subpopulations of ILCs (two replicates each). Differential H3K4me3 marked promoters were identified through the application of DEseq2 (Likelihood ratio test, v.1.40.2)31 on the union set of peaks. Multiple testing was mitigated using the Benjamini and Hochberg method. ILC1, ILC2, and ILC3-specific H3K4me3 marked promoters were identified by hierarchical clustering of differential promoters. Representative tracks were created by passing RPM normalized bigwig files to the UCSC Genome Browser.

Data from Bruce et al. J Clin Invest, 127(5):1813-1825. doi: 10.1172/JCI91816, PMID: 28375154. FASTQ files were downloaded from GEO (GSE95811)4. Adapter sequences were removed using (cutadapt v1.12). Reads were quality filtered using fastq quality filter in FASTX-Toolkit (v0.0.12) with options -Q 33, -p 90, and q 20. Reads were aligned to mm10 genome using STAR (v2.5.2b) with the following options: --quantMode TranscriptomeSAM, --outFilterMismatchNmax 2, --alignIntronMax 1000000, --alignIntronMin 20, --chimSegmentMin 15, --chimJunctionOverhangMin 15, --outSAMtype BAM Unsorted, --outFilterType BySJout, --outFilterScoreMin 1. Transcript-level expression values (TPM) were estimated using Salmon (v0.11.3) for RefSeq transcripts. TPM data was collapsed into gene-level expression values using a tximport. Refseq was used for gene annotation.

Sequence adapters were trimmed using cutadapt (v. 1.12) with the following options -a CTGTCTCTTATA -A CTGTCTCTTATA and --minimum-length 36 and set for paired-end sequence data. Reads were then quality filtered using fastq_quality_filter in FASTX-Toolkit (v. 0.0.14), with the options -Q 33, -p 90, and -q 20. PCR duplicates were restricted by limiting the same sequence to a max of 5 copies. After this duplicate threshold was reached, the remaining reads were excluded (In house scripts). As one read of a read-pair may have been excluded during filtering, fastq files were synced following the filtering step to ensure accurate alignment. Reads were aligned to either mm10 or hg38 using STAR (v2.5.2b) with options chimSegmentMin 15, --outFilterMismatchNmax 2, --chimJunctionOverhangMin 15, --outSAMtype BAM Unsorted, --outFilterScoreMin 1, --outFilterType BySJout and --outFilterMultimapNmax 1. Samtools (v. 1.3.1) and bedtools (v. 2.26) were then used to create bigwig files. These files only include fragment data for the first 5bp from the 5 end and the last 4bp from the 3 end of fragments. Regions of chromatin accessibility (peaks) were defined using MACS (v. 2.1.2) with options nomodel, --shift 0, --extsize 5. Sites of differential chromatin accessibility were identified using DESeq2 (v. 1.40.2) with default parameters using a union set of peaks. Motif analysis was performed using findMotifsGenome.pl from HOMER (v. 4.11.1). Representative tracks of normalized ATAC signal were generated by visualizing bigwig files on the UCSC genome browser.

From Gury-BenAri et al. Cell, 2016, 166(5):1231-1246.e13, doi: 10.1016/j.cell.2016.07.043, PMID: 27545347. The UMI count table was downloaded from GEO (GSE85152). The count table was calculated as previously described8. The first gene name was selected to represent features when more than one possible annotation was available. Cells with less than 200 UMIs were discarded from downstream analysis.

Paired-end FASTQ files were pre-processed and aligned to the mouse reference genome (GRCm38/mm10) using cellranger-arc count (v. 2.0.0) with default parameters. Next, we selected nuclei with a total RNA read count <25,000, total RNA read count >1000, total ATAC read count <70,000, total ATAC read count >5000, and mitochondrial counts <20% for downstream analysis. We then integrated the datasets using RNA data only or with both RNA and ATAC. Integration using RNA was accomplished using the IntegrateData function within Seurat passing default parameters (v. 4.3.0.1)10. The dimensionality of the data was reduced using principal component analysis (PCA), and Uniform Manifold Approximation and Projection for Dimension Reduction (UMAP). Cells were then clustered using the FindClusters function within Seurat. Prior to the integration of multi-modality data, the RNA and ATAC count matrices for each sample were merged. The merge function within Seurat was used to concatenate the RNA count matrices. To create the merged ATAC count matrix, we first identified a union set of peaks across all samples and calculated the number of ATAC fragments overlapping those shared genomic coordinates for each sample using FeatureMatrix (Signac v. 1.10.0). The RNA and ATAC count matrices were then merged by sample, and the data were integrated using the Weighted nearest neighbor analysis (Seurat) to develop shared inference32. Differentially expressed genes were identified using a Wilcoxon rank sum test as implemented in the package presto (v. 1.0.0) or with the FindMarkers function in Seurat. Heatmap of differentially expressed genes depicts mean-centered and normalized RNA abundance. Normalized (SCTransform) and uncorrected (pre-integration) RNA counts were used for differential testing. A 2-cell cluster (pre- and post-transplant mouse data, AAGGATTAGCTCATAA-1_2, AGTGGACAGCTATTAG-1_2) was identified and excluded from downstream analysis. To determine differential regions of chromatin accessibility, we also used a Wilcoxon rank sum test (presto, v. 1.0.0) on TF-IDF normalized ATAC counts. Heatmap of differential regions of chromatin accessibility depicts mean-centered and normalized ATAC signal. Per-cell accessibility for motifs (motif enrichment scores) was calculated using the package chromVAR (v. 1.22.1). The JASPER 2020, CORE, vertebrate motif database was used during motif identification. To identify putative TF regulators for each cluster of cells, the AUC statistics calculated by presto during the differential expression and differential motif enrichment analysis (Wilcox rank sum test (p adj <0.05, RNA.logFC> 0 and motif.p adj <0.05, motif.logFC> 0)) were averaged, and the TFs with the highest value were considered top candidates. Average per-cell chromatin accessibility (ATAC signal) across genes previously associated with ILC1 and ILC2 isolated from small intestinal lamina propria of mice8 was calculated using the FeatureMatrix from the Signac Package. For ontology analysis, we used Enrichr33 and tested for significant overlap between genes associated with post-transplant cells and gene sets found in the mouse gene atlas database. The average marker expression of ILC1, ILC2, ILC3, and NK cells was defined by averaging the normalized gene expression for genes previously associated with each cell type11. Classification of post-transplant cells as ILC1, ILC2, or ILC3 was based on lineage defining genes previously associated with each type of ILC8. Seurat was used to integrate post-transplant single nucleus RNA data with previously published8 MARS-seq RNA abundance data as previously described10. Cells were classified by calculating the average rank of genes associated with each type of ILC and labeling each cell with the cell type with the highest rank. Undetermined signifies a tie in ranking. Upset plots were created using UpSetR (v. 1.4.0).

Paired-end FASTQ files were pre-processed and aligned to the mouse (GRCm38/mm10) or human reference genome (GRCh38/hg38) using cellranger-atac count (v. 2.0.0) with default parameters. To compare the average normalized ATAC signal across each patient sample at hILC2 sites of CA (defied with bulk ATAC data), we first calculated the number of ATAC fragments overlapping the 7456 associated sites of CA using FeatureMatrix (Seurat, v. 4.3.0.1), respectively. We then merged these count matrices and normalized the data using TF-IDF as implemented in Seurat (v. 4.3.0.1). The same operations were performed for the pc-hILC2 associated sites of CA (n=5,051) as well as random sites (n=7,456) of chromatin accessibility shared between hILC2 and pc-hILC2s. Samples were grouped into six patient conditions, four according to transplant status and aGVHD, two healthy donors, and expanded ILC2s derived from an additional single healthy donor. Differential ATAC was tested using patient condition as a categorical variable in a linear model. The model was fit in R and the coefficients were evaluated to highlight different effects for patient conditions. We then grouped the sample into four categories: healthy donor, ILC2, pre- and post-transplant samples (independent of aGVHD) and repeated the above analysis. For both tests, we assessed significance using p<0.05. Identification of genes with differential ATAC signals between pre- and post-transplant patients was performed using the sum of ATAC signals at each gene for all patient samples (calculated with FeatureMatrix). The 6 pre-transplant and 6 post-transplant samples were then analyzed as biological replicates of each condition, and differential analysis was performed using DESeq2. Ontology analyses were performed using g:profiler (v. 0.2.2)34. For differential analysis of aggregate ATAC signal for each gene average ATAC signal was defined as the total normalized ATAC signal over all gene bodies plus 2kb upstream for all pre- (n=6) and post-transplant (n=6) patient samples. Genes with differential ATAC signals were then identified using DESeq2.

Survival differences were evaluated using a Mantel-Cox log-rank test. Survival curves were generated using the Kaplan-Meier method. Differences in GVHD clinical and pathology scores were determined using 2-way ANOVA, with Bonferroni correction for repeated measures of multiple comparisons. Statistical analysis of ATAC-seq and RNA-seq data is described above. Unless otherwise noted in the figure legends, all other continuous variables were compared using a 2-tailed Students t test with Welchs correction. A P-value of 0.05 was considered statistically significant.

Further information on research design is available in theNature Portfolio Reporting Summary linked to this article.

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Type II innate lymphoid cell plasticity contributes to impaired reconstitution after allogeneic hematopoietic stem cell transplantation - Nature.com

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Close-up of hematopoietic niche in bone marrow: artsakon - stock.adobe.com

The BLA of tab-cel, an off-the-shelf, allogeneic, T-cell immunotherapy, has been accepted and granted priority review by the FDA for the treatment of adult and pediatric patients aged 2 years and older with EBV+ PTLD who have received at least 1 prior therapy. A PDUFA target action date of January 15, 2025, has been set.1

There are currently no FDA-approved therapies in this setting, marking a notable unmet need for patients.

The acceptance of the tab-cel BLA is a significant milestone towards making this first-of-its-kind treatment available to patients in the US, said Pascal Touchon, president and chief executive officer of Atara, in a press release. The FDAs granting of priority review highlights the high unmet need in EBV+ PTLD, which is a devastating disease with limited treatment options and a poor overall survival rate. We continue to work closely with the Pierre Fabre Laboratories team to help prepare for the potential launch in the US in early 2025, along with the potential label expansion multicohort phase 2 EBVision trial [NCT04554914].

The BLA is supported by data from the phase 3 ALLELE study (NCT03394365). The study investigated tab-cel in 43 patients with EBV+ PTLD following hematopoietic cell transplant (HCT) or solid organ transplant (SOT) after rituximab (Rituxan) and chemotherapy failed. Patients received tab-cel at 2 x 106 cells/kg on days 1, 8, and 15 of 35-day cycles.2

The overall response rate (ORR) was 51.2% (95% CI, 35.5%-66.7%). The ORR in patients who underwent HCT (n = 14) was 50.0% (95% CI, 23.0%-77.0%), and 51.7% (95% CI, 32.5%-70.6%) in patients who received SOT (n = 29). The median time to response was 1.0 month (range, 0.7-4.7). Out of the 22 responders, 12 had a duration of response (DOR) longer than 6 months, and the median DOR was 23.0 months (95% CI, 6.8-not evaluable [NE]).

The median overall survival (OS) was 18.4 months (95% CI, 6.9-NE) in the overall population, not reached in the HCT population (95% CI, 5.7-NE), and 16.4 months (95% CI, 5.0-NE) in the SOT population. One-year OS rates were 61.1% (95% CI, 43.7%-74.5%) in the overall population, 70.1% (95% CI, 38.5%-87.6%) with HCT, and 56.2% (95% CI, 34.6%-73.2%) with SOT.

Regarding safety, serious treatment-emergent adverse events (TEAEs) were reported in 57.1% of patients in the HCT group, and 7.1% of patients experienced a fatal TEAE. In the SOT group, 51.7% and 13.8% experienced serious and fatal TEAEs, respectively. No fatal TEAEs were deemed related to treatment. There were no reports of tumor flare reactions, infusion reactions, cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, marrow rejection, or transmission of infectious diseases. There were no reports of graft-vs-host disease or organ rejection that were considered related to tab-cel.

Previously, tab-cel was granted FDA breakthrough therapy designation and orphan drug designation for the treatment of rituximab-refractory EBV-associated lymphoproliferative disease.1

Original post:
FDA Accepts Application of Tab-Cel, First-in-Class Therapy for EBV+ PTLD - Targeted Oncology

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A German man has probably been cured of HIV, a medical milestone achieved by only six other people in the more than 40 years since the AIDS epidemic began.

The German man, who prefers to remain anonymous, was treated for acute myeloid leukemia, or AML, with a stem cell transplant in October 2015. He stopped taking his antiretroviral drugs in September 2018 and remains in viral remission with no rebound. Multiple ultra-sensitive tests have detected no viable HIV in his body.

In a statement, the man said of his remission: A healthy person has many wishes, a sick person only one.

The case, which investigators said offered vital lessons for HIV cure research, is expected to be presented Wednesday by Dr. Christian Gaebler, a physician-scientist at the Charit-Universittsmedizin Berlin, at the 25th International AIDS Conference in Munich.

The longer we see these HIV remissions without any HIV therapy, the more confidence we can get that were probably seeing a case where we really have eradicated all competent HIV, Gaebler said.

As with all previous cases of potential HIV cure, experts are eager to temper public excitement with a caveat: The treatment that apparently thwarted the virus in the seven patients will ever be available to only a select few. All contracted HIV and later developed blood cancer, which demanded stem cell transplants to treat the malignancy.

The transplants in most cases from donors selected because their immune cells, the cells that HIV targets boasted a rare, natural resistance to the virus and were instrumental in apparently eradicating all viable, or competent, copies of the virus from the body.

Stem cell transplants are highly toxic and can be fatal. So it would be unethical to provide them to people with HIV except to treat separate diseases, like blood cancer.

HIV is monumentally difficult to cure because some of the cells it infects are long-living immune cells that are in or enter a dormant state. Standard antiretroviral treatment for HIV works only on immune cells that, typical of infected cells, are actively making new viral copies. Consequently, HIV within resting cells stays under the radar. Collectively, such cells are known as the viral reservoir.

At any moment, a reservoir cell can start producing HIV. That is why if people with the virus stop taking their antiretrovirals, their viral loads typically rebound within weeks.

A stem cell transplant has the potential to cure HIV in part because it requires destroying a persons cancer-afflicted immune system with chemotherapy and sometimes radiation and replacing it with a donors healthy immune system.

In five of the seven cases of definite or possible HIV cure, doctors found donors who had rare, natural defects in both copies of a gene that gives rise to a particular protein, called CCR5, on the surface of immune cells. Most HIV strains attach to that protein to infect cells. Without functional CCR5 proteins, immune cells are HIV-resistant.

The German mans donor had just one copy of the CCR5 gene, meaning his immune cells most likely have about half the normal quantity of that protein. In addition, he had only one copy of the gene himself. Together, those two genetic factors may have upped his chances of a cure, Gaebler said.

While having two copies of the defective CCR5 gene is rare, occurring in about 1% of people with native northern European ancestry, having one copy occurs in about 16% of such people.

So the study suggests that we can broaden the donor pool for these kinds of cases, Dr. Sharon Lewin, director of the Peter Doherty Institute for Infection and Immunity in Melbourne, Australia, said in a media briefing last week.

Interestingly, a man treated in Geneva whose possible HIV cure was announced last year had a donor with two normal copies of the CCR5 gene. So his transplanted immune cells were not HIV-resistant.

Those two recent European cases raise critical questions about the factors that actually contribute to a successful HIV cure.

The level of protection one might have predicted from transplant should not have been enough to prevent the virus from surviving and rebounding, Dr. Steven Deeks, a leading HIV cure researcher at the University of California, San Francisco, who is not involved with the German mans care, said of his case. There are several testable theories, so I am optimistic we will learn something here that could shape the next generation of cure studies.

Gaebler said having HIV-resistant immune cells in the mix surely greatly improves the chances of success in curing the virus with a stem cell transplant. And yet, he said, lacking that safety net, or having one with some holes in it, as with the German man, does not preclude success.

We need to understand how the new immune system successfully grafted into his body and how it successfully eliminated HIV reservoirs over time, he said. Suggesting that the transplanted immune cells may have attacked the viral reservoir, he said, The donors innate immune system might have played an important role here.

All were initially known by pseudonyms based on where they were treated.

Adam Castillejo, aka the London patient. Castillejo, 44, a Venezuelan man living in England, received a stem cell transplant for AML in 2016 and stopped HIV treatment in 2017. He is considered cured.

Marc Franke, the Dsseldorf patient. Treated with a stem cell transplant for AML in 2013, Franke, 55, went off antiretrovirals in November 2018 and is considered cured.

Paul Edmonds, aka the City of Hope patient. Edmonds, the oldest potential cure case at 63 when he received a stem-cell transplant for AML in 2019, received reduced-intensity chemotherapy because of his age. Off antiretrovirals since March 2021, he will be considered cured when he hits five years with no viral rebound. In an interview, he expressed excitement over the new case of a man probably cured, as well, and said, My vision is clear: a world where HIV is no longer a sentence, but a footnote in history.

The New York patient. The first woman and person of mixed-race ancestry possibly to be cured, she was diagnosed with leukemia in 2017 and received a stem cell transplant augmented with umbilical cord blood, which allowed for a lower genetic match with her donor, thus broadening the donor pool.

The Geneva patient. In his 50s, he was diagnosed with a rare blood cancer in 2018 and has been off of HIV treatment since November 2021. Researchers remain cautious about his cure status because his immune cells are not HIV resistant.

Franke, Edmonds and Castillejo, who have become friends, are expected to attend the HIV conference in Munich.

More here:
A 7th person with HIV is probably cured after stem cell transplant for leukemia, scientists say - AOL

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Re-establishing immune tolerance in multiple sclerosis: focusing on novel mechanisms of mesenchymal stem cell regulation of Th17/Treg balance -...

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Seventh person likely 'cured' of HIV, doctors announce - El Paso Inc.

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Jul 19, 2024 14:00:00

A German HIV patient has been symptom-free for six years after undergoing a stem cell transplant, making him likely the seventh person to be essentially cured of HIV after receiving a stem cell transplant, doctors have announced.

Seventh person likely 'cured' of HIV, doctors announce

According to the research abstract, the German man in long-term remission was first diagnosed with HIV in 2009, underwent a bone marrow transplant for leukemia in 2015, and then stopped taking antiretroviral drugs to reduce the amount of HIV in his blood in 2018. Nearly six years have passed since then, and he has been deemed to have achieved long-term remission as he has not developed HIV or cancer.

'We can never be absolutely certain that the last traces of HIV have been eradicated,' said Dr. Christian Gabler of Charit University Hospital, who treated the patient. 'However, this patient's case is a strong indicator of HIV cure.'

'Researchers are hesitant to use the word 'cure' because it's not clear how long cases like this need to be followed for, but more than five years in remission means this man is 'near cure,'' said Sharon Lewin, president of the International AIDS Society.

Lewin said there's an important difference between this man's case and other HIV patients who have achieved long-term remission: All but one of them reportedly received stem cells from donors who carried a rare mutation that stops HIV from entering the body's cells.

All of these donors were found to have a defective CCR5 gene, meaning they had inherited two copies of the mutated gene (one from each parent), which gave them 'intrinsic immunity to HIV,' Lewin said.

However, this patient is the first to have received stem cells from a donor who inherited only one mutated gene.

While only 1% of Europeans have inherited two copies of the mutated CCR5 gene, as many as 15% have only one, which suggests that more donors may be accepted in the future, the researchers said.

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Doctors say 60-year-old German man likely to become seventh person in the world cured of HIV - GIGAZINE

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This new model, which mimics human bone marrow, could offer a novel approach to testing drugs and techniques for treating blood disorders like sickle cell disease and blood cancers

Scientists from the University of Glasgow have developed the first bioengineered bone marrow model capable of supporting long-term hematopoietic stem cells (LT-HSCs), essential for bone marrow transplants and in vitro studies.

This groundbreaking research, published in Nature Communications, replicates key aspects of the human bone marrow microenvironment, enabling the support and culture of these rare stem cells outside the human body.

LT-HSCs are crucial for bone marrow transplants as they can replenish blood cells after treatments for blood cancers. However, culturing these cells in the lab has been challenging as they quickly change or die once outside the body. Due to this limitation, scientists have to rely on non-human animal models to test drugs affecting blood cell production and targeting blood diseases such as leukaemias. These models often provide poor predictions of drug outcomes.

In the study, led by Dr. Hannah Donnelly, LT-HSCs were cultured out of the body by using specially engineered gels mimicking the bone marrow environment.

Dr Donnelly said: LT-HSCs are notoriously difficult to culture outside the body yet hold enormous clinical value.

Here, we show that by using gels engineered to mimic the environment where they reside in the bone marrow, we can support and study these cells in the lab, ultimately harnessing their full clinical potential.

The scientists showed that gene editing of LT-HSCs in these gels is feasible, potentially offering a new way to test new drugs and techniques for treating blood disorders such as sickle cell disease and blood cancers, thus reducing dependence on animal models.

Professor Matt Dalby, Director of Innovation, Engagement, and Enterprise at the School of Molecular Biosciences, University of Glasgow, highlighted the impact of their research on drug testing: Currently used animal models are poor predictors of drug outcomes, and many of the blood disease treatments on offer such as mRNA drugs and human-specific small molecules dont test well in animal models.

By creating ambitious models of the bone marrow which contain human cells and have the ability to mimic blood cell growth we are thrilled to show for the first time that it is possible to test true human blood cells out with the human body, and the implications for accelerating therapies for diseases such as sickle cell disease and blood cancers gives us huge reason to be hopeful.

Professor Manuel Salmeron Sanchez, Chair of Biomedical Engineering and Head of the School of Engineering, added that the use of this new model, which mimics bone marrow will allow them to focus on the earliest stages of diseases, providing new understanding, screening methods, and drugs.

This research is part of a major investment in leukemia research in the UK, funded by the UKRIs Engineering and Physical Sciences Research Council (EPSRC). Leukaemia kills over 300,000 people globally each year, but early diagnosis of the disease remains a challenge, which reduces the impact of treatments.

The study titled Bioengineered niches that recreate physiological extracellular matrix organization to support long-term haematopoietic stem cells, provides hope for better understanding, diagnosis, and treatment of blood disorders and cancers.

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New bioengineered bone marrow model offers hope for blood cancer therapy - Pharmacy Business

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Type VI CRISPR-Cas systems, of which Cas13 is the defining member, provide adaptive immunity in prokaryotes by targeting RNA transcripts of invading mobile genetic elements. Cas13-mediated RNA targeting occurs through the action of a Cas13 protein and its CRISPR RNA (crRNA), which function together as an RNA-guided ribonuclease.

All Cas13s possess two higher eukaryotes and prokaryotes nucleotide-binding (HEPN) domains; these have been shown to dimerise intramolecularly to form the active site in response to target-transcript recognition.

HEPN domains, which are not exclusive to Cas13, are known for their high diversity and poor sequence conservation, which impedes standard homology searches and makes evolutionary analyses challenging. As a result, compared to other widely study Cas endonucleases, e.g., Cas9 and Cas12, few distinct Cas13 subtypes have been identified to date, and their evolutionary origins remain poorly understood.

To address those challenges, a team led by Nobel Laureate Jennifer Doudna built an automated structural-search pipeline that combines the speed of machine learning-based search methods with the sensitivity of traditional structure alignment programmes. Using this pipeline, they identified an ancestral clade of Cas13 (Cas13an) and traced Cas13 origins to defence-associated ribonucleases (1).

The team shows that in spite of its small size compared to other Cas13s, Cas13an can selectively target green fluorescent protein (GFP) transcripts when co-expressed with GFP-targeting crRNAs in E. coli, and that the HEPN domain is essential for this activity.

Cas13an also provided defence against diverse bacteriophages when co-expressed with selected phage-targeting crRNAs in E. coli. The study revealed that Cas13an employs a single active site for both CRISPR RNA processing and RNA-guided cleavage in contrast to the larger Cas13s, revealing two modes of activity for the ancestral nuclease domain.

The findings, which were published in Science today, add to the current understanding of CRISPR-Cas evolution and should create new opportunities for precise RNA editing.

References

1. P. H. Yoon et al., Science 10.1126/science.adq0553 (2024).

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Structure-guided discovery reveals ancient clade of Cas13 ribonucleases - CRISPR Medicine News

Recommendation and review posted by Bethany Smith

There are different types of biotechnology protocols for genome/gene editing (GE), but the preferred one is the Clustered Regularly Interspaced Short Palynodromic Repeat (CRISPR) Cas9 system. Advantages include precision, the ability to design variants tailored to needs, and optimal operational cost and time.

CRISPR was first identified in 1987 as a bacterial defence system against viral infections. The Nobel Prize-winning research (Chemistry, 2020) of Jennifer Doudna and Emmanuelle Charpentier (2012) provided a novel translational biotech protocol to precisely target and cleave a specific DNA sequence in any living organism, facilitating its transfer to any other living organism.

Since then, CRISPR-edited biotech applications have revolutionised human welfare initiatives in healthcare (new medicines, treatment of viral infections, clinical diagnostics, cure of inherited genetic disorders such as retinal degeneration, boosting immunity, powerful DNA vaccines, etc.), agriculture (crop and livestock transformation for high yield, pests/parasite eradication), energy (bio-fuels), biodiversity conservation, and climate change. However, CRISPR applications in human reproductive biology could pose serious threats to human identity and social order if not handled with prudence.

The scope of CRISPR-edited biotech applications demonstrates that the Biological Cellular Universe/Space is as enchanting and intellectually challenging as the external universe/space, contributing to our knowledge base and driving global industrial markets (corporate science) for socio-economic development. Yet, it has remained in the shadows of the physical sciences dominated technology ecosystem.

Interestingly, a publication database survey by P D Ramos and others in 2023 revealed low awareness of the impact of CRISPR among the general public. Communicating the importance of CRISPR and other global techno-science developments to stakeholders should be prioritised.

Increasing CRISPR capabilities in human reproductive biology have ignited intense ethical debates across the globe. The 2018 reports of the birth of a CRISPR-edited human child jolted and compelled intellectuals to take serious note of the adverse impact on biological human identity and ethical practices. A new era of bio-politics is upon us.

Ethical challenges: Techno-science developments such as AI, CRISPR, and their regulatory frameworks are in a perpetual arms race, with the latter more often lagging. The chances of maverick scientists attempting to transform human embryos with malicious intentions should be anticipated and prevented. The apprehensions of Oppenheimer, Neil Bohr, and Fermi (their discoveries in nuclear fission led to the making of an atomic bomb) are equally applicable to CRISPR-edited applications, including human babies.

At the heart of the ethical landscape is the precautionary principle invoked since 1970 for environmental threats due to genetically modified crop plants. Agricultural biotechnologists and environmentalists are engaged in heated debates about whether the principle is being applied excessively, stifling innovation and delaying human welfare, or whether it should be strictly enforced until all the safety concerns are addressed.Notwithstanding, 72 countries have accepted biotech crops, including the United States (71.5 million hectares), Brazil (52.8 million hectares), Argentina (24.0 million hectares), Canada (12.5 million hectares), and India (11.9 million hectares). The global agricultural biotechnology market is estimated to reach $110 billion by 2030.

The theoretical trajectories of ongoing research at the MIT Centre for Brains, Minds, and Machines on human brain-AI interfaces and the CRISPR-edited birth of a human baby seem to converge on the development of a human-like robot or robot-like human, with potential performance competencies surpassing human cognitive abilities. If realised, it would be one of the greatest ethical threats that humanity has ever faced.

Science philosopher and visionary C P Snow, in his book, The Two Cultures and the Science Revolution, called upon humanist studies to counter the technologico-Benthamite culture, which misuses science in ways that cheapen, impoverish, and dehumanise life. According to Yoshua Bengio, extreme governance measures would be needed to prevent misadventures in AI. This is also true for CRISPR or any other technology with a potential threat to ethical practices.

Regulatory Landscape: WHO is set to create a Global Regulatory Framework to verify the science behind CRISPR applications and to regulate human gene editing. In the US, the Food and Drug Administration regulates gene therapy products through a risk-based approach, evaluating each therapy on a case-by-case basis to ensure that it meets rigorous safety standards. The European Medicines Agency and the National Medical Products Administration in China have established similar frameworks. Argentina, Canada, Brazil, Australia, South Africa, and Japan have also taken similar initiatives; a global consensus remains elusive.

In India, genetically modified organisms and their products are regulated by the Environment (Protection) Act (1986) and the Rules for the manufacture, use, import, export, and storage of hazardous microorganisms, genetically engineered organisms, or cells (1989).

Harnessing the benefits of the techno-science revolution would be a meaningful mission only when its inherent fundamentalism is dealt with strongly by a robust policy framework with accountability and self-regulation legally assigned to all stakeholders. (The writer is a former professor and registrar, Bangalore University)

(The writer is a formerprofessor and registrar, Bangalore University)

Published 17 July 2024, 20:39 IST

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Ethics and benefits of gene editing - Deccan Herald

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Alzheimer disease risk reduced by hormone therapy for breast cancer treatment | Image Credit: Graphicroyalty - Graphicroyalty - stock.adobe.com.

There is an association between hormone therapy use for breast cancer and protection against Alzheimer disease and related dementias (ADRD) when aged 65 years and older, according to a recent study published in JAMA Network Open.1

Thirty-one percent of all new cancer cases in the United States are breast cancer, and 83% of invasive breast cancers are observed in women aged at least 50 years. Data has indicated a median age of 62 years during diagnosis, and a median age of 69 years at breast cancer death.2

Over time, breast cancer survival has improved, leading to over 2.5 million breast cancer survivors aged over 65 years.1 This has increased concerns about treatment-related complications among older adults.

Alzheimer disease is reported in 10.8% of patients aged 65 years and older and is the seventh leading cause of death in the United States. The number of people with ADRD is expected to increase over time, leading to concerns about development in breast cancer survivors.

Investigators conducted a study to determine the association between hormone-modulating therapy (HMT) among breast cancer patients and ADRD risk. Demographic, sociocultural, and clinical information about breast cancer patients was obtained from the Surveillance, Epidemiology, and End Results Medicare linked database.1

Participants included women aged at least 65 years recently diagnosed with breast cancer between 2007 and 2009. HMT types included selective estrogen receptor modulators (SERMs), aromatase inhibitors (AIs), and selective estrogen receptor degraders (SERDs).

ADRD was defined as the primary outcome of the analysis, reported based on International Classification of Diseases, Ninth Revision (ICD-9) and ICD-10 codes. ADRD subtype codes were also included to account for all ADRD patients. Covariates included demographic, sociocultural, medical, and treatment variables.

There were 18,808 breast cancer patients included in the final analysis, 65.7% of whom had HMT exposure within 3 years after diagnosis and 34.3% did not have HMT exposure. Patients were most commonly aged 75 to 79 years, with a mean age at diagnosis of 75 years in the HMT group and 76 years in the non-HMT group.1

A mean time to start HMT of 5.6 moths from diagnosis was reported, with 76.1% of HMT users initiating with AIs, 23.6% with SERMs, and only 0.3% with SERDs. HMT lasted for a mean 24 months within 3 years after breast cancer diagnosis.

ADRD was reported in 23.7% of HMT users and 27.9% of non-HMT users by the end of the follow-up period. Death was reported in 26.4% and 27.5%, respectively. This indicated a significant association between HMT use and reduced risk of ADRD, with a hazard ratio (HR) of 0.93.1

HRs were also significant for AI and SERM separately, at 0.93 and 0.89, respectively. However, SERD was not significantly associated with reduced risk of ADRD, with an HR of 0.37.

An age-modified association between HMT and ADRD risk was identified during subgroup analyses. Patients aged 65 to 69 years had the most reduced risk with an HR of 0.48. In comparison, by the age of 80 years, HMT was positively associated with ADRD, with an HR of 1.40.

These results indicated an association between HMT use and improved protection against ADRD among breast cancer patients, with age considered an important modifier in this link. Investigators recommended further research to validate these associations in diverse populations.1

Reference

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Alzheimer disease risk reduced by hormone therapy for breast cancer treatment - Contemporary Obgyn

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Imagine waking up after being frozen for decades, only to discover youre broke. Thats a nightmare nobody wants, especially the rich. Making sure their wealth lasts is easier than reversing death, though.

Cryonics, or freezing the body after death in hopes of future revival, is attracting serious attention. According to Bloomberg Law, estate lawyers are developing "revival trusts" to keep wealth intact for those who opt for cryopreservation.

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Once considered a crazy idea, it is now somewhat trendy. Alcor Life Extension Foundation, one of the largest cryonics facilities, has about 5,500 people planning to be frozen, and some estate lawyers have already helped hundreds of people set up revival trusts to preserve their wealth until they can be revived.

Revival trusts are based on some big assumptions but are taken seriously enough to be discussed at industry conferences. These trusts differ from dynasty trusts because they aim to benefit the revived person. Across the country, the laws are already changing to allow trusts to last for centuries, with some states like Florida permitting trusts to continue for up to 1,000 years.

Despite uncertainties, the quest for immortality through cryonics is gaining traction. According to Business Insider, tech billionaires like Peter Thiel, Sam Altman, and Jeff Bezos invest heavily in anti-aging and cryonics research.

Trending: Rory McIlroys mansion in Florida is worth $22 million today, doubling from 2017 heres how to get started investing in real estate with just $100

Thiel plans to be cryogenically preserved, viewing it as an ideological statement. He believes humanity should "either conquer death or at least figure out why its impossible."

Altman has invested $180 million in Retro Biosciences, a startup that aims to extend healthy human life spans. Bezos has invested in Altos Labs, a startup that is developing therapies to stop or reverse aging.

The quest to cheat death is becoming more mainstream. Take Bryan Johnson, a tech executive known for his ambitious anti-aging efforts. Johnson reportedly spends $2 million a year on his anti-aging regimen. This includes taking 111 pills daily, eating all his food within a strict time frame between 6 a.m. and 11 a.m., and employing a light therapy mask. At one point, he even received blood plasma infusions from his teenage son, although he stopped this practice due to a lack of evidence supporting its benefits.

See Also: This Jeff Bezos-backed startup will allow you to become a landlord in just 10 minutes, and you only need $100.

HBOs docuseries How To with John Wilson explored cryopreservation in its final episode, offering a glimpse into this strange and futuristic world. The show stressed that its not just the wealthy interested in cryonics; many regular people are drawn to the idea, dreaming of a futuristic world or simply wanting to witness future progress.

Still, cryonics is expensive. Too expensive for the common folk. Alcor, for example, charges $80,000 to freeze a head and $200,000 for a whole body, plus annual dues. Most members pay for this by naming Alcor as their life insurance beneficiary.

Despite the high costs and uncertainties, people who hope for a second chance at life continue to invest in cryonics and revival trusts.

The pursuit of longevity and reversing aging is often driven by the belief that aging is a disease that science can eventually cure. While the technology to fully overcome aging isnt available yet, cryonics offers a hopeful bridge to that future.

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Back From The Dead And Broke? Not For The Wealthy 5,500 Betting On Cryonics: Ensuring Wealth Beyond The Grave - Benzinga

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JCR Pharmaceuticals Highlights Innovative Gene Therapy Research at the 7th International Forum of Lysosomal Disorders - The Bakersfield Californian

Recommendation and review posted by Bethany Smith

A pharmacist at a health-care centre in India dispenses free medicine to a person with sickle-cell disease.Credit: Rafiq Maqbool/AP Photo/Alamy

Last November, the United Kingdom became the first country to authorize the use of a therapy called Casgevy, based on CRISPR gene-editing technology, for the treatment of sickle-cell disease. Within a few weeks, three other countries the United States, Bahrain and Saudi Arabia had done the same. In December 2023, the United States also approved the use of Lyfgenia, another gene therapy, to treat the disease.

Sickle-cell disease kills nearly 400,000 people each year globally. It causes red blood cells to become sickle-shaped and clog blood vessels, which can result in severe pain and tissue damage, among other problems1. More than 75% of people with the disease one of the most common inherited disorders in the world are born in sub-Saharan Africa and India. The 2021 Global Burden of Disease Study, a regional and global effort to assess mortality and disability resulting from major diseases, found it to be the 12th leading cause of death globally in children under five1. In Africa, more than 50% of infants or children diagnosed with sickle-cell disease die before the age of five2.

Until the advent of gene therapies, the only cure was a bone-marrow transplant. This requires finding a healthy donor, followed by invasive treatment over weeks3.

Given all this, obtaining regulatory approval for two gene therapies is a phenomenal achievement. Yet at prices of US$2.2 million and $3.1 million per treatment, respectively, for Casgevy (exaxamglogene autotemcel) and Lyfgenia (lovotibeglogene autotemcel), the risk is that both will be withdrawn from the market because too few people or health-care systems can afford them.

This has already happened for four other gene therapies, including a related treatment called Zynteglo (betibeglogene autotemcel), for -thalassaemia. Another inherited blood disorder, -thalassaemia causes anaemia, tiredness and weakness in about 3% of the global population, but its incidence can reach 20% in regions including Africa, the Middle East and southeast Asia4. In 2021, Zynteglo was withdrawn from the European market after its developer, the pharmaceutical company Bluebird Bio, based in Somerville, Massachusetts, failed to persuade public bodies such as the United Kingdoms National Institute for Health and Care Excellence (NICE) to approve it. Zynteglo costs $1.8 million per treatment.

Researchers, drug developers and drug manufacturers are squandering the chance to make gene therapies viable even in wealthier countries, let alone transformative for the world. To seize the opportunity, they must take into account the populations most in need, as well as the global market for treatments both when developing and when valuing the drugs. This means reconsidering who is enrolled in clinical trials and where those trials are conducted. It also means partnering with low- and middle-income countries (LMICs), and facilitating the development and production of gene therapies in the nations that need them most.

Casgevy and Lyfgenia are among the latest examples of treatments (see Forging ahead) that involve making alterations to peoples genomes through the replacement, deletion or insertion of genetic material. Since 2004, regulators worldwide have authorized 30 other gene therapies for genetic disorders, including immune and red-blood-cell disorders, retinal degeneration and leukodystrophy a set of conditions affecting the central nervous system as well as for severe cases of some cancers5. Of the 12 genetic disorders that can now be treated using gene therapies, 9 were previously incurable.

Source: Ref. 5

For Casgevy and Lyfgenia, the challenges didnt start with costs. In both cases, participants in the clinical trials did not represent the populations most affected by the disease they are meant to treat.

For Casgevy, trial participants were from the United States, Canada or Europe. For Lyfgenia, the pilot trial included three people from France. All participants in the main trial were from the United States, and the drug was administered only in US clinics. But in North America and Europe, around 1 in 2,000 to 1 in 3,300 people have sickle-cell disease, compared with around 1 in 1,300 in South America and the Caribbean, 1 in 1,000 in India, 1 in 500 in the Middle East, and 1 in 100 in Africa6.

Whats more, because US and European regulators urge drug developers to focus first on those who are made sickest by the disease (which, in the United States and Europe, includes adults), all trial participants for both drugs were older than 12 and most were older than 21 despite the preponderance of sickle-cell disease among children globally. Casgevy is now being evaluated in a phase III clinical trial in people aged 211, but only in the United States, the United Kingdom, Germany and Italy.

This lack of representation in drug trials of those who are most affected by the disease is a violation of article 27 of the Universal Declaration of Human Rights, which states that everyone has the right to share in scientific advancements and its benefits. It is especially problematic for gene therapies for diseases that are prevalent in Africa, where human populations are the most genetically ancient and diverse in the world. Treatments might not work in genetic contexts different from those in which they were tested7, and to produce gene therapies that are as effective as possible globally, drug developers should be testing them in populations that are ancient in evolutionary terms.

Failure to consider the global population during trials could affect the effectiveness and safety of drugs in diverse populations. It is certainly affecting the pricing of gene therapies.

The multimillion-dollar price tags which exclude the costs of clinical care do not actually reflect how much the drugs cost to manufacture. Besides regulatory and research-and-development costs, these prices reflect the perceived maximum value that these therapies add to the person being treated and to society for example, through avoiding medical costs that would otherwise be incurred during someones life under standard clinical care. (People with sickle-cell disease might receive pain medication or transfusions of red blood cells during a pain crisis, say.) Such value-based pricing assessments are generally made by the drug developers themselves, or by a lengthy government review process. Typically, developers will evaluate their own products and governments and independent researchers conduct independent evaluations.

A person with sickle-cell disease receives a blood transfusion at a hospital in Kansas City, Missouri.Credit: Tammy Ljungblad/The Kansas City Star/Tribune News Service via Getty

Yet the way in which gene therapies are currently valued is riddled with difficulties.

Most value-based pricing models do not consider need, affordability or disease prevalence. Moreover, the perception of value varies for different populations and can change over time. In Europe and the United States, for example, sickle-cell disease is classed as a rare genetic disease (even though worldwide it is one of the most common inherited disorders). And this categorization changes how a drug to treat the disease is valued; societies are thought to be more willing to shoulder the costs of an expensive treatment if only a relatively small number of people are affected by the disease8.

Estimates of value added assume that recipients of treatments are cured for life. But the data presented by drug companies to authorities, such as the United Kingdoms National Health Service, often come from only two years of follow-up.

Those evaluating the drugs do not consider that lower-priced treatments might become available in the future say, if some part of the manufacturing process becomes automated. Evaluators also assume that manufacturing will only ever happen in high-income countries, even though drugs could be produced more cheaply in nations such as India, where the costs of labour and locally produced components, including gene-editing reagents, are much lower than in Europe or the United States.

Perhaps most crucially, drug evaluators use clinical data, for instance on the number of times people report a pain crisis to health-care providers, collected only from those in the countries where they expect the drug to be marketed9. In other words, estimates of the value of gene therapies are based on clinical data that are not collected from most of the people with the disease that the therapies are designed to treat.

All this means that gene therapies are perceived to be less cost-effective and more expensive to produce than they would be if their development, production, marketing and uptake shifted to countries where the relevant diseases are most prevalent. For sickle-cell disease, this includes Nigeria, India, the Democratic Republic of the Congo, Tanzania and Uganda10.

The capacity of LMICs to pursue research and development is much greater than many people in wealthier nations might assume. The Drugs for Neglected Diseases Initiative, an international non-profit organization, has brought 13 new drugs to market over the past 20 years, in part by including clinicians, researchers and trial participants from countries such as Ethiopia, Kenya, Malaysia, India and Brazil in the research-and-development cycle (see go.nature.com/3vj59yc).

Global inequities in COVID-19 vaccination have been a powerful reminder of the importance of local manufacturing of both vaccines and treatments. And governments across the world have been pushing hard for this.

A woman in Kano, Nigeria, massages the legs of her daughter, who has sickle-cell disease.Credit: KC Nwakalor/New York Times/Redux/eyevine

Through initiatives such as the New Partnership for Africas Development, the African Union is increasingly supporting the local manufacturing of treatments, vaccines and interventions such as mosquito nets, for example. Similar investment is happening in India. In October last year, Indias equivalent of the US Food and Drug Administration, the Central Drugs Standard Control Organization, approved the use of a home-grown chimeric antigen receptor T-cell therapy, called NexCAR19, to treat blood cancers.

The same government buy-in, national entities and infrastructure must support the local manufacturing of approved gene therapies, to give local populations a chance to access them. The cost savings made by shifting the manufacturing of some of these therapies to Africa or Asia could improve peoples access to them in certain high-income countries too. This is particularly true in Europe, which has more regulatory flexibility than does the United States.

Once it became clear, in 2022 and 2023, that regulators would be reviewing both Casgevy and Lyfgenia and probably approving their use for sickle-cell disease, other biotech companies, including Aruvant Biosciences, based in New York City; Sangamo, based in Richmond, California; and Bioverativ, part of the multinational drug-maker Sanofi; abandoned the development of three gene-therapy products for the disease. Although these pipelines were lagging behind those for Casgevy and Lyfgenia, clinical trials had been indicating that these other drugs would also be effective and safe.

Two years of COVID-19 in Africa: lessons for the world

Agreements around intellectual property would need to be negotiated. But, in principle, abandoned drug-development pipelines could be transferred to LMICs immediately. This would jump-start research and development for gene therapies locally, without imposing high-income-country requirements on low-resource settings. In countries such as India, for example, the rules around what clinical treatments (if any) people should have received before undertaking gene therapy will differ from those derived from clinical data collected in the United States11.

Most of the intellectual property in cell and gene therapy is owned by academic research centres. But in cases where a commercial developer owns the intellectual property, tax incentives, expanded government funding or publicprivate partnerships could all support the transfer of technology to regions where the disease of interest is more prevalent.

To help to achieve this kind of technology transfer, governments of LMICs need to build the trust of US and European biotech corporations and academic research centres not just by increasing their own investment in research and training, but also by conducting transparent assessments of their countries scientific, infrastructural and funding capacity.

There is considerable political will to address diseases that hit local populations the hardest. This year, Tanzania committed 3.6 billion shillings (around US$1,400,000) to support the use of bone-marrow transplants to treat children with sickle-cell disease. And depending on how much their costs can be brought down, there could be a strong global market for gene therapies.

No matter their income level, parents will do anything they can to save their childs life. Since 2011, clinics in Nigeria have been providing bone-marrow transplants to Africans to treat sickle-cell disease. In India, hundreds of people have received a bone-marrow transplant to treat sickle-cell disease over the same period. In most cases, recipients and their relatives have crowdsourced the $25,00050,000 needed per treatment.

The Global Gene Therapy Initiative (GGTI), of which we are both founding members, aims to enable people anywhere in the world to find out more about the development of gene therapies. Last year, one of our colleagues, Elizabeth Merab, an award-winning Kenyan journalist in health and science, and a member of the GGTIs international advisory board, died from complications of sickle-cell disease at the age of 31.

In 2022, Merab addressed various stakeholders, including one of us (J.E.A.), at a meeting about the role of gene therapies in treating sickle-cell disease and HIV at the Sunnylands Estate in Rancho Mirage, California. It had been three years since news outlets around the world had reported how, in a much-anticipated experiment, clinicians had used a CRISPR-based gene therapy to try to treat sickle-cell disease in a woman called Victoria Gray.

At the Sunnylands Estate, Merab, who was diagnosed aged ten, told us how she had overheard the doctor tell her parents that her options were limited. Hydroxyurea, a drug that reduces symptoms for some people, became available in the 1980s, but didnt work for her. Later, she learnt about bone-marrow transplants, but her doctors told her that she would have to receive the treatment outside Africa and pay for it herself. Then, at the meeting, she learnt about gene therapy for sickle-cell disease.

The only thing more difficult than hearing that you have a disease for which there are no cures, is to hear that you have a disease for which cures are available, but they are not available to you, she told us.

Everyone with a devastating disease should have access to a cure when one exists. True progress will come only when low-income countries are included in the development of gene therapies.

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Make gene therapies more available by manufacturing them in lower-income nations - Nature.com

Recommendation and review posted by Bethany Smith

The gene therapy marketis predictedto experience rapid growth over the coming years. But with that growth will come many complexities that contract research organizations (CROs) must navigate to keep these unique clinical trials on track.

Despite just 39differentgene therapies recorded on the market in June 2023, according to GlobalData figures, more than 4,450 gene therapy drugs are currently in preclinical and clinical trials.

GlobalDatas State of the Pharmaceutical Industry 2024 report predicts that oncology will account for 44% of the cell and gene therapy (CGT) market by 2029. Trials are also increasing in other therapeutic areas, signalling the increase in research funding and product opportunity for diseasessuchas hemophilia, Alzheimers, primary immunodeficiencies, and even hereditary blindness.

The sponsor portfolio is definitelya lotmore diverse these days, notes Nan Shao, Executive Vice President of Global Operations at Veristat. They have greater confidence in cell and gene therapy. And because of that confidence, a lot more funding gets allocated even in the larger companies now investing in developing CGT.

Despite scientific and technological advances, the cost of gene therapy trials remains a significant hurdle, and reducing expenses is a considerable challengegiventhe inherent complications of such trials. That means CROs must find a middle ground for optimizing results within budget constraints.

With a limited number of patients available for trials of rare disease treatments, ensuring accurate data collection and recordkeeping is vital. All the more reason why executing your clinical trials with the right data management platform iskey for achieving accurate data collection, significant savings on trial costs, and a return on investment for pharma and biotech companies, while also ensuring more patients can access the transformative treatments coming from gene therapy trials.

Many of the genetic disorders thatcan be treatedwith gene therapy areextremely rare with some affecting just one person in a million.Gene therapy trials are limited by the number of patients available with certain conditions.As a result, it is vital tomake full use ofany data gathered.

CGT trials require scrupulous management of patients, sites, and sponsors to deliver successful outcomes.In the modern pharma industry,electronic data capture (EDC) has emerged as the best way to reduce inefficiencies, streamline data capture, and optimize a trials results.

Data is of the most critical value for success, and that dependency on data is only going to increasemore and more, notes Shao. However, in a CGT trial, we identified that it is hard for the typical EDCto be ableto capture all the data and adapt to the changes you need very quickly.

Mismanagement of patient data can trigger trial integrity risk or minimally cause inefficiencies in data collection, and place extra burden on sites and CROs to resolve discrepancies.Withgene therapy trial costs already running high, CROs must do everything they can to eliminate these risks and inefficiencies to ensure trials stay compliant, on schedule, and within budget.

Costing is a critical element for us as a CRO. Because many clients that reach out to us have the budget planned upfront, says Shao. These costs are critical to their decision to outsource to another provider, as they need to know we can keep their studies on time and on budget.

Moreover, because CGT trials often recruit froma very smallpatient pool, patient dropouts can severely disrupt a trial and add further costly delays. For cell and gene therapies, the deployment of an effective ePRO solution is critical for helping to foster patient engagement in trials, solicit patient input conscientiously, and ensure that patients understand everything required of them.

I worked on a Phase I cell therapy trial when I was a statistician myself, and it was very different from a typical Phase I study, explains Shao. There were a lot of unexpected challenges along the way regarding data and patients. You dont know how patientsare going toreact to some of these investigational therapies. So, you need tohave the abilityto quickly adjust your database as the study goes and typical EDC setups arent always able to accommodate this.

For their CGT trials, Shao and her team at Veristat have been using the cloud-based EDC platform from Zelta by Merative. The Zelta platform is uniquely flexible and scalable, allowing users to choose the modules they want for their study, making it compatible with virtually all trial types, regardless of complexity or size.

At its core, a trialsmainpurpose is to produce reliable data to understand the efficacy and safety of new treatments. Accurately recording a patients experience is vital. Yet an overcomplicated, hard-to-use EDC platform can also result in data anomalies due to a lack of user understanding, misinterpretations, or data that are missing entirely. The Zelta platform manages highly complex processes without compromising usability, thanks to features like flexible page layouts and automated queries, enabling CGT trial operators to get the most out of their data.

Shao estimates that Veristat has reduced clinical database costs by approximately 30% incertaintrials, resultinginhighlysignificant savings.Compared to other EDC solutions,Zelta has also helped Veristat reduce the database build duration oftheir complex CGT trialsfrom as long as 10 weeks to eight or less.

Being able to shave a couple of weeks off a trials schedule is huge for us, adds Shao. We save on costs, and it also leads to the quicker launch of a product, which is highly meaningful for those affected by diseases.

Alongside reducing the timeframe for launching life-saving therapiesto the market, Veristat found that the Zelta platform which offers ePRO integrated with EDC reduces the burden of technology integrations, both making managing patient data easier and helping patients engage better with trial processes.

Zelta EDC makes transferring patients from one site to another smoother. In long-term studies, patients regularly move to a different place, requiring their data to be easily transferred. Zelta EDC simplifies this process, thereby enhancing patient engagement.

Additional integrated modules, such as ePRO and eCOA forms, help improve a patientsunderstanding of their own conditions and treatments, while also reducing a CROs workload by automatically transporting inputted data to case report forms (CRFs). Scheduled notifications offered by the ePRO remind patients to input data at therighttimes and ensure that databases remain accurate.

For rare disease studies, you dont have a lot of patients you cant lose them, says Shao. Zeltas translation functionalities areespecially importantfor CGT trials, as patients aredistributed across the globeand speak different languages. This feature has absolutely made comprehension for patients far simpler. The Zelta platform is easy to use and has made the trial experience less stressful for patients, which is also highly important.

Zeltas high performance and the willingness of their team to support customers so that the platform can adapt to any trials needs are furtherkeybenefits from a CRO perspective.

In this industry, you have to be able to scale up and meet the different complexities of trials, notes Shao. Through this partnership with Zelta and with the familiarity of many years of work, thechannels of communication between us are streamlined. We can provide feedback and advance the Zelta product so it can better support our work. The Zelta team are very efficient at addressing questions, and that willingness to collaborate is super important to us as we are always under high pressure to deliver.

Adaptable, scalable, and intuitive for patients, Zelta can help CROs manage data demands for even the most complex cell and gene therapy trials.

To learn more about how Zelta by Merative can support CROs in tackling the biggest challenges facing their clinical trials, download the specially commissioned report below.

Give your business an edge with our leading industry insights.

Read more here:
Gene therapy: How the CRO of Veristat cut trial database costs by 30% - Clinical Trials Arena

Recommendation and review posted by Bethany Smith

Lewes, Delaware, July 17, 2024 (GLOBE NEWSWIRE) -- The Global Gene Therapy Market Size is projected to grow at a CAGR of 26.88% from 2024 to 2031, according to a new report published by Verified Market Research. The report reveals that the market was valued at USD 7.53 Billion in 2024 and is expected to reach USD 50.6 Billion by the end of the forecast period.

Download PDF Brochure: https://www.verifiedmarketresearch.com/download-sample?rid=40223

Browse in-depth TOC on Global Gene Therapy Market Size

202 - Pages

126 Tables

37 Figures

Scope Of The Report

Gene Therapy Market Overview

Technological Advancements in Genetic Engineering: The gene therapy market is being propelled forward by rapid breakthroughs in genetic engineering technologies. These advancements improve the accuracy and effectiveness of gene therapies, which in turn attract investments and stimulate market expansion. Maintaining a lead in the use of technology guarantees a competitive advantage and creates opportunities for generating additional income.

Increasing Prevalence of Genetic Disorders: The increasing prevalence of genetic abnormalities worldwide is a major factor contributing to the growth of the gene therapy market. The increasing number of patients in search of efficient treatments has led to a boom in the demand for gene therapies. The increasing number of patients presents significant prospects for enterprises to enhance their market share and impact.

Favorable Regulatory Environment: The time-to-market for gene therapies is being reduced as a result of the acceleration of the approval process by supportive regulatory frameworks. Regulatory agencies are increasingly acknowledging the potential of gene therapy, offering incentives and streamlined development pathways. This advantageous environment fosters investment and innovation, which in turn propels market expansion.

To Purchase a Comprehensive Report Analysis: https://www.verifiedmarketresearch.com/download-sample?rid=40223

High Treatment Costs: The exorbitant expenses linked to gene therapy treatments continue to be a substantial obstacle. These expenditures have the potential to restrict patient availability and burden healthcare budgets. Businesses must prioritize cost-reduction measures and implement value-based pricing models in order to overcome this obstacle and improve their market penetration.

Ethical and Safety Concerns: The gene therapy market is constrained by ethical issues and potential safety risks. Public acceptance and regulatory clearances can be impeded by concerns regarding the long-term effects of genetic changes. To achieve market expansion, it is necessary to address these concerns by implementing transparent communication and strict safety measures.

Limited Healthcare Infrastructure in Developing Regions: The lack of sufficient healthcare infrastructure in underdeveloped nations hinders the implementation of gene treatments. The market expansion can be hindered by the limited availability of advanced medical facilities and experienced professionals. Establishing strategic alliances and making investments in healthcare development are crucial in order to access these new markets and stimulate future expansion.

Geographic Dominance:

North America has a strong hold on the gene therapy market because of its well-developed healthcare infrastructure, substantial investments in research and development, and favorable regulatory rules. This dominance expedites market expansion as the region evolves into a center for innovation, enticing multinational corporations and promoting progress. The market expansion is also facilitated by Europe's robust biopharmaceutical industry and favorable laws. On the other hand, the Asia-Pacific region exhibits significant potential for quick expansion as a result of escalating investments in healthcare and a growing emphasis on genetic research.

Gene Therapy Market Key Players Shaping the Future

Major players, including Pfizer, Novartis AG, Biogen, Gilead Sciences, Inc., MolMed S.p.A., Spark Therapeutics, Inc., Orchard Therapeutics plc., SIBIONO, Bluebird bio, Inc., Shanghai Sunway Biotech Co. Ltd. and more, play a pivotal role in shaping the future of the Gene Therapy Market. Financial statements, product benchmarking, and SWOT analysis provide valuable insights into the industry's key players.

Gene Therapy Market Segment Analysis

Based on the research, Verified Market Research has segmented the global Gene Therapy Market into Product, Indication, Delivery Method, And Geography.

To get market data, market insights, and a comprehensive analysis of the Global Gene Therapy Market, please Contact Verified Market Research.

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10 Best Cell And Gene Therapy Companies unlocking potential of DNA

Visualize Gene Therapy Market using Verified Market Intelligence -:

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Gene Therapy Market Surges to USD 50.6 Billion by 2031, Propelled by 26.88% CAGR - Verified Market Research - GlobeNewswire

Recommendation and review posted by Bethany Smith

Creative Biolabs introduces recombinant viral vector development mechanisms and features some essential products. New York, USA - July 17, 2024 - Gene therapy has emerged as a beacon of hope for treating many intractable diseases, although it somehow remains a subject of debate. Central to the success of gene therapy are viral vectors, which play a critical role in delivering therapeutic genes to target cells. Creative Biolabs undertakes viral vector development to deliver validated vector products, thus supporting scientists and pharmaceutical companies in their quest for novel, potent gene therapies.

Image: https://www.getnews.info/uploads/0c59d26f78bf6dd58aafee5bc68d7d8c.jpg

The Impact of Viral Vectors on Gene Therapy

"Recent industry news, released at the beginning of July about adeno-associated viruses (AAVs), has highlighted advancements in gene therapy, emphasizing the critical role of viral vectors in these successes. Viral vectors are engineered viruses used to deliver genetic material into cells, a crucial step in gene therapy. Their design, efficiency, and safety directly impact therapeutic outcomes. With advancements in viral vector technology, the potential to treat genetic disorders, cancers, and other diseases has significantly improved." According to a scientist at Creative Biolabs.

Custom Recombinant Viral Vector Development [https://www.creative-biolabs.com/gene-therapy/viral-vector-design-and-construction.htm]

The design and construction of recombinant viral vectors are critical components of effective gene therapy. Creative Biolabs excels in developing high-efficiency viral vectors that deliver therapeutic DNA accurately and safely. Their expertise encompasses a variety of viral vectors, including adenovirus, adeno-associated virus, lentivirus, and retrovirus.

Recombinant Adeno-Associated Virus

Due to their demonstrated safety and efficacy in both preclinical and clinical settings (over 162 Phase I, II, and III clinical trials, and clinical efficacy has been achieved in at least six human diseases), recombinant adeno-associated viruses [https://www.creative-biolabs.com/gene-therapy/category-recombinant-adeno-associated-virus-304.htm] are favored in gene therapy. Creative Biolabs develops a variety of rAAV serotype vectors, including AAV2, AAV5, AAV8, and AAV9, which have different tissue-tropism and can express transgenes for an extended period of time.

"From initial concept to final toxicity and safety assessments, we offer comprehensive services for the development of sophisticated adeno-associated virus vectors, including design, purification, and titration."

Creative Biolabs' online store lists some popular products and also welcomes requests for AAV customization.

Recombinant Adenovirus

Adenoviruses are powerful tools for gene therapy, particularly for cancer and other applications requiring high transgene expression. Creative Biolabs manages the development of recombinant adenoviruses and can tailor the project according to varying research objectives.

"Our adenoviruses are advantageous in their ability to infect both dividing and non-dividing cells, have a high packaging capacity of up to 8 kb, and have the outstanding safety of not being integrated into the host chromosome." The scientist added.

Recombinant Lentivirus

Recombinant lentivirus [https://www.creative-biolabs.com/gene-therapy/category-recombinant-lentivirus-306.htm] vectors represent a batch of efficient vehicles that can contribute to long-term gene expression and highly effective gene therapy. Creative Biolabs' expertise ensures the generation of lentiviral vectors with high transduction efficiency and stability, which can potentially apply to preclinical gene therapy R&D against vascular diseases, diabetes mellitus, rheumatoid arthritis, cancers, etc.

For more information about Creative Biolabs' viral vector development services and to explore their comprehensive product offerings, visit https://www.creative-biolabs.com/gene-therapy.

About

Creative Biolabs is a leading biotechnology company specializing in gene therapy development, antibody production, and immunotherapy solutions. With a strong focus on innovation and customer service, Creative Biolabs provides a wide range of high-quality products and services to support biomedical research and drug development worldwide. Media Contact Company Name: Creative Biolabs Contact Person: Candy Swift Email: Send Email [http://www.universalpressrelease.com/?pr=how-do-vectors-reign-over-the-efficacy-of-gene-therapy-creative-biolabs-breaks-out-the-facts] Phone: 1-631-830-6441 Country: United States Website: https://www.creative-biolabs.com/gene-therapy

This release was published on openPR.

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How Do Vectors Reign Over the Efficacy of Gene Therapy? Creative Biolabs Breaks Out the Facts - openPR

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"It is very disheartening for a patient to know there is a potential treatment available, but they can't access it because of where they reside," says Dr. Harsha Rajasimha. "Biopharmaceutical sponsors also struggle to find eligible patients, missing genetic diversity."

While the underlying science for the design and development of CGTx is advancing rapidly, the industry is successfully applying AI-driven drug discovery algorithms to generate drug candidates faster than ever before waiting for clinical evidence generation of safety and efficacy. However, the operational and logistical efficiency gains are yet to catch up to execute over 1000 gene therapy and over 2000 cell therapy clinical trials that are currently active. Most of these qualified CGTx clinical trial sites are in the U.S. and the E.U., while most patients worldwide remain without access.

As Dr. Harsha Rajasimha, CEO and Founder of Jeeva Clinical Trials Inc., notes, "It is very disheartening for a patient or family to know that there is a potential treatment available somewhere, but they can't access it because of where they reside. On the other hand, Biopharmaceutical sponsors are unable to identify enough eligible patients to enroll from within the geographies they operate in. Even when they are successful in enrolling the target number of patients, they are likely missing the genetic diversity or other critical aspects of the disease heterogeneity. Moreover, each genetic disease has a unique distribution of prevalence globally and can disproportionately affect different populations."

Ignoring genetic diversity weakens treatment effectiveness across populations. This has real-world consequences, as exemplified by the Indian diaspora in the US. A study examining 193 rare disease trials found that participants of Indian descent accounted for just 1% of the patient pool. (6) The general dearth of data on Indian patients has led to situations where they received FDA-approved treatments that were ultimately ineffective for their genetic profiles.

Challenges Unique to CGTx clinical trials CGTx represents a novel and advanced treatment modality with one-and-done administration. Clinical trials for these therapies demand patient-friendly trial designs that fit into their lifestyle with the least burden. These studies tend to involve much smaller patient population compared to other trials involving small molecule drugs or biologics. This means, researchers will need to gather more frequent data points from smaller patient populations including from caregivers and observers of the patients. Most of these patients are severely debilitated due to the disease's nature requiring special needs, choice of communication channels such as video, audio, texting, email, and other special accommodations.

Ensuring long-term patient safety remains challenging for CGTx. The FDA requirement for 15 years of safety follow-up after treatment demands integrated clinical trial management infrastructure including remote patient engagement and patient-centric apps. Additionally, CGTx trials have a need to be more inclusive of non-English speakers and more decentralized due to sparse distribution of the target populations.

Given this set of complex requirements, researchers have relied on CROs selecting 20-30 different software tools and point solutions to make one clinical study successful. Net result is siloed data and fragmented infrastructure resulting in significant integration and interoperability costs.

Patient-Centric Solution to Modernize Genetic Disease Clinical Research There is good news! Jeeva anticipated the need for human-centric and inclusive clinical research software solutions early on and has developed and validated mature solutions for almost six years now.

Team Jeeva is pioneering patient-centric clinical research software and CRO solutions to lead the way for genetic disease research and CGTx clinical trials at an Enterprise scale, centralizing the management of all studies under a single-login and subscription-based service. "As a rare dad and patient advocate, I realized the only way to address these challenges holistically is with a comprehensive unified solution rather than with piecemeal point solutions that do not integrate and automate the process end-to-end," Rajasimha recounts. And adds, "We cared enough to make time and investments to thoughtfully develop a cost-effective and human-centric solution for patient registries, natural history studies, CGTx clinical trials, and long-term follow-up studies."

Today Jeeva delivers optimized solutions that combines software, experts, and standard processes collectively as a turnkey configurable solution including study specific patient engagement portals. The company's comprehensive clinical research solutions cover software or CRO solutions for protocol design, IRB submissions, site qualification and initiation, patient screening, referral, randomization or enrollment, clinical data management, clinical trial management, patient engagement, biostatistical analysis, and reporting or manuscript preparation for publications. Optimizing all these processes under one-login makes it cost-effective for small population clinical trials or population scale registries or cohort studies.

"Having validated the clinical research software solution for use in settings such as GCP, 21 CFR part 11, HIPAA, with academic medical centers, Children's hospital, and biopharma sponsors, we are partnering with clinical-stage biopharmaceutical sponsors to accelerate the development of affordable CGTx as well as health economics outcomes research (HEOR) studies", Rajasimha highlights.

"With the Diverse and Equitable Participation in Clinical Trials (DEPICT) Act now in play, (7) sponsors of clinical trials must submit a 'diversity action plan' outlining how they will achieve diverse participant enrollment," says Rajasimha. The Jeeva's inclusive clinical research solutions align with the recent FDA guidance to Improve Enrollment of Participants from Underrepresented Populations in Clinical Trials. (8)

Leading Organizations are Choosing Jeeva to Speed up Clinical Research Modern decentralized and hybrid clinical trials powered by AI are key to unlocking medical breakthroughs. They can boost access and capture richer patient data by making trials remote and inclusive, ensuring diverse representation of patients in their native languages.

COMBINEDBrain, a non-profit organization for rare neurodevelopmental disorders, partnered with Jeeva for this study to capture both quantitative and qualitative data with minimal patient burden. Dr. Terry Jo Bichell, Founder of COMBINEDBrain, states, "We are pleased to collaborate with Jeeva for the eCOA module for our investigator initiator observational study to understand independent toileting abilities by individuals with neurogenetic brain disorders." The study aims to understand the effect of treatments on independent toileting abilities via BYOD surveys with branching logic and scoring, while reducing caregiver and patient burden. Using Jeeva electronic clinical outcomes assessments (eCOA), a software solution that allows researchers to collect, track, and analyze patient and observer reported data, researchers aim to accelerate clinical research programs for various CNS disorders.

CGTx is among the most expensive treatments ever produced, with some exceeding $2 million per dose. (9) We need bold and disruptive models coming from anywhere in the world to ensure access and affordability of CGTx. Jeeva is honored to partner with ImmunoACT to support their vision for making affordable CAR-T Cell therapies. "We needed an innovative platform for our first clinical trial with minimal financial burden and not requiring us to carry a huge IT infrastructure internally. Collaboration with Jeeva was an excellent choice for our CAR-T cell/gene therapy for leukemia and B-cell lymphoma which recently received approval from the Indian regulatory agency for a tenth of the cost compared to the existing CAR-T therapies. This collaboration has been fruitful in storing and sharing clinical data as per regulatory requirements," says Dr. Rahul Purwar, Founder of ImmunoACT and Associate Professor at the Indian Institute of Technology (IIT), Mumbai, India.

Rajasimha and his team were at the ASGCT annual conference earlier this year in Baltimore, MD. Last week, Rajasimha moderated a session on cross-border data sharing for accelerating genetic disease diagnosis and insights at the North America Rare Disease Summit (NARDS) 2024 in Chicago, IL, and will be chairing the Indo US Bridging RARE Summit Nov 16-18, 2024, in New Delhi, India.

Jeeva Pledges Free Software Solutions for N-of-1 Clinical Trials In a groundbreaking move, Jeeva Clinical Trials Inc. has pledged to provide its software free of charge for all N-of-1 clinical trials like the recently conducted phase 1 trial, AAV gene therapy for hereditary spastic paraplegia type 50 indefinitely. (10) This commitment aims to support personalized medicine and ensure that even the rarest conditions receive the attention they deserve, fostering a more inclusive and effective approach to clinical research.

"This is how we walk the talk of patient-centricity in clinical trials", says an optimistic Rajasimha.

About Jeeva Clinical Trials Inc. ("Jeeva") Founded by Dr. Harsha Rajasimha after his deeply personal, family, and professional experiences, Jeeva's mission to "Modernize Clinical Research with Human-Centric Software and CRO solutions" propels their innovative clinical trial management platform with AI and workflow automation under one bundled subscription. Jeeva empowers global biopharmaceutical, medical device, and nutraceutical sponsors, simplifying patient engagement and evidence generation, achieving 70% greater efficiency in research. Trusted by prestigious organizations like Frantz Viral Therapeutics and George Mason University, their technology supports diverse study designs, from traditional to fully decentralized models, across disease areas including oncology and rare diseases. With empathy and determination, team Jeeva has developed a patient-centric and unified platform that enables sponsors to conduct clinical trials more effectively, breaking down barriers and fostering a globally inclusive and diverse participant pool. This includes facilitating remote patient participation. Discover more about how Jeeva is reimagining the future of clinical trials athttps://jeevatrials.com/.

References 1. "Current FDA Approved Gene & Cell Therapies Mirus Bio." Mirusbio, 31 May 2024, mirusbio.com/fda-approved-gene-cell-therapies/. Accessed 5 July 2024. 2. "Gene Therapy Market Size Poised to Surge USD 52.40 Billion by 2033." BioSpace, 18 Apr. 2024, biospace.com/article/releases/gene-therapy-market-size-poised-to-surge-usd-52-40-billion-by-2033/. 3. "FDA Expands Approval of Gene Therapy for Patients with Duchenne Muscular Dystrophy." FDA, 20 June 2024, fda.gov/news-events/press-announcements/fda-expands-approval-gene-therapy-patients-duchenne-muscular-dystrophy. 4. Gardner, Jonathan. "Takeda Drug for Rare Types of Epilepsy Misses Goal in Late-Stage Trial." BioPharma Dive, 24 June 2024, biopharmadive.com/news/takeda-ovid-dravet-lennox-gastaut-failure-soticlestat/719115/. 5. Pagliarulo, Ned. "Biogen Gene Therapy Misses Goal in Eye Disease Study." BioPharma Dive, 14 May 2021, biopharmadive.com/news/biogen-gene-therapy-eye-study/600204/#:~:text=An%20experimental%20gene%20therapy%20did. Accessed 10 July 2024. 6. Chakraborty, Monoswi, et al. "Rare Disease Patients in India Are Rarely Involved in International Orphan Drug Trials." PLOS Global Public Health, vol. 2, no. 8, 15 Aug. 2022, p. e0000890, doi.org/10.1371/journal.pgph.0000890. 7. "Diverse and Equitable Participation in Clinical Trials Act or the DEPICT Act." Congress.gov, Congress of the United States, 3 Feb. 2022, congress.gov/bill/117th-congress/house-bill/6584. 8. "Diversity Action Plans to Improve Enrollment of Participants from Underrepresented Populations in Clinical Studies." fda.gov, 3 July 2024, fda.gov/regulatory-information/search-fda-guidance-documents/diversity-action-plans-improve-enrollment-participants-underrepresented-populations-clinical-studies. 9. Stein, Rob. "NPR Choice Page." Npr.org, 2019, npr.org/sections/health-shots/2019/05/24/725404168/at-2-125-million-new-gene-therapy-is-the-most-expensive-drug-ever. 10. Dowling JJ, Pirovolakis T, Devakandan K, Stosic A, Pidsadny M, Nigro E, et al. AAV gene therapy for hereditary spastic paraplegia type 50: a phase 1 trial in a single patient. Nature Medicine [Internet]. 2024 Jun 28;16. Available from: nature.com/articles/s41591-024-03078-4

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South Africas National Nuclear Regulator (NNR)has approved a 20-year life extension for the 924MW Unit 1 of the Koeberg nuclear power plant, located near Cape Town in western South Africa, allowing the reactor to operate until July 2044. However, the NNR has deferred a life extension decision on the 930MW Unit 2 until late 2025, since an assessment of the second reactors safety case is still ongoing.

In January 2024, the NNR had agreed to Eskoms request to separate the Unit 1 and 2 licences to align with their respective commercial operating dates, with Unit 1 having started operating in July 1984 and Unit 2 in November 1985.

The 1.9GW Koeberg nuclear power plant is the only currently active nuclear plant on the African continent and produces about 5% of the South Africas electricity. In December 2023, South Africas Ministry of Electricity announced that it would start a procurement process to develop an additional 2.5GW of nuclear capacity in the country, based mostly on Small Modular Reactors.

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South Africa regulator approves life extension for the Koeberg nuclear plant Unit 1 - Renewables Auctions and the Energy Transition

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The South African Nuclear Energy Corporation (Necsa) has expressed confidence that the National Nuclear Regulator (NNR) will extend the operating licence of Unit 2 at Koeberg Nuclear Power Station for a further 20 years after granting the same to Unit 1.

The NNR on Monday granted Eskom a licence to continue operating Koeberg Nuclear Power Station Unit 1, which provides 930MW to the grid, for another 20 years until July 21, 2044.

Necsa said it welcomed the NNRsfinalisation of the Long Term Operation (LTO) assessment and recommendation giving the green light for Eskom to extend operations at Unit 1.

Necsa group CEO Loyiso Tyabashe commended the NNR for ensuring nuclear safety oversight to all licensed nuclear operators and for taking time and effort in an extensive public participation process, where Necsa also got an opportunity to share its support for the life extension of Koeberg.

We congratulate Eskom for taking due care in their submission to the NNR, which has ensured that the approval is granted for Unit 1. With this track record we are confident that Unit 2 will follow suit, and Necsa is in full support, Tyabashe said.

The Koeberg Nuclear Power Station extension guarantees South Africans a 20-year continuation of secure, clean and affordable energy, he said.

Eskoms chief nuclear officer, Keith Featherstone, said the granting of the licence was a testament to the hard work and continued commitment of our teams to nuclear safety and Eskoms generation recovery plan.

The International Atomic Energy Agency (IAEA), which serves as a global intergovernmental forum for scientific and technical co-operation in the peaceful use of nuclear technology, confirmed it conducted a Safety Aspects of Long Term Operation (SALTO) mission at Koeberg, from March 22 to 31, 2022.

The SALTO peer review is a comprehensive safety review directly addressing strategy and key elements for the safe long-term operation of nuclear power plants. A follow-up mission is planned for September 2024, the IAEA said.

Some countries have given a high priority to extend the designed lifetime of their reactors from 40 years to 60 or 80 years, subject to regulatory approval.

To achieve the goal of the long-term safe, economic and reliable operation of a nuclear power plant, a Plant Life Management, or PLiM, programme is essential.

PLiM programmes for long-term operation are in place in many countries, including in South Africa.

World Nuclear Association spokesperson Henry Preston said the lifetime extension of a nuclear power plant was a demonstration of the hard work and commitment to nuclear safety culture by the industry.

Keeping clean energy assets, such as Koeberg, online should be greatly celebrated. Nuclear provides 24/7 clean energy supporting both energy security and sustainability.

The association explained that nuclear power plants are routinely extended, particularly water-cooled reactors like Koeberg.

Citing examples in the US and Sweden, where water-cooled reactors were granted extensions up to 80 years, the association said most plants are initially built and licensed for 40 to 60 years, then are periodically reviewed and can be extended beyond that if they meet regulatory requirements.

The Koeberg Alert Alliances Peter Becker believes the NNR had been under great pressure to make the decision.

We dont believe they have had time to fully consider all the submissions from the public. The independence of the NNR has also been questioned by the IAEA, which described it as insufficiently independent.

Cape Times

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Nuclear industry welcomes Koebergs life extension - IOL

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TAMPA, Fla. Its a topic you dont hear discussed much: men developing breast cancer.

Breast cancer is far less common in men than it is in women. However, according to the American Cancer Society, about one in one thousand men will develop this form of cancer.

You walk through a door with a sign that says No Men Beyond This Point, so thats your first introduction to getting a mammogram as a man, said Ben Porch whos been getting mammograms since 2020. Most of the time, I was given a pink gown to wear.

Usually, his screenings came back clear.

That is until 2023.

Well, on this particular one, they said, Could you just wait a minute? We might want to get some more images. And I thought to myself, Well, that doesnt sound so good, explained Porch.

After getting a biopsy, the doctors found what they suspected: breast cancer.

Its not something you want to be told, but, like I said, given the history, I wasnt completely surprised by the diagnosis, said Porch

The reason why he wasnt surprised was because his sister had died from breast just years prior and his father had beaten breast cancer himself.

He thanks genetic testing for allowing him to know there was a possibility hed eventually develop breast cancer and he recommends everyone take a genetic test to know what illnesses theyre at risk of developing.

Its literally a simple test that comes with a small little test tube and you spit into it and cap, send it off and they send you back the results, explained Porch.

After doctors at Tampa General and USF removed the cancer cells, Ben was considered cancer-free on May 9, 2023.

He said the experience of battling breast cancer wasnt easy, but he had his family there every step of the way.

It was a traumatic experience at the time, said Porch to his wife. But, you know, looking back on it and having you there to support me through the whole thing was the way I survived.

Now, Porch is focused on staying strong and healthy. He swam when he was younger and decided to return to the sport.

It was really important after the surgery to get back to some exercise that would help exercise the chest area and really help with the stretching and building back the muscle tone again, said Porch.

As Porch mentioned, genetic testing is more accessible to the average person, allowing you to know - through science - what illnesses you may develop in your lifetime and knowing that will allow you can stay out in front of it.

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Florida man says genetic testing likely saved his life before receiving a breast cancer diagnosis - ABC Action News Tampa Bay

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GeneDx Holdings Corp. WGS has made the biggest gains on the Russell 2000 Index in 2024 as the biotechnology company moves toward more comprehensive genetic testing.

The Maryland-based companys shares have soared 1,101% so far this year as of midday Thursday, according to Tradingview.

Goldman Sachs analyst Matthew Sykes attributes much of GeneDXs positive momentum to shifting its testing. The company went from panel-based tests, which look for variants in more than one gene, to exome/genome testing, which analyzes the bulk of a persons DNA to find genetic variations.

Also Read: GeneDx Stock Climbs After Better-Than-Expected Q1 Results, Raises FY24 Guidance

We remain optimistic about WGS's continued focus on converting its mix shift of panel-based tests to whole exome/genome-based tests, Sykes wrote in a note on Wednesday.

As of 1Q24, 30% of their tests were exome/genome-based, whereas this metric was 16% in 1Q23.

He said the transition has expanded the companys margins from 33% in the first quarter of 2023 to 61% in this years first quarter.

We see gross margins continuing to improve going forward, yet see more moderated growth in out years, reaching the mid-high 60% range exiting 2026, he wrote.

We see this mix shift evolution as the key driver of WGS's growth in the near term given their initial focus on rare disease/pediatrics.

Goldman Sachs maintains revenue estimates for GeneDx at $243 million for 2024, $269 million for 2025 and $306 million for 2026. It expects the company to post losses per share of $1.07 for this year and $0.21 for next year and earnings per share of $0.35 for 2026.

It has given GeneDx a Neutral rating and has increased its price target on the stock from $12.50 to $28.

Analysts expect GeneDx to post a $0.30 loss per share when it reports second-quarter earnings on July 30, up from a $0.33 loss per share registered for the first quarter, according to Benzinga Pro.

GeneDx has distanced itself from stocks held by runner-up small-cap companies Massachusetts-based Corbus Holdings Inc. CRBP and Root, Inc. ROOT.

Corbus has risen 834% since the beginning of 2024, while Root, an Ohio-based online car insurance company, has gained 670%.

Price Action: GeneDx has slipped 3.36% to $32.18 by Thursdays midday trading, while Corbus has fallen 5.26% to $55.86 and Root has risen 1.49% to $80.59.

Other leading small-cap stocks on Russell 2000

Below are the remaining companies that round out the top-10 list of top performers in the Russell 2000.

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GeneDx Leads Russell 2000 This Year As It Shifts To More Comprehensive Genetic Testing - Benzinga

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