Category Archives: Gene Medicine

When oncologists talk about cancer targets, theyre usually referring to mutated genes that can be thwarted with drugs. Researchers at the University of Pennsylvania used gene-editing technology CRISPR to elucidate a different sort of target in acute myeloid leukemia (AML)and to uncover a way to target it with drugs.

A team at Penns medical school discovered that an epigenetic regulatory protein called ZMYND8 governs the expression of genes that are critical for the growth and survival of AML cells. Inhibiting ZMYND8 in mouse models shrank tumors. The researchers also found a biomarker that they believe could predict which patients are likely to respond to ZMYND8 inhibition, they reported in the journal Molecular Cell.

AML is one of the hardest leukemias to treat, with a five-year survival rate of about 27% in adults. The Penn team had been searching for precision medicine approaches that could improve the prognosis for adults with AML, and they turned to CRISPR for help.

ZMYND8 is known as a histone reader in cancer that can recognize epigenetic changes and influence gene expression involved in metastasis.

Using CRISPR, the Penn team disrupted various functions of proteins in cancer cells and mapped their functions on a molecular level. When they blocked the epigenetic reader function of ZMYND8 in mouse models, it not only caused tumors to shrink, but also improved survival, they said in a statement. With CRISPR, they were able to pinpoint a pocket on ZMYND8 that they believe could be targeted with drugs.

RELATED: Novartis-backed Penn study proposes boosting CAR-T responses in CLL by waking up 'war weary' T cells

Several efforts to develop new treatments for AML have hit roadblocks of late. The FDA placed a hold on trials of Aprea Therapeutics eprenetapopt in AML after worrisome side effects appeared in a trial of the drug in myelodysplastic syndrome. Amgen had been developing a bispecific antibody for AML, AMG 427, but stopped a phase 1 trial after some patients developed the dangerous side effect cytokine release syndrome. The company is now investigating ways to optimize the treatment approach, a spokesperson said earlier this month.

Several immuno-oncology approaches to AML are under development, including engineered natural killer cell therapies, and researchers are investigating a range of targeted approaches such as combining MDM2 and BET blockers.

The Penn researchers wanted to see whether they could predict how sensitive AML cells might be to ZMYND8 inhibition, so they turned to blood samples from patients treated at Penn Medicine. They found that high expression of a particular gene in those cells, IRF8, could serve as a biomarker of response to ZMYND8 inhibition.

CRISPR revealed here, for the time, an unexpected epigenetic-linked molecular circuity that AML is dependent on, and one that we can potentially manipulate, said co-author Shelley Berger, Ph.D., professor at the Perelman School of Medicine and director of the Penn Epigenetics Institute, in the statement. It opens a new door toward better treatments for these patients using next-generation epigenetic inhibitors.

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CRISPR pinpoints new leukemia target and a 'pocket' that could make it druggable - FierceBiotech

BEIJING, Aug. 23, 2021 (GLOBE NEWSWIRE) -- Genetron Holdings Limited (Genetron Health or the Company, NASDAQ: GTH), a leading precision oncology platform company in China that specializes in offering molecular profiling tests, early cancer screening products and companion diagnostics development, today announced the signing of a strategic partnership with Shanghai Yikon Genomics Technology Co., Ltd. (Yikon Genomics), a company that focuses on reproductive health diagnostic testing. Genetron Health expects this partnership to contribute to its 2021 revenues.

Under the agreement, Yikon Genomics will have the exclusive rights to use Genetron Healths S5 instrument for reproductive health applications in the China market. Yikon Genomics currently offers pre-pregnancy, prenatal and inheritance disorder testing solutions for a network of over 400 hospital partners in China. The partners will cooperate with each other to drive forward registration processes for new assays that are developed on the S5 platform. Genetron Health will also support Yikon Genomics commercialization efforts. GENETRON S5 has been successfully used in many different oncology settings, and through this partnership, will be expanding its applications to include reproductive health, widening the Companys scope of precision medicine.

Approved by the NMPA in 2019 and based on new semiconductor sequencing technology, GENETRON S5 is Chinas desktop, clinical-grade, medium-throughput next generation sequencing (NGS) platform. GENETRON S5s advantages lie in its fast detection, flexible throughput, low initial sample size requirements, and comprehensive range of different applications. Genetron Health has used this platform to develop in-vitro diagnostic (IVD) kits that cover multiple cancer types and different sample types, including the 8-gene Lung Cancer (Tissue) assay. With GENETRON S5, the Company has developed an integrated solution for molecular diagnostics laboratories, and carried out clinical trials and scientific research partnerships with many different organizations. These efforts have enabled hospitals in China to adopt NGS technology for independent, clinical diagnostic use.

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"GENETRON S5s flexible and open characteristics have laid the groundwork for clinical applications in the reproductive health field. We are committed to using an open platform to provide versatile, multi-dimensional solutions for our hospital partners, said Sizhen Wang, co-founder and CEO of Genetron Health. We are pleased to become Yikon Genomics strategic partner. We hope to leverage our respective strengths so that we can introduce a comprehensive range of high-performance, personalized, precision medicine solutions to patients, making innovative genetic technology more accessible to the public."

"Genetron Health focuses on precision medicine and genomics research, possesses a high-quality innovation platform, and has a strong track record of successfully commercializing new technologies, said Sijia Lu, co-founder and CEO of Yikon Genomics. We think there are significant synergies in this partnership, and we are excited to adopt the 'platform + reagent' strategy for Chinas reproductive health market."

About Genetron Holdings Limited

Genetron Holdings Limited (Genetron Health or the Company) (Nasdaq:GTH) is a leading precision oncology platform company in China that specializes in cancer molecular profiling and harnesses advanced technologies in molecular biology and data science to transform cancer treatment. The Company has developed a comprehensive oncology portfolio that covers the entire spectrum of cancer management, addressing needs and challenges from early screening, diagnosis and treatment recommendations, as well as continuous disease monitoring and care. Genetron Health also partners with global biopharmaceutical companies and offers customized services and products. For more information, please visit ir.genetronhealth.com.

About Yikon Genomics

Yikon Genomics, established in 2012, is dedicated to the development and application of single-cell whole-genome amplification and sequencing technologies. The companys primary focus is reproductive health, providing sophisticated testing solutions for pre-pregnancy, prenatal and inheritance disorders in China. Yikon Genomics have partnered with over 400 medical institutions and hospitals in China, as well as a number of world-class research institutes. Its business covers 32 provinces and municipalities in China, and through partnerships with international reproductive medicine centers, has expanded to more than 20 countries worldwide, including the United States, United Kingdom, Russia, and Japan.

Safe Harbor StatementThis press release contains forward-looking statements within the meaning of federal securities laws which involve risks and uncertainties that could cause the actual results to differ materially from the anticipated results and expectations expressed in these forward-looking statements. These statements are made under the safe harbor provisions of the U.S. Private Securities Litigation Reform Act of 1995. Statements that are not historical facts, including statements about the Companys beliefs and expectations, are forward-looking statements. Forward-looking statements involve inherent risks and uncertainties, and a number of factors could cause actual results to differ materially from those contained in any forward-looking statement. In some cases, forward-looking statements can be identified by words or phrases such as may, will, expect, anticipate, target, aim, estimate, intend, plan, believe, potential, continue, is/are likely to or other similar expressions. Further information regarding these and other risks, uncertainties or factors is included in the Companys filings with the SEC. All information provided in this press release is as of the date of this press release, and the Company does not undertake any duty to update such information, except as required under applicable law.

Media Relations ContactYanrong Zhaoyanrong.zhao@genetronhealth.com

Investor Relations ContactHoki Lukhoki.luk@genetronhealth.com

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Genetron Health Reaches Strategic Partnership with Yikon Genomics, Expanding S5 Platforms Reach to Reproductive Health Field - Yahoo Finance

SOUTH PLAINFIELD, N.J., Aug. 23, 2021 /PRNewswire/ --PTC Therapeutics, Inc. (NASDAQ: PTCT) today announced the publication of a manuscript, "Gene Therapy in the Putamen for Curing AADC Deficiency and Parkinson's Disease," in the European Molecular Biology Organization Journal. The paper describes a pioneering approach that delivers gene therapy to a specific part of the brain called the putamen, which is helping successfully treat a previously intractable, devastating disorder and transforming the lives of children born with AADC deficiency (AADC-d)1.

"I am excited about what the success of this new approach means for the children and families living with AADC deficiency," said Stuart W. Peltz, Ph.D., Chief Executive Officer, PTC Therapeutics. "AADC deficiency is a terrible, life-shortening condition that requires around-the-clock care. The data reported in this article show that the surgical approach of delivering our novel PTC-AADC gene therapy directly to the putamen robustly produces dopamine in the brain that results in sustained and substantial functional improvements in children with AADC deficiency."

Currently there are no approved disease-modifying therapies for treating AADC-d, and the success of symptomatic treatment using combinations of vitamin B6, dopamine (DA) agonists, and monoamine oxidase inhibitors is very limited, especially in severe cases2.

The paper, authored by global experts in the United States, Taiwan, France, Germany, and Japan, describes three clinical trials in which AAV2-hAADC was infused into the putamen of children with AADC-d via brain surgery. Prior to treatment, most of the children with AADC-d had never developed muscle control, could not lift their heads, move on their own or talk, and nearly all were bed ridden. Every child in the trials showed significant improvements following treatment with PTC's novel gene therapy, PTC-AADC1.

The clinical benefits and safety profile of PTC-AADC has been demonstrated across multiple trials, with the first patient dosed more than 10 years ago, in 2010. The trials together represent the largest cohort of AADC-d patients ever studied.

"The remarkable results published have been life-changing for the children we have treated," said co-author and investigator Paul Wuh-Liang Hwu, National Taiwan University Hospital. "Before this treatment, the children with AADC deficiency couldn't lift their heads, but now some can sit and stand with help, and have even begun learning to talk."

AADC deficiency is a debilitating neurological disorder that involve motor dysfunction caused by dopamine deficiencies. Dopamine is a neurotransmitter that is critical for motor and mental development1. The studies demonstrate that the restoration of DA synthesis in the putamen via gene therapy using low doses of AAV2-hAADC is well tolerated, leads to sustained improvements in motor and nonmotor symptoms of AADC deficiency, and beneficial for the patients. The novel gene therapy, PTC-AADC was delivered to the putamen because it is more easily accessible via surgery than other sites, and therefore, may result in fewer surgical complications. In neurological disorders such as AADC-d, the putamen is directly impacted by the loss of DA synthesis in the striatum1.

PTC-AADC is currently under review by the European Medicines Agency's Committee for Medicinal Products for Human Use with an opinion expected in the fourth quarter of 2021.

About aromatic L-amino acid decarboxylase (AADC) deficiencyAADC deficiency is a fatal, ultra-rare genetic disorder that causes severe disability and suffering from the first months of life, affecting every aspect of life physical, mental, and behavioral1,2,[3]. The suffering of children with AADC deficiency is exacerbated by episodes of distressing seizure-like oculogyric crises, which can happen daily and last for hours, causing the eyes to roll up in the head, frequent vomiting, behavioral problems, difficulty sleeping, and life-threatening complications such as respiratory infections and gastrointestinal problems2,[4],[5],[6].

Current management options yield limited improvement for the majority of patients with AADC-d.2Managing patients with AADC-d requires a multidisciplinary team of specialists and complex coordination of care to address significant health issues, including developmental delays, infections, orthopaedic and cardiac complications, and other comorbidities2

While several diagnostic tests for AADC deficiency are available, the condition remains largely undiagnosed or misdiagnosed for other conditions with similar symptoms, such as cerebral palsy and some forms of epilepsy4,[7].

About PTC Therapeutics, Inc.PTC Therapeutics is a science-driven, global biopharmaceutical company focused on the discovery, development and commercialization of clinically differentiated medicines that provide benefits to patients with rare disorders. PTC's mission is to provide access to best-in-class treatments for patients with an unmet medical need, using its ability to globally commercialize products as the foundation to drive investment in a robust and diversified pipeline of transformative medicines. The Company's strategy is to leverage its strong scientific expertise and global commercial infrastructure to maximize value for its patients and other stakeholders. To learn more about PTC, please visit us at http://www.ptcbio.com and follow it on Facebook, on Twitter at @PTCBio, and on LinkedIn.

For More Information:

Investors Kylie O'Keefe+1 (908) 300-0691[emailprotected]

Media Jane Baj+1 (908) 912-9167[emailprotected]

Forward-Looking StatementsThis press release contains forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995. All statements contained in this release, other than statements of historic fact, are forward-looking statements, including statements regarding: the future expectations, plans and prospects for PTC, including with respect to the expected timing of clinical trials and studies, availability of data, regulatory submissions and responses and other matters; expectations with respect to PTC's gene therapy platform, including any regulatory submissions and manufacturing capabilities; PTC's expectations with respect to the licensing, regulatory submissions and commercialization of its other products and product candidates; PTC's strategy, future operations, future financial position, future revenues, projected costs; and the objectives of management. Other forward-looking statements may be identified by the words, "guidance", "plan," "anticipate," "believe," "estimate," "expect," "intend," "may," "target," "potential," "will," "would," "could," "should," "continue," and similar expressions.

PTC's actual results, performance or achievements could differ materially from those expressed or implied by forward-looking statements it makes as a result of a variety of risks and uncertainties, including those related to: the outcome of pricing, coverage and reimbursement negotiations with third party payors for PTC's products or product candidates that PTC commercializes or may commercialize in the future; expectations with respect to PTC's gene therapy platform, including any regulatory submissions and potential approvals, manufacturing capabilities and the potential financial impact and benefits of its leased biologics manufacturing facility and the potential achievement of development, regulatory and sales milestones and contingent payments that PTC may be obligated to make; significant business effects, including the effects of industry, market, economic, political or regulatory conditions; changes in tax and other laws, regulations, rates and policies; the eligible patient base and commercial potential of PTC's products and product candidates; PTC's scientific approach and general development progress; and the factors discussed in the "Risk Factors" section of PTC's most recent Quarterly Report on Form 10-Q and Annual Report on Form 10-K, as well as any updates to these risk factors filed from time to time in PTC's other filings with the SEC. You are urged to carefully consider all such factors.

As with any pharmaceutical under development, there are significant risks in the development, regulatory approval, and commercialization of new products. There are no guarantees that any product will receive or maintain regulatory approval in any territory, or prove to be commercially successful, including PTC-AADC.

The forward-looking statements contained herein represent PTC's views only as of the date of this press release and PTC does not undertake or plan to update or revise any such forward-looking statements to reflect actual results or changes in plans, prospects, assumptions, estimates or projections, or other circumstances occurring after the date of this press release except as required by law.

1Hwu WL, Kiening K, Anselm I et al. Gene Therapy in thePutamen forCuring AADC Deficiency and Parkinson Disease'. EMBOMolecMedicine. 2021. DOI 10.15252/emmm.202114712. Available at: https://www.embopress.org/doi/10.15252/emmm.202114712. Last accessed August 2021.2Wassenberg T, et al. Consensus guideline for the diagnosis and treatment of aromatic l-amino acid decarboxylase (AADC) deficiency. Orphanet J Rare Dis. 2017;12(1):12.3Williams K et al. Symptoms and impacts of aromatic l-amino decarboxylase (AADC) deficiency: A qualitative study. Poster presented at ISPOR 2021, May 17-20, 20214Pearson T et al. AADC deficiency from infancy to adulthood: Symptoms and developmental outcome in an international cohort of 63 patients. J Inherit Metab Dis. 2020 Sep;43(5):1121-1130.5Chien YH, et al. 3-O-methyldopa levels in newborns: Result of newborn screening for aromaticl-amino-acid decarboxylase deficiency. Mol Genet Metab. August 2016;118(4):259-263.6Buesch K et al. Caring for an Individual with Aromatic L-Amino Acid Decarboxylase (AADC) Deficiency: Analysis of Reported Time for Practical and Emotional Care and Paid/Unpaid Help. Poster presented at ISPOR 2021, May 17-20, 2021.7Chien YH, et al. 3-O-methyldopa levels in newborns: Result of newborn screening for aromaticl-amino-acid decarboxylase deficiency. Mol Genet Metab. August 2016;118(4):259-263

SOURCE PTC Therapeutics, Inc.

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Targeting the Putamen with Gene Therapy Leads to Sustained Improvements in Motor and Non-Motor Functions in Children with AADC Deficiency - PRNewswire

SHANGHAI, Aug.23, 2021 /PRNewswire/ -- Hepagene Therapeutics, Inc., a clinical stage biopharmaceutical company focusing on novel therapies for patients with liver diseases, today announced positive results from its Phase I study of HPG1860 conducted in the United States. HPG1860 is a non-bile acid, potent, selective and full FXR agonist being developed for treatment of non-alcoholic steatohepatitis (NASH) and primary biliary cholangitis (PBC). Findings show that treatment with HPG1860 was safe, well-tolerated and demonstrated a robust target engagement with a favorable pharmacokinetic (PK) profile after 14 days of once daily dosing in healthy volunteers. Detailed results will be presented at upcoming AASLD international liver conference.

The Hepagene phase I trial was a first-in-human, randomized, placebo-controlled, double-blind single-ascending dose (SAD) and multiple-ascending dose (MAD) trial, in which healthy volunteers received once-daily HPG1860 doses ranging from 10 mg to 100 mg in the SAD cohorts and 5 mg to 20 mg in the MAD cohorts for 14 days. The primary objective of the trial was to evaluate safety/tolerability and the secondary objectives were to assess PK parameters and FXR target engagement, the latter through measurement of fibroblast growth factor 19 (FGF19) and 7-hydroxy-4-cholesten-3-one (C4), blood biomarkers of bile acid synthesis and metabolic homeostasis that increases and decreases respectively with FXR activation.

HPG1860 was safe and generally well-tolerated with no serious adverse events reported. Most adverse events were mild in severity. Importantly, pruritus only occurred in highest dose cohort (20 mg) and LDL-cholesterol increases were not seen at any dose level. HPG1860 exhibited a favorable PK profile as well as robust FXR target engagement with notable C4 regression 93.1%, 97.0% and 97.6% decrease observed after the last dose in MAD 5 mg, 10 mg and 20 mg cohorts compared with placebo. The magnitude of C4 decrease can be used to project potential liver fat reduction level in NASH patients, with 30% relative liver fat reduction being associated with increased likelihood of histological benefits upon liver biopsy.

"We are encouraged by the overall safety profile of HPG1860, and meaningful target engagement seen at as low as the 5 mg dose level. We plan to evaluate the 3 mg, 5mg and 8 mg dose levels in our upcoming Phase IIa trial in NASH patients," said Que Liu, M.D., PhD, Chief Medical Officer ofHepagene.

"It is encouraging to see that there was no significant increase in LDL cholesterol despite excellent FXR target engagement with sustained C4 suppression." said Rohit Loomba, MD, MHSc, Professor of Medicine, and Director, UCSD NAFLD Research Center, University of California at San Diego, La Jolla, CA.

"NASH is a complex liver disease with multiple pathways involved in liver cell injury, inflammation and fibrosis development. FXRs have been shown to impact the underlying pathology of NASH in a meaningful way. Combination therapy, involving multiple mechanisms of action, is likely going to be needed to combat this disease effectively, providing an opportunity for HPG1860. The early data presented here are very encouraging from a safety and tolerability perspective and I am looking forward to beginning the phase 2 study." said Stephen Harrison, MD, Medical Director of Pinnacle Clinical Research in San Antonio, Texas.

Based on the Phase 1 safety and PK/PD data, Hepagene plans to advance three dose levels of HPG1860 3 mg, 5 mg and 8 mg in a 12-week, randomized, placebo-controlled Phase IIa trial enrolling about 80 patients with NASH in US. The selected doses are projected to inhibit C4 to levels that are likely to result in meaningful reductions in liver fat content. The trial is scheduled to start in the last quarter of 2021, with an interim analysis planned in the first half of 2022.

About HPG1860

HPG1860 is an investigational potent and selective full FXR agonist with a non-bile acid scaffold and is currently in first-in-human clinical phase I study. Through regulation of gene expression of bile acids, FXR serves as a key controller of bile acid homeostasis. FXR has been studied for its role in modulating inflammation and the expression of FXR is down-regulated during NASH development. HPG1860 exhibited superb efficacy and safety profile in preclinical research.

About NASH

Nonalcoholic fatty liver disease (NAFLD) is rapidly becoming the most common liver disease worldwide, with an approximate prevalence of 20-30% in western countries. An estimated 20-25% of these patients will further progress to NASH, marked by steatohepatitis, ballooning and inflammation. Typically, NASH is accompanied with liver fibrosis that can progress to liver cirrhosis and hepatocellular carcinoma.

About Hepagene Therapeutics, Inc.

Hepagene Therapeutics, Inc. devotes its drug discovery and development efforts towards discovering, developing and delivering innovative medicines that help patients prevail over liver diseases, especially non-alcoholic steatohepatitis (NASH), chronic Hepatitis B infection and liver cancer.

SOURCE Hepagene Therapeutics, Inc.

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Hepagene Therapeutics, Inc. Announces Positive Results from Phase I Trial of HPG1860 - PRNewswire

Introduction

The lifelong administration of combination antiretroviral therapy (ART) can effectively suppress viral replication and reduce morbidity and mortality of people living with HIV (PLWH).1 There are multiple classes of ART drugs, including nucleoside reverse transcriptase inhibitors (NRTI) including lamivudine (3TC) and azidothymidine (AZT), non-nucleoside reverse transcriptase inhibitors (NNRTI) including nevirapine (NVP), protease inhibitors (PI) including Lopinavir/Ritonavir (LPV/r) and the integrase strand transfer inhibitor (INSTI) raltegravir (RAL).2 In recent years, the rapid expansion of access to ART has led to the emergence of multi-class drug resistance (MDR), defined as a virus mutant with resistance to at least three different drug classes.3

A previous study of a large cohort of cART-experienced patients in Italy showed a dramatic drop in drug resistance from 8085% in 1999 to around 36% in 2018. In recent years (201118), the percentage of isolates with at least three classes of drug resistance has remained stable at around 5% (range 36%).4 The majority of these patients have been found to have a long history of HIV infection, with previous exposure to suboptimal therapies, and to have, over time, accumulated many mutations resistant to several drug classes.4 The viral evolutionary dynamics within these patients that leads to the development of MDR has not been well documented.

Most drug resistance data have been collected from patients infected with HIV-1 subtype B in the United States, Oceania, and Europe. When ART has become increasingly available in new geographic areas, drug resistance in a diverse group of M subtypes and distinct circulating recombinant forms (CRFs) has evolved. CRF01_AE emerged in Southeast Asia in the 1990s, expanded rapidly in China, and is now the most prevalent HIV-1 form in Southeast Asia.5,6 Previous studies have identified a 920% higher resistance mutation frequency at reverse transcriptase positions in CRF01_AE than in subtype B, and a 1218% higher predicted cross-resistance to future therapy options.7 The influence of genetic variation across subtypes has therefore become an active area of research into resistance evolution and disease progression.

In our previous study of the evolutionary patterns during ART failure, plasma and peripheral blood mononuclear cells (PBMC) were longitudinally sampled at different time points from a single patient who suffered several periods of ART failure before successful reduction of viral load. The different intrapatient evolutionary dynamics patterns of env and pol viral segments witness not only the emergence of drug resistant mutants, but also the switch of tropism.8

In the current study, the same longitudinal approach was applied to learn more about the viral evolutionary dynamics during the development of four-class MDR in a single patient infected with the CRF01_AE experiencing ART failure and subsequent mortality. The distribution and percent of drug resistance mutants in the reverse transcriptase (RT), protease (PR) and integrase (IN) genes were determined by next generation sequencing, and the demographic history of the HIV DNA reservoir in PBMC was reconstructed by applying phylodynamics methods.

A 27-year-old patient was diagnosed as HIV-positive in August 2008. PBMC and plasma samples were collected at different time points from September, 2013 to June, 2017 (Figure 1). The study was approved by the institutional review boards of the First Affiliated Hospital, School of Medicine, Zhejiang University (Reference Number: 2020265). Written informed consent was provided by the patient to allow the case details and any accompanying images to be published.

Figure 1 Schematic representing the treatment and sampling protocols used in this study. This patient initiated antiretroviral therapy with 3TC+AZT+NVP in August 2008, switched to 3TC+AZT+LPV/r in August 2013, and to 3TC+AZT+LPV/r+RAL in March 2015. Samples used in the study were collected at different time points shown on top of the schematic. Rectangles represent plasma and circles represent PBMC.

Plasma samples were tested for viral load during treatment. The patient had been diagnosed as HIV-positive in August 2008 and initiated ART with 3TC+AZT+NVP. The ART regimen was switched to 3TC+AZT+LPV/r in August 2013 because of unsuppressed viral load (1*105 copies/mL) and detection of reverse transcriptase resistant mutations, both to NRTI and NNRTI. One month later, in September, 2013, viral load decreased to about 1.4*103 copies/mL, and was under the detection limit (50 copies/mL) from March, 2014 to December 2014. In March, 2015, the ART regimen was changed, to 3TC+AZT+LPV/r+RAL, again due to unsuppressed viral load (5.4*104 copies/mL). By June, 2017, two years later, the viral load had increased, to 1.8*105 copies/mL (Table 1), and was followed by the patients death in August, 2017.

Table 1 Characteristics of Drug-Resistant Mutant Sequences Isolated from Plasma

All collected samples during treatment were sequenced by Sanger sequencing and Next Generation Sequencing (NGS) techniques. The purified PR/RT amplicon and IN amplicon were randomly interrupted by Covaris ultrasonic breaker and then used for library preparation (NEBNext Ultra II DNA Library Prep Kit for Illumina) according to manufacturers instructions. Sequencing was carried out by the Illumina high-throughput sequencing platform (Nova-Seq). After data processing and quality filtering performed to obtain clean data, fastq files were aligned and generated the codon frequency tables using fastq2codfreq script (https://hivdb.stanford.edu/page/codfreq/). Then, the codon frequency tables were submitted to HIVdb-NGS beta for genotypic resistance interpretations and quality control analysis. Minimum detection threshold was set to 1% for all samples, because detection below a frequency of 1% may cause failed quality assessment. ShoRAH was applied to convert NGS sequence variants into haplotypes.9

MUSCLE software (v3.8.31)10 was used to align all RT, PR and IN sequences from plasma viral RNA and cellular DNA collected during the ART therapy. Alignments were manually edited and trimmed to 297 nucleotides for PR (HBX2: 22532549), 903 nucleotides for RT (HBX2: 25503452) and 780 nucleotides for IN (HBX2: 42905069) using BioEdit software (v7.0.9). Shorter sequences and sequences with stop codons or gaps larger than a nucleotide triplet were removed from the alignments. The best-fitting nucleotide substitution model was selected with jModeltest software (v2.1.7),11 using the Akaike Information Criterion (AIC). Phylogenetic trees were inferred using PhyML software (v3.0).12 Bootstrap analysis was performed on 1000 replicates.

The demographic history of the HIV reservoir in PBMC was estimated using the BEAST software13 and implemented in the Bayesian Markov chain Monte Carlo (MCMC) method. The Bayesian skyline model14 and strict clock model were incorporated in the MCMC method. Multiple independent MCMC runs were performed and assessed for consistency. Convergence of relevant parameters and Bayesian skyline results were assessed by effective sample sizes over 200 in Tracer v1.6 (http://tree.bio.ed.ac.uk/software/tracer/).

Over the course of three periods of treatment failure, the patient developed a four-class drug resistant virus population, in which we identified thirteen mutations associated with drug resistance. Five were in the RT gene - M41L, K65R, K70T, Y181C and G190A; four in the PR gene - M46I, I54L, L76V, and I84; and four in the IN gene - E138K, G140A, S147G, Q148R.

Sampling for this study was initiated after the patient was first diagnosed with ART failure, five years after ART treatment was first initiated. By that time, In September, 2013, almost 100% of PBMC virus already had mutants resistant to NRTI and NNRTI, and these levels persisted throughout periods of treatment, even during 2014, when plasma viral load was under the limit of detection.

After the introduction of the protease inhibitor Lopinavir/Ritonavir (LPV/r) to the patients ART, PI resistant mutants developed slowly in PMBC DNA. After one month, none were found; after sixteen months, less than 20% were mutants. After three years (two months prior to the patients death) PI mutants in PMBC DNA were still under 50%. PI resistant mutants in plasma had a different pattern. At sixteen months after the introduction of the PI no sequences could yet be identified because the viral level was too low for amplification. Eventually, substantially higher PI mutant levels were able to be found in plasma - almost 100% two years after a PI drug was switched to ART, by which time viral load had increased to 5.4*104 copies/mL.

Integrase strand transfer inhibitor (INSTI) mutations evolved much more quickly, replacing approximately 75% of the wild genotype in HIV DNA one year after addition of the integrase inhibitor raltegravir to the patients ART, and almost 100% after two years.

INSTI-resistant mutations, E138K, G140A, S147G and Q148R, replaced approximately 75% of the wild genotype in HIV DNA one year after addition of RAL to ART, and almost 100% 14 months later, by which time viral load reached 1.8*105 copies/mL. These results are displayed in Table 1 and Figure 2.

Figure 2 The development of Drug Resistant Mutants in Reverse Transcriptase (RT), Protease (PR) and Integrase (IN) Sequences in DNA from PBMC. Change in percent of drug resistant mutations in RT sequences, PR sequences and IN sequences. The vertical axes represent the percent of drug resistant mutants. Time scale is in calendar years and months.

In the RT gene, K65R and K70T mutations cause low resistance to 3TC and increased susceptibility to AZT. The Y181C and G190A mutants are associated with high-level resistance to NVP. M41L is a non-polymorphic mutation selected by thymidine analogs AZT. In the PR gene, M46I, L76V and I84V are non-polymorphic mutants selected by protease inhibitors. These mutants reduce susceptibility to LPV/r. In the IN gene, E138K, G140A and Q148R are also non-polymorphic mutants, selected by INSTI (RAL). Q148R is associated with high-level reductions in RAL susceptibility, particularly when it occurs in combination with E138K or G140A mutants (Table 2). All drug resistant mutation associations are based on the Stanford drug resistance database.15

Table 2 Characteristics of Drug-Resistant Mutant Sequences Isolated from PBMC

Because there were sufficient sequence data points from PBMC HIV DNA, Bayesian skyline plots were reconstructed to infer the dynamic of the effective population of RT, PR, and IN sequences in the PBMC. The effective population of RT sequences was shown to be stable over the entire testing period. However, the effective population of protease and integrase sequences underwent a significant increase in genetic variation during the period of treatment failure. After the switch of LPV/r to ART, the effective population of PR sequences first decreased and then increased with drug mutants selected by LPV/r. The effective population of IN sequences also decreased after the administration of PI, and stayed low for about six months. After the administration of INSTI, the effective population of IN sequences increased because of the drug resistant mutants selected by RAL. (Figure 3).

Figure 3 Demographic History of RT, PR and IN Sequences in DNA from PBMC. Bayesian skyline plots showing the effective population in the RT sequences (A), PR sequences (B) and IN sequences (C). Median estimates of the effective number of infections using Bayesian skyline (black curve) are shown in each graphic together with 95% highest probability density intervals of the Bayesian skyline estimates (blue area). The vertical axes represent the estimated effective number of infections on a logarithmic scale. Time scale is in calendar years. Vertical dotted lines indicate when a protease inhibitor (PI) and integrase strand transfer inhibitor (INSTI) were added to ART.

In this study, the mutant sequences have emerged during the development of a new four-class drug resistant HIV-1 CRF01_AE variant in a single patient, during several periods of therapy failure. This is a serious and challenging development since PLWHs harboring multi-class drug resistant virus have a high burden of disease, with a worrying incidence of malignancies and poorer survival after treatment failure.3,16

By the studys first sample collection point, almost 100% of viral sequences already had mutants resistant to NRTI and NNRTI in PBMC, so no significant change in the effective population of these sequences was observed over time. However, PI and INSTI drug resistant mutants gradually replaced the wild genotype, and drove the increase of genetic variability in HIV DNA. Demographic histories of these developments were generated by Bayesian skyline plot analysis, and demonstrate the genetic diversity in viral segment sequences over time, expressed as effective population.

This studys sequencing data showed significantly reduced genetic variability in both protease and integrase PBMC-derived variants directly following the administration of PI. A study by Besson et al investigated the decay of HIV DNA on ART and showed that the infected cell populations decline initially but then achieve a steady state with the persistence of about 10% of infected cells during effective ART.17 The different phase of decay occurs from the death of infected cells with different half-lives from days to months.18 The effective population increased when the drug resistant mutants were selected.

One previous study reported that the prevalence of INSTI resistance remained low compared with PI and RT resistance in ART-treated populations, but expanded with increased INSTI use between 2009 and 2016.19 The development of INSTI resistance described in this study suggests how that resistant pathway is evolving. Here the CRF01_AE virion developed INSTI resistant mutants by changes at position Q148, the most common mutant pathways previously described in all subtypes.20 There have been numerous reports of the emergence of substitutions involving position Q148 in response to RAL pressure. As substitutions at position Q148 impart a severe fitness cost,20 they are rapidly compensated for by various secondary resistance mutants, and the addition of at least two secondary mutants seems to confer the highest fold changes in resistance to second-generation INSTIs.21 E138K and G140A, identified in our study, are two of these mutants. The prevalence of the INSTI resistance mutants in CRF01_AE needs further investigation through a larger sample.

Drug-resistant mutants in HIV DNA emerged before they appeared in plasma through the use of next generation sequencing. The difference could be caused by the higher level of cell-associated HIV-1 RNA than in plasma RNA, which may contribute to the generation of new viral genomes, when plasma virus remains below the limit of detection.22 Some mutants could also remain in HIV DNA through persistence and/or proliferation of infected cells. These integrated and unintegrated provirus in latently infected cells may have a delayed contribution to the pool of resistant virus.23

While our study is limited to a single patient and several sampling timepoints, our data set and analysis demonstrated for the first time the evolution of sequences in the development of a four-class drug resistant HIV-1 CRF01_AE virion. It revealed dynamic shifts in the viral population and in drug-resistance mutants, while under the influence of complex ART regimens. This study utilized all samples available for this patient. Collection of baseline samples prior to initiation of ART, and at more sampling time points during treatment, will help us analyze evolutionary change in patient viral population. Our findings also suggested that next generation sequencing can be a very effective tool to detect a low level of drug resistance in HIV DNA, which could be critical for the clinical management of patients, especially those already experiencing virological failure while on particular ART regimens.

Both clinicians and patients need to be aware that a wide pattern of resistance can represent a strong negative prognostic factor for survival. Early detection of the development of drug resistant mutants should become a priority to prevent the further development of resistance through modification of ART regimens and as part of patient education to strengthen adherence to therapy.

The datasets used in this study are available from the corresponding author on reasonable request.

The study was approved by the institutional review boards of the First Affiliated Hospital, School of Medicine, Zhejiang University (Reference Number: 2020265). Written informed consent was provided by the patient to allow the case details and any accompanying images to be published.

We gratefully thank Susan Joyce Herzog for assistance in editing our manuscript.

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work. First co-author: These authors contribute equally to this manuscript: Xiaorong Peng and Yufan Xu.

This study was supported by National Special Research Program for Important Infectious Diseases (No. 2017ZX10202102-002-002).

The authors declare no conflicts of interest for this work.

1. Palella FJ, Delaney KM, Moorman AC, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. N Engl J Med. 1998;338:853860. doi:10.1056/NEJM199803263381301

2. Smith SJ, Zhao XZ, Passos DO, Lyumkis D, Burke TR, Hughes SH. Integrase strand transfer inhibitors are effective anti-HIV drugs. Viruses. 2021;13:205. doi:10.3390/v13020205

3. Zaccarelli M, Tozzi V, Lorenzini P, et al. Multiple drug class-wide resistance associated with poorer survival after treatment failure in a cohort of HIV-infected patients. Aids. 2005;19:10811089. doi:10.1097/01.aids.0000174455.01369.ad

4. Armenia D, Di Carlo D, Flandre P, et al. HIV MDR is still a relevant issue despite its dramatic drop over the years. J Antimicrob Chemother. 2020;75:13011310. doi:10.1093/jac/dkz554

5. Feng Y, He X, Hsi JH, et al. The rapidly expanding CRF01_AE epidemic in China is driven by multiple lineages of HIV-1 viruses introduced in the 1990s. Aids. 2013;27:17931802. doi:10.1097/QAD.0b013e328360db2d

6. Peng X, Wu H, Peng X, Jin C, Wu N. Heterogeneous evolution of HIV-1 CRF01_AE in men who have sex with men (MSM) and other populations in China. PLoS One. 2015;10:e0143699. doi:10.1371/journal.pone.0143699

7. Huang A, Hogan JW, Luo X, et al. Global comparison of drug resistance mutations after first-line antiretroviral therapy across human immunodeficiency virus-1 subtypes. Open Forum Infect Dis. 2016;3:ofv158. doi:10.1093/ofid/ofv158

8. Peng X, Xu Y, Huang Y, Zhu B. Intrapatient evolutionary dynamics in an individual infected with HIV-1 CRF01_AE who experienced periods of treatment failure. AIDS Res Hum Retroviruses. 2021;37:139146. doi:10.1089/aid.2020.0213

9. Zagordi O, Bhattacharya A, Eriksson N, Beerenwinkel N. ShoRAH: estimating the genetic diversity of a mixed sample from next-generation sequencing data. BMC Bioinform. 2011;12:119. doi:10.1186/1471-2105-12-119

10. Edgar RC. MUSCLE: a multiple sequence alignment method with reduced time and space complexity. BMC Bioinform. 2004;5:113. doi:10.1186/1471-2105-5-113

11. Darriba D, Taboada GL, Doallo R, Posada D. jModelTest 2: more models, new heuristics and parallel computing. Nat Methods. 2012;9:772. doi:10.1038/nmeth.2109

12. Guindon S, Dufayard JF, Lefort V, Anisimova M, Hordijk W, Gascuel O. New algorithms and methods to estimate maximum-likelihood phylogenies: assessing the performance of PhyML 3.0. Syst Biol. 2010;59:307321. doi:10.1093/sysbio/syq010

13. Drummond AJ, Suchard MA, Xie D, Rambaut A. Bayesian phylogenetics with BEAUti and the BEAST 1.7. Mol Biol Evol. 2012;29:19691973. doi:10.1093/molbev/mss075

14. Minin VN, Bloomquist EW, Suchard MA. Smooth skyride through a rough skyline: bayesian coalescent-based inference of population dynamics. Mol Biol Evol. 2008;25:14591471. doi:10.1093/molbev/msn090

15. Shafer RW. Rationale and uses of a public HIV drug-resistance database. J Infect Dis. 2006;194(Suppl 1):S518. doi:10.1086/505356

16. Galli L, Parisi MR, Poli A, et al. Burden of disease in PWH harboring a multidrug-resistant virus: data from the PRESTIGIO registry. Open Forum Infect Dis. 2020;7:ofaa456. doi:10.1093/ofid/ofaa456

17. Besson GJ, Lalama CM, Bosch RJ, et al. HIV-1 DNA decay dynamics in blood during more than a decade of suppressive antiretroviral therapy. Clin Infect Dis. 2014;59:13121321. doi:10.1093/cid/ciu585

18. van Zyl G, Bale MJ, Kearney MF. HIV evolution and diversity in ART-treated patients. Retrovirology. 2018;15:14. doi:10.1186/s12977-018-0395-4

19. Kamelian K, Lepik KJ, Chau W, et al. Prevalence of human immunodeficiency virus-1 integrase strand transfer inhibitor resistance in British Columbia, Canada between 2009 and 2016: a longitudinal analysis. Open Forum Infect Dis. 2019;6:ofz060. doi:10.1093/ofid/ofz060

20. Anstett K, Brenner B, Mesplede T, Wainberg MA. HIV drug resistance against strand transfer integrase inhibitors. Retrovirology. 2017;14:36. doi:10.1186/s12977-017-0360-7

21. Tsiang M, Jones GS, Goldsmith J, et al. Antiviral activity of bictegravir (GS-9883), a novel potent HIV-1 integrase strand transfer inhibitor with an improved resistance profile. Antimicrob Agents Chemother. 2016;60:70867097. doi:10.1128/AAC.01474-16

22. Scully EP, Gandhi M, Johnston R, et al. Sex-based differences in human immunodeficiency virus type 1 reservoir activity and residual immune activation. J Infect Dis. 2019;219:10841094. doi:10.1093/infdis/jiy617

23. Wang YM, Dyer WB, Workman C, Wang B, Sullivan JS, Saksena NK. Molecular evidence for drug-induced compartmentalization of HIV-1 quasispecies in a patient with periodic changes to HAART. Aids. 2000;14:22652272. doi:10.1097/00002030-200010200-00007

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Early detection of the development of drug resistance | IDR - Dove Medical Press

Dublin, Aug. 20, 2021 (GLOBE NEWSWIRE) -- The "Gene Therapy - Technologies, Markets & Companies" report from Jain PharmaBiotech has been added to ResearchAndMarkets.com's offering.

Gene therapy technologies are described in detail including viral vectors, nonviral vectors and cell therapy with genetically modified vectors.

Gene therapy is an excellent method of drug delivery and various routes of administration as well as targeted gene therapy are described. There is an introduction to technologies for gene suppression as well as molecular diagnostics to detect and monitor gene expression. Gene editing technologies such as CRISPR-Cas9 and CAR-T cell therapies are also included. Gene therapy can now be combined with antisense techniques such as RNA interference (RNAi), further increasing the therapeutic applications.

Clinical applications of gene therapy are extensive and cover most systems and their disorders. Full chapters are devoted to genetic syndromes, cancer, cardiovascular diseases, neurological disorders and viral infections with emphasis on AIDS. Applications of gene therapy in veterinary medicine, particularly for treating cats and dogs, are included.

Research and development is in progress in both the academic and the industrial sectors. The National Institutes of Health (NIH) of the US is playing an important part. As of 2016, over 2050 clinical trials were completed, were ongoing, or had been approved worldwide. A breakdown of these trials is shown according to the geographical areas and applications.

Since the death of Jesse Gelsinger in the US following a gene therapy treatment, the FDA has further tightened the regulatory control on gene therapy. A further setback was the reports of leukemia following the use of retroviral vectors in successful gene therapy for adenosine deaminase deficiency. Several clinical trials were put on hold and many have resumed now. Four gene medicines have been approved by the FDA. The report also discusses the adverse effects of various vectors, safety regulations and ethical aspects of gene therapy including gene editing and germline gene therapy.

The markets for gene therapy have been difficult to estimate as there only a few approved gene therapy products Gene therapy markets are estimated for the years 2020-2030. The estimates are based on the epidemiology of diseases to be treated with gene therapy, the portion of those who will be eligible for these treatments, competing technologies and the technical developments anticipated in the next decades. In spite of some setbacks, the future for gene therapy is bright. The markets for DNA vaccines are calculated separately as only genetically modified vaccines and those using viral vectors are included in the gene therapy markets

The voluminous literature on gene therapy was reviewed and selected 750 references are appended in the bibliography. The references are constantly updated. The text is supplemented with 79 tables and 25 figures.

Profiles of 202 companies involved in developing gene therapy are presented along with 266 collaborations. There were only 44 companies involved in this area in 1995. In spite of some failures and mergers, the number of companies has increased more than 4-fold in 2 decades. These companies have been followed up since they were the topic of a book on gene therapy companies by the author of this report.

Benefits of this report

Story continues

Up-to-date on-stop information on gene therapy with 79 tables and 25 figures

Evaluation of gene therapy technologies

750 selected references from the literature

Estimates of gene therapy markets from 2020-2030

Profiles of 202 companies involved and collaborations in this area

Who should read this report?

Biotechnology companies developing gene therapy

Academic institutions doing research in gene therapy

Drug delivery companies

Pharmaceutical companies interested in gene therapy

Gene therapy companies

Venture capital and investment companies

Key Topics Covered:

Executive Summary

1. Introduction

2. Gene Therapy Technologies

3. Clinical Applications of Gene Therapy

4. Gene Therapy of Genetic Disorders

5. Gene Therapy of Cancer

6. Gene Therapy of Neurological Disorders

7. Gene Therapy of Cardiovascular Disorders

8. Gene therapy of viral infections

9. Research, Development and Future of Gene Therapy

10. Regulatory, Safety, Ethical Patent Issues of Gene Therapy

11. Markets for Gene Therapy

12. Companies involved in Gene Therapy

13. References

For more information about this report visit https://www.researchandmarkets.com/r/v69ou

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Global Gene Therapy Technologies, Markets & Competitive Landscape Report 2021 with Profiles of 202 Companies and 266 Collaborations in this Area -...

For a long time, gene and cell therapies were a treatment option for the future. Now, the pace of development is moving at breakneck speed, with a number of firsts and $14.1billion in financing collected over the initial half of the year.

The Alliance for Regenerative Medicine has documented the acceleration on all fronts in a new report looking at the first half of 2021.

Most notably was Intellias demonstration of CRISPR gene-editing in humans through phase 1 data for patients with transthyretin (ATTR) amyloidosis. But thats not all for regenerative medicine, which includes cell and gene therapies, gene editing and tissue-based therapies.

Companies developing these therapies have collected $14.1 billion in the first half alone, which is 71% of what was raised during all of 2020. The alliance called this surge the strongest half on record. 2020 already broke financing records, with $20 billion, and the report suggests 2021 could exceed that total.

RELATED:Intellia hits a 'home run' with gene-editing results, setting up entire field for a grand slam

Cell-based immuno-oncology has for the first time surpassed gene therapy in financing, notching $6.6 billion compared to $6.4 billion, respectively. The broader category of cell therapy, including stem cell treatments for Parkinson's disease, meanwhilepicked up $1.1 billion.

Gene therapies and gene-modified cell therapy products are on track to notch the highest annual number of regulatory approvals. Three have already been approved. Bluebird bios Skysona nabbed an EU nod for the rare neuromuscular disease cerebral adrenoleukodystrophy. Bristol Myers Squibb and bluebirds multiple myeloma CAR-T drug Abecma was cleared by the FDA in late March. And Bristol Myers long-awaited CAR-T liso-cel, now called Breyanzi, was approved in February.

Waiting in the regulatory queue in the U.S. and EU isJohnson & Johnson and Legend Bios cilta-cel in multiple myeloma, which will compete with Abecma. Other companies have approvals pending around the world.

Even with these approvals, however, cell and gene therapies face hurdles once they are cleared for the market. Bluebird bio, for instance, has pulled back from European markets after failing to reach a consensus on pricing for the one-time treatment Zynteglo.

RELATED: With the pricing situation 'untenable' in Europe, bluebird will wind down its operations in the 'broken' market

The pipeline is nevertheless filled to the brim with new therapies. The report counted 1,320 industry-sponsored trials underway worldwide, including 158 that are in phase 3. Academic and other research is responsible for an additional 1,328 non-industry trialsincluding 85 late-stage studies.

Indications run the gamut of diseases, but are mostly concentrated in oncology for the industry-sponsored trials, followed by central nervous system (CNS) disorders and rare genetic diseases. Academic research similarly focuses on oncology, followed by infectious diseases and CNS.

CAR-T therapies, which take a patients own cells and power them up to fight cancer before being returned to the body, have been particularly dominate in R&D. Abecma is one example, but the J&J-Legend cilta-cel showed some promising data in June, with a 98% overall response rate in multiple myeloma. The therapy is currently being reviewed by EU and U.S. regulators, with a decision expected later this year.

RELATED:ASCO: J&J's anti-BCMA CAR-T pads its case ahead of speedy review and Bristol Myers showdown

More readouts are expected from Precision BioSciences and CRISPR Therapeutics, which are working on separate BCMA-targeted CAR-T therapies.

The alliance counts 566 companies as developing regenerative medicines and advanced therapies in the U.S. and 588 industry-sponsored trials with U.S. sites.

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Regenerative medicine nears banner year with $14.1B cash infusion, regulatory milestones and a well-stocked pipeline - FierceBiotech

Heidi Marsh, 46, of Seattle, tested positive for the PALB2 mutation after her mother a breast cancer and pancreatic cancer patient was found to have it. She said her own doctor was unaware of the gene.

My OB-GYN was aware of my moms history and never suggested genetic testing, Ms. Marsh said. She never heard of it. I educated her. The oncologist she sent me to did not suggest surgery.

But Seattle Cancer Care Alliance, a partner of Fred Hutchinson Cancer Research Center, where Ms. Marshs mother had been an oncology nurse, did know about the gene mutation. The group immediately put together a team that included a surgical oncologist, a pancreatic cancer specialist, a geneticist, a nutritionist and a social worker.

This has been life-changing, said Ms. Marsh, who had her fallopian tubes removed in April. (She was told most ovarian cancer first occurs in the tubes. She plans to remove her ovaries after menopause.)

She will have breast monitoring with alternating mammograms and breast M.R.I.s every six months. She has already had an endoscopic ultrasound to look at her pancreas.

She has found a Facebook group, PALB2 Warriors, to be helpful. Because she has a background in health care she was a phlebotomist she says she looks further than individual postings, to studies that are placebo-controlled and peer-reviewed for information. But when it comes to personal stories of experience with prophylactic mastectomies and reconstruction, she says that is invaluable.

This was not remotely on my radar screen, she said. In one sense I feel empowered. But I also feel like I am waiting for the other shoe to drop, that cancer will be inevitable.

But mostly, she is thankful that she knows about PALB2 and the risks involved.

Its an alarm clock and a wake-up call, she said. You can do something about it if you choose.

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This Breast Cancer Gene Is Less Well Known, but Nearly as Dangerous - The New York Times

DALLAS Aug. 21, 2021 A first-in-kind kidney cancer drug developed from laboratory and translational studies conducted at UTSouthwestern Medical Center received approval from the Food and Drug Administration, providing a new treatment for patients with familial kidney cancer.

FDA approval of belzutifan culminates a 25-year journey at UTSW from gene discovery to a first-in-class drug.

Mercks belzutifan grew out of the discovery at UTSouthwestern of a protein, HIF-2, that is key to fuel the growth of kidney and other cancers. HIF-2 was discovered by Steven McKnight, Ph.D., Professor of Biochemistry.

This is an exciting milestone for patients with inherited forms of kidney cancer who are in need of more effective therapies, said David Russell, Ph.D., Vice Provost and Dean of Research, and Professor of Molecular Genetics, who collaborated in the early stages of the research.

The drug, once called PT2977, was developed based on a backbone discovered by UTSW researchers, with further drug development efforts conducted by a spinoff company named Peloton Therapeutics, which was launched on the UTSW campus and eventually acquired by Merck.

Drs. McKnight and Russell first identified HIF-2 in the 1990s.

HIF-2 was considered undruggable for many years until two more UTSW scientists at the time Richard Bruick, Ph.D., Professor of Biochemistry, and Kevin Gardner, Ph.D., Professor of Biophysics, who also directs a structural biology center at the City University of New York did the structural and biochemical work showing that the HIF-2 molecule contains a pocket that is potentially druggable. The two scientists then identified multiple compounds that fit into this pocket and inhibited the activity of HIF-2.

The history of belzutifans development demonstrates the value of cross-disciplinary collaborations at academic medical centers and how that can translate to new treatments for diseases, said Dr. Russell. It also underscores the value of investing in basic science discoveries at the core of advancements in medicine.

In 2011, several researchers spun off Peloton Therapeutics, and by 2019, when Merck acquired the company, at least three HIF-2 agents were under investigation.

James Brugarolas, M.D., Ph.D., Director of the UTSW Kidney Cancer Program

James Brugarolas, M.D., Ph.D., Director of the Kidney Cancer Program at UTSouthwesterns Harold C. Simmons Comprehensive Cancer Center, showed that the drug was effective against kidney cancer.

With funding from a prestigious National Cancer Institute SPORE award, they showed in a publication inNaturein 2016 that the drug was able to inhibit HIF-2in human kidney tumors transplanted into mice and stop their growth.

This and other studies led to the first clinical trial of PT2385, a precursor to PT2977, which became belzutifan. The trial, which was led by the UTSW Kidney Cancer Program, showed that the drug was well-tolerated and active.

The approval of belzutifan represents a new paradigm in the treatment of kidney cancer, said Dr. Brugarolas, Professor of Internal Medicine. By exclusively targeting HIF-2, which is essential for kidney cancers but dispensable for normal processes, belzutifan specifically disables cancer cells while sparing normal cells. Belzutifan is the best-tolerated kidney cancer drug today and one suitable for patients with familial kidney cancer. It is a testament to the prowess of designer drugs and carefully chosen targets of which it is a prime example.

1997UTSouthwestern biochemist Steven McKnight, Ph.D., and molecular geneticist David Russell, Ph.D., report the discovery of the HIF-2 gene, which they call EPAS1. The team shows that HIF-2 binds to another protein, HIF-1. The HIF-2 partner functions like a pair of tweezers to grab DNA. HIF-2 binds DNA at specific places to initiate the production of other proteins such as VEGF, which support kidney cancer growth.

2003The laboratories of Richard Bruick, Ph.D., and Kevin Gardner, Ph.D., uncover aspects of the atomic blueprint of HIF-2. They show how HIF-2 docks with HIF-1 to assemble into a functional HIF-2 complex. They identify a cavity within the HIF-2 protein, hypothesizing that it may offer a foothold for a drug. Working with UTSouthwesterns High-Throughput Screening laboratory, Drs. Bruick and Gardner develop a test to identify chemicals among 200,000 drug-like molecules that bind to the HIF-2 cavity, preventing HIF-2 binding to HIF-1. By interfering with HIF-2 binding to HIF-1, these compounds block HIF-2 action. The most promising chemicals undergo a refinement process by medicinal chemists at UTSouthwestern.

2010Peloton Therapeutics is founded by UTSW researchers to develop the HIF-2 blocking chemicals into drugs. Peloton scientists create libraries of related compounds, ultimately identifying PT2385 and PT2977 to test in humans. A related drug, PT2399, is identified for laboratory work.

2016Dr. James Brugarolas validates HIF-2 as a target in kidney cancer. In experiments incorporating more than 250 mice transplanted with human kidney tumors, researchers show that PT2399 blocks HIF-2 while not affecting related proteins, is active against 50% of human kidney tumors, and has more activity and is better tolerated than sunitinib (the most commonly used drug for renal cancer treatment at the time).

2018Dr. Kevin Courtney reports the results of a phase 1 clinical trial testing PT2385 in humans. The trial represents the first-in-human study of a first-in-class inhibitor of HIF-2. The trial, which involves 51 patients, shows that PT2385 is safe, well tolerated, and active against ccRCC in humans. More than 50 percent of patients see their cancer regress or stabilize. A patient of Dr. Brugarolas sees benefit for more than a year despite prior progression on seven drugs.

2019U.S. drug manufacturer Merck acquires Peloton Therapeutics for $1.05 billion, with an additional $1.15 billion contingent on sales and regulatory milestones.

2020Through studies of tumor biopsy samples from patients who participated in the Phase 1 clinical trial, Drs. Courtney, Brugarolas, and Ivan Pedrosa, M.D., Ph.D., report the identification of drug resistance mutations in patients, establishing HIF-2 as the first-known core dependency of kidney cancer.

Dr. Brugarolas holds The Sherry Wigley Crow Cancer Research Endowed Chair in Honor of Robert Lewis Kirby, M.D. Dr. McKnight holds the Distinguished Chair in Basic Biomedical Research. Dr. Pedrosa holds the Jack Reynolds, M.D., Chair in Radiology. Dr. Russell holds the Eugene McDermott Distinguished Chair in Molecular Genetics. Disclosures: UTSouthwestern and some of its researchers will receive financial compensation, through prior agreements with Peloton, based on belzutifans FDA approval.

About UTSouthwestern Medical Center

UTSouthwestern, one of the nations premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institutions faculty has received six Nobel Prizes, and includes 25 members of the National Academy of Sciences, 16 members of the National Academy of Medicine, and 13 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 2,800 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UTSouthwestern physicians provide care in about 80 specialties to more than 117,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 3 million outpatient visits a year.

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FDA approval of belzutifan culminates 25-year journey at UTSW from gene discovery to a first-in-class drug - UT Southwestern

The onset of gene therapy and development in tissue engineering, as well as stem cells, are boosting the regenerative medicine market. The rising regulatory approvals for the growth of advanced therapy medicinal products will propel growth in the market. There has been an urgent requirement to develop new therapies for the treatment against SARS-COV-2 to cure patients. Different initiatives are also taken for the manufacturing of cell and gene therapy.

The increasing number of regenerative medicine products, growing investments in research activities for regenerative medicines, and rising number of cancer, genetic disorders, and chronic diseases are further creating lucrative opportunities in the regenerative medicine market. Further, private agencies and government bodies have increased investments and are also conducting different programs for improvements in the R&D activities in the regenerative medicine market. Furthermore, the companies are making collaborations to strengthen R&D abilities to ensure their reach at local as well at global platforms.

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Regenerative Medicine Market: Key Trends

The researchers perspective towards regenerative medicine has been revolutionized with the technological advancements in the therapies that are based on stem cells. The technical progress in stem cell therapy has boosted regenerative medicine developments. For example, haematogenic stem cells are used for the treatment of blood disorders and leukemia. Further, nanotechnology is also used to engineer regenerative medicine and stem cells. The advent of new technology has enabled the development of nanofiber scaffolds with the help of nanofabrication techniques. All these recent developments cumulatively boost the regenerative medicine market.

Efficient treatment options are possible with continuous R&D due to the increasing prevalence of cancer. Different public companies and government organizations are making investments for the research and development in regenerative and advanced cell therapies for the treatment of cancer. These global efforts are further expected to propel growth in the regenerative medicine market.

The key vendors in the industry, along with quality control services, engineering, characterization, manufacturing, management, and some other facilities for R&D and clinical trials, are boosting growth in the regenerative medicine market.

Regenerative Medicine Market: Competitive Dynamics and Key Developments

The key industry player companies are making heavy investments to develop regenerative therapies in order to meet clinical demands in the market. The companies are concentrating to introduce therapies for age-related and oncology-related degenerative disorders. Furthermore, the strategic agreements and collaborative efforts for the development of products and technology sharing will create lucrative opportunities in the regenerative medicine market.

A considerable number of market strategies, such as mergers and acquisitions have developed a growth in the regenerative medicine market. Such as, Agilis Biotherapeutics has been acquired by PTC Therapeutics. Astellas has also acquired Quethera & Universal Cells. The arrival of well-established pharmaceutical organizations is expected to increase M&A activities, which will boost growth in the regenerative medicine market.

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Some of the key market players in the regenerative medicine market include:

Regenerative Medicine Market: Regional Assessment

North America has dominated in the regenerative medicine market in the past year and is also expecting the same in the upcoming years. It is contributing a larger amount in the market revenue. A large number of industry players in the North American regenerative medicine market are the key reasons for the growth. The research institutes presence and advanced technologies for the development of different therapies are increasing the count of clinical trials in the region, and it further boosts growth in the regenerative medicine market.

Different government initiatives and raising funds from private as well as government bodies are also contributing to the revenue generation in the regenerative medicine market. The increasing facilities and infrastructure is also anticipated to boost growth in the regenerative medicine market in the Asia Pacific region.

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TMR Research is a premier provider of customized market research and consulting services to business entities keen on succeeding in todays supercharged economic climate. Armed with an experienced, dedicated, and dynamic team of analysts, we are redefining the way our clients conduct business by providing them with authoritative and trusted research studies in tune with the latest methodologies and market trends.

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Regenerative Medicine Market Key Players are making Heavy Investments to Develop Regenerative Therapies in order to meet Clinical Demands - BioSpace