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$8.8 million to fund research into interaction of specific genes with demographic, lifestyle factors

With an $8.8 million grant from the National Institutes of Health (NIH), researchers at Washington University School of Medicine in St. Louis will study how an individuals risks of cardiometabolic diseases are influenced by the interaction of specific genes with demographic and lifestyle factors.

Researchers at Washington University School of Medicine in St. Louis have received a four-year, $8.8 million grant to ramp up research aimed at unraveling how an individuals risks of cardiometabolic diseases, such as heart disease and Type 2 diabetes, are influenced by the interaction of specific genes with demographic and lifestyle factors.

Going beyond the small percentage of disease risk explained by genes alone, this study will explore how an individuals gender, race, ethnicity, smoking, alcohol use, diet and exercise levels may combine with genetic risks to trigger the metabolic processes that underlie heart disease.

By investigating genomic and lifestyle contributors to cardiometabolic health through their interactions across genders and diverse populations, our research can help advance the emerging field of precision medicine, said principal investigator D.C. Rao, PhD, professor of biostatistics, of genetics, of psychiatry and of mathematics.

Raos key co-investigators at the School of Medicine include cardiologist Lisa de las Fuentes, MD, professor of medicine and of biostatistics, and statistical geneticist C. Charles Gu, PhD, associate professor of biostatistics and of genetics.

Precision medicine uses information about a persons genetic makeup, metabolism and other biological and lifestyle factors to optimize strategies that potentially can prevent or treat a health condition. Such personalized approaches to treatment are more likely to be successful for individual patients, rather than a one-size-fits-all approach.

Funded by the National Institutes of Health (NIH), this new investigation will be the third in a series of similar studies in which Rao and his team use statistical analysis to identify gene-lifestyle interactions associated with cardiovascular and cardiometabolic diseases the leading causes of death in the United States and worldwide.

Their original study identified promising gene-lifestyle interactions, including several tied to African ancestry, but the study lacked the sample size necessary to robustly validate the interactions as statistically significant.

The current study, involving investigators from within and outside the U.S., will overcome that hurdle by expanding the sample size tenfold to include data from more than 1 million individuals, including people from several countries outside the United States. With a sample of 912,000 people of European ancestry, 231,000 of Asian ancestry, 91,000 of African ancestry and 33,000 of Hispanic ancestry, it will be the largest, most diverse investigation of gene-lifestyle interactions attempted.

By focusing heavily on gene-lifestyle interactions, Raos study represents a shift from traditional genomewide association studies (GWAS), which rapidly scan the genomes of many people to find genetic variations associated with a particular disease. His approach, known as a genomewide interaction study (GWIS), adds the potential to show how smoking, alcohol consumption, physical activity, obesity, sleep duration and other lifestyle factors interact with genes to influence high blood pressure, diabetes, cholesterol levels and other metabolic traits that may increase the risk of a heart attack or stroke.

The study aims to identify new gene-lifestyle interactions that contribute to cardiometabolic disease risk, and to better understand the molecular mechanics underlying these interactions, Gu said. By detailing associated molecular biomarkers and traits, such as DNA methylation, gene expression and metabolites, the study could reveal new opportunities for disease intervention.

Added de las Fuentes: Our findings could reveal new diagnostic and therapeutic tools, identify targets for novel drug development and serve as the foundation for a more precise, more personalized approach to health care for heart disease, diabetes, and other metabolic diseases. This project has high potential to move the field forward.

Washington University School of Medicines 1,700 faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Childrens hospitals. The School of Medicine is a leader in medical research, teaching and patient care, consistently ranking among the top medical schools in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Childrens hospitals, the School of Medicine is linked to BJC HealthCare.

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Research to explore how genes, other factors affect cardiometabolic disease risk Washington University School of Medicine in St. Louis - Washington...

SAN FRANCISCO, Aug. 12, 2021 /PRNewswire/ --The global regenerative medicine marketsize is expectedto reach USD 57.08 billion by 2027, growing at a CAGR of 11.27% over the forecast period, according to a new report by Grand View Research, Inc. Recent advancements in biological therapies have resulted in a gradual shift in preference toward personalized medicinal strategies over the conventional treatment approach. This has resulted in rising R&D activities in the regenerative medicine arena for the development of novel regenerative therapies.

Key Insights & Findings:

Read 273 page research report, "Regenerative Medicine Market Size, Share & Trends Analysis Report By Product (Cell-based Immunotherapies, Gene Therapies), By Therapeutic Category (Cardiovascular, Oncology), And Segment Forecasts, 2021 - 2027", by Grand View Research

Furthermore,advancements in cell biology, genomics research, and gene-editing technology are anticipated to fuel the growth of the industry. Stem cell-based regenerative therapies are in clinical trials, which may help restore damaged specialized cells in many serious and fatal diseases, such as cancer, Alzheimer's, neurodegenerative diseases, and spinal cord injuries. For instance, various research institutes have adopted Human Embryonic Stem Cells (hESCs) to develop a treatment for Age-related Macular Degeneration (AMD).

Constant advancements in molecular medicines have led to the development of gene-based therapy, which utilizes targeted delivery of DNA as a medicine to fight against various disorders. Gene therapy developments are high in oncology due to the rising prevalence and genetically driven pathophysiology of cancer. The steady commercial success of gene therapies is expected to accelerate the growth of the global market over the forecast period.

Grand View Research has segmented the global regenerative medicine market on the basis of product, therapeutic category, and region:

List of Key Players of Regenerative Medicine Market

Check out more studies related to Global Biotechnology Industry, conducted by Grand View Research:

Gain access to Grand View Compass, our BI enabled intuitive market research database of 10,000+ reports

About Grand View Research

Grand View Research, U.S.-based market research and consulting company, provides syndicated as well as customized research reports and consulting services. Registered in California and headquartered in San Francisco, the company comprises over 425 analysts and consultants, adding more than 1200 market research reports to its vast database each year. These reports offer in-depth analysis on 46 industries across 25 major countries worldwide. With the help of an interactive market intelligence platform, Grand View Research helps Fortune 500 companies and renowned academic institutes understand the global and regional business environment and gauge the opportunities that lie ahead.

Contact:Sherry JamesCorporate Sales Specialist, USAGrand View Research, Inc.Phone: 1-415-349-0058Toll Free: 1-888-202-9519Email: sales@grandviewresearch.comWeb: https://www.grandviewresearch.comFollow Us: LinkedIn| Twitter

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Regenerative Medicine Market Size Worth $57.08 Billion By 2027: Grand View Research, Inc. - Markets Insider

VTX-801 Receives U.S. FDA Fast Track Designation for the Treatment of Wilson Disease

Paris, France and New York, NY, August 12, 2021 Vivet Therapeutics (Vivet), a clinical-stage biotechnology company, and Pfizer Inc. (NYSE: PFE) today announced the U.S. Food and Drug Administration (FDA) has granted Fast Track designation to VTX-801, Vivets clinical-stage gene therapy for the treatment of Wilson Disease a rare, genetic disorder that reduces the ability of the liver and other tissues to regulate copper levels, causing severe hepatic damage, neurological symptoms, and potentially death. The FDAs Fast Track program is designed to facilitate the development, and expedite the review of, novel potential therapies that are designed to treat serious conditions and fill unmet medical need.

VTX-801 is a novel investigational gene therapy to be evaluated in a Phase 1/2 clinical trial to determine the safety, tolerability, and pharmacological activity of a single intravenous infusion in adult patients with Wilson Disease. Pfizer is collaborating with Vivet on the clinical supply of VTX-801 for the Phase 1/2 clinical trial.

The FDAs decision to grant VTX-801 Fast Track designation underscores the urgent need for new therapeutic options to address this devastating disease, which, if left untreated, can be fatal, said Seng Cheng, Senior Vice President and Chief Scientific Officer of Pfizers Rare Disease Research Unit. We are pleased to collaborate with Vivet on this important development program, which we believe, if successful, could make a meaningful difference in the lives of patients living with Wilson Disease.

Dr. Michael Schilsky, Principal Investigator at Yale University School of Medicine (Connecticut, United States), said, We are proud to participate in this important clinical trial. If VTX-801 is successfully developed, it has the potential to be a truly innovative medicine with the ability to restore copper metabolism after a single injection, addressing significant unmet medical needs for patients with Wilson Disease.

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With the FDAs authorization of the IND application for VTX-801 combined with Pfizers state-of-the-art gene therapy manufacturing capabilities we are well-positioned to rapidly advance development of this potential therapy, concluded Jean-Philippe Combal, CEO and co-founder of Vivet.

About Fast Track designation

Fast Track is a process designed to facilitate the development, and expedite the review of, drugs to treat serious conditions that address an unmet medical need, by providing a therapy where none exists or providing a therapy which may be potentially better and shows some advantage over available therapy. Fast Track designation includes opportunities for more frequent meetings with the FDA to discuss trial design, development plans, data needed to support drug approval, submission of a New Drug Application (NDA) on a rolling basis, and eligibility for accelerated approval and priority review, if relevant criteria are met.

Visit FDAs website for more information

About VTX-801

VTX-801 is a novel investigational gene therapy for Wilson Disease, which has been granted Orphan Drug Designation (ODD) by the Food and Drug Administration (FDA) and the European Commission (EC) and Fast Track designation by the FDA. Wilson Disease, a rare genetic disorder, is caused by mutations in the gene encoding the ATP7B protein, which reduces the ability of the liver and other tissues to regulate copper levels, causing severe hepatic damage, neurologic symptoms and potentially death.

VTX-801 is a novel, investigational rAAV-based gene therapy vector designed to deliver a miniaturized ATP7B transgene encoding, a functional protein that has been shown to restore copper homeostasis, reverse liver pathology and reduce copper accumulation in the brain of a mouse model of Wilson Disease. VTX-801s rAAV serotype was selected based on its demonstrated tropism for transducing human liver cells.

About GATEWAY - Phase 1/2 Clinical Trial of VTX-801 in Wilson Disease

The GATEWAY trial (NCT04537377) is a multi-center, non-randomized, open-label, Phase 1/2 clinical trial designed to assess the safety, tolerability, and pharmacological activity of a single intravenous infusion of VTX-801 in adult patients with Wilson Disease, prior to and following background WD therapy withdrawal.

Six leading centers in the United States and Europe are expected to participate in the GATEWAY Phase 1/2 trial. The trial is expected to enroll up to sixteen adult patients with Wilson Disease and will evaluate up to three doses of VTX-801. Patients will participate in a pre-dosing observational period and will be administered a prophylactic steroid regimen.

The primary endpoint of the GATEWAY trial is to assess the safety and tolerability of VTX-801 at 52 weeks after a single infusion. Additional endpoints include changes in disease-related biomarkers, including free serum copper and serum ceruloplasmin activity, as well as radiocopper-related parameters and VTX-801 responder status to allow standard-of-care withdrawal.

A list of sites, contact information and more details on the study are available on:https://clinicaltrials.gov/ct2/show/NCT04537377

To learn more about gene therapy on Wilson Disease, visit: https://patienteducation.asgct.org/

About Vivet Therapeutics

Vivet Therapeutics is a clinical-stage emerging biotechnology company developing novel gene therapy treatments for rare, inherited metabolic diseases.

Vivet is building a diversified gene therapy pipeline based on novel recombinant adeno-associated virus (rAAV) technologies developed through its partnerships with, and exclusive licenses from, the Fundacin para la Investigacin Mdica Aplicada (FIMA), a not-for-profit foundation at the Centro de Investigacin Medica Aplicada (CIMA), University of Navarra based in Pamplona, Spain.

Vivets lead program, VTX-801, is currently under clinical development.

Vivets second gene therapy product, VTX-803 for PFIC3, received US and European Orphan Drug Designation in May 2020.

Vivet is supported by international life science investors including Novartis Venture Fund, Roche Venture Fund, HealthCap, Pfizer Inc., Columbus Venture Partners, Ysios Capital, Kurma Partners and Idinvest Partners.

Please visit us at http://www.vivet-therapeutics.com and follow us on Twitter at @Vivet_tx, on Facebook at Facebook/Vivet-Therapeutics and LinkedIn.

About Pfizer: Breakthroughs That Change Patients Lives

At Pfizer, we apply science and our global resources to bring therapies to people that extend and significantly improve their lives. We strive to set the standard for quality, safety and value in the discovery, development and manufacture of health care products, including innovative medicines and vaccines. Every day, Pfizer colleagues work across developed and emerging markets to advance wellness, prevention, treatments and cures that challenge the most feared diseases of our time. Consistent with our responsibility as one of the world's premier innovative biopharmaceutical companies, we collaborate with health care providers, governments and local communities to support and expand access to reliable, affordable health care around the world. For more than 170 years, we have worked to make a difference for all who rely on us. We routinely post information that may be important to investors on our website at http://www.Pfizer.com. In addition, to learn more, please visit us on http://www.Pfizer.com and follow us on Twitter at @Pfizer and @Pfizer News, LinkedIn, YouTube and like us on Facebook at Facebook.com/Pfizer.

Pfizer Disclosure Notice

The information contained in this release is as of August 12, 2021. Pfizer assumes no obligation to update forward-looking statements contained in this release as the result of new information or future events or developments.

This release contains forward-looking information about Vivet Therapeutics (Vivet) investigational gene therapy, VTX-801, including its potential benefits, that involves substantial risks and uncertainties that could cause actual results to differ materially from those expressed or implied by such statements. Risks and uncertainties include, among other things, the uncertainties inherent in research and development, including the ability to meet anticipated clinical endpoints, commencement and/or completion dates for our clinical trials, regulatory submission dates, regulatory approval dates and/or launch dates, as well as the possibility of unfavorable new clinical data and further analyses of existing clinical data; the risk that clinical trial data are subject to differing interpretations and assessments by regulatory authorities; whether regulatory authorities will be satisfied with the design of and results from the clinical studies; whether and when any applications may be filed in any jurisdiction for VTX-801; whether and when any such applications may be approved by regulatory authorities, which will depend on myriad factors, including making a determination as to whether the products benefits outweigh its known risks and determination of the products efficacy and, if approved, whether VTX-801 will be commercially successful; decisions by regulatory authorities impacting labeling, manufacturing processes, safety and/or other matters that could affect the availability or commercial potential of VTX-801; uncertainties regarding the impact of COVID-19 on Pfizers business, operations and financial results; and competitive developments.

A further description of risks and uncertainties can be found in Pfizers Annual Report on Form 10-K for the fiscal year ended December 31, 2020 and in its subsequent reports on Form 10-Q, including in the sections thereof captioned Risk Factors and Forward-Looking Information and Factors That May Affect Future Results, as well as in its subsequent reports on Form 8-K, all of which are filed with the U.S. Securities and Exchange Commission and available at http://www.sec.gov and http://www.pfizer.com.

Contacts

Vivet Media Contact: Thomas Daniel-Robintdaniel@vivet-therapeutics.com

Pfizer Media Contact: Jerica Pitts212-733-1226Jerica.Pitts@pfizer.com

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VTX-801 Receives U.S. FDA Fast Track Designation for the Treatment of Wilson Disease - Yahoo Finance

Researchers from the CU School of Medicine Department of Orthopedics have been awarded a $3.4 million National Institutes of Health grant to study the genetics of bone density and to look for therapeutic targets to counter bone loss.

With the grant, Cheryl Ackert-Bicknell, PhD, associate professor of orthopedics at the CU School of Medicine, plans to map the key genes and pathways involved with bone cell activity. Using that information, researchers hope to find targets for more effective treatments to counter bone loss. Ackert-Bicknells fellow principal investigator on the grant is Charles Farber, PhD, associate professor of public health sciences at University of Virginia.

Bone is in a constant state of remodeling, Ackert-Bicknell said, and her study is designed to look at cells known as osteoblasts, which work to build bones. When a healthy body is functioning properly, osteoblasts work in balance with other cells called osteoclasts to maintain sufficient bone mineral density.

In the process of walking from your car to here, you did microcrack damage to your bone, Ackert-Bicknell explained. The osteoclasts job is to home to that site of the microcrack, eat a hole out all the way around that microcrack and the osteoblast comes and fills that in. Thats called normal bone turnover. Thats most of your life. If the osteoclasts go haywire and there is insufficient building of new bone, thats osteoporosis.

Current therapies to cause the body to build the right amount of new bone are limited. These therapies can often only be used for a limited time, and none can be used in children. There is a need for better therapies, Ackert-Bicknell said, but they cannot be developed without improved understanding of how a healthy body gets bone density just right.

Thats where Ackert-Bicknells study comes in. She plans a comprehensive analysis of how the genes influence the process. She will conduct a genome-wide association study that seeks to identify genetic variations that are associated with osteoblast function and bone mineral density.

Osteoblasts build bone. Osteoclasts chew up bone. And thats how I always teach it: Blasts build and clasts chew, Ackert-Bicknell said. Osteoblasts do two things to make bone. They make a protein matrix and then they mineralize that matrix. For that to be accomplished, the osteoblast has to get to the right place, and it has to proliferate. So, it is proliferating, it is migrating, then it is making that bone by making matrix, and it is mineralizing that matrix.

Previous studies of osteoblasts have shown that its characteristics are highly heritable, or transmissible from parents to children. But how osteoblasts form and do their work is not fully understood. What might appear to be a small change on osteoblast behavior can have significant developmental consequences. Ackert-Bicknell cited an example of how knocking out a single gene in one type of bone cell can result in an obese mouse.

You can actually knock out a gene, just in these osteoblast bone cells, and get an obese mouse, she said. In that cell only. It is the only cell in the whole body that makes that gene, and you end up with an obese mouse. This just shows how bone is tied into all of physiology.

To get a better understanding of those connections, Ackert-Bicknells new study will look at the network of all the genes expressed in this cell and their relative expression in different contexts of genetics.

To do this, we must compare bone image after bone image to identify variations that could be meaningful in relation to the genetics, said Douglas Adams, PhD, associate professor of orthopedics, who has worked with Ackert-Bicknell on previous studies that underpin the work in this new award.

Adams is also working with Ackert-Bicknell on another NIH grant studying how the leading treatment for osteoporosis might have variable efficacy because of genetic differences between patients. To conduct such studies, researchers grind through thousands of data points to discover links that have yet to be uncovered. By identifying those unknown connections, the team hopes to discover new ways to treat disorders of bone mineralization.

Its sort of along the lines of looking under the streetlamp for your keys, Ackert-Bicknell said. As long as your keys fell down where the lamp is shining light youve got a good chance of finding them. In our work, we are looking outside of the streetlight for the things we havent studied before.

Lets face it, what we know now isnt giving us enough drug targets, enough information. It isnt helping us. The most unique pathways and the ones that are going to get us drugs are not the ones we have already studied.

Ackert-Bicknells new grant provides funding for a five-year research project. Coupled with the parallel active NIH grant held by both Ackert-Bicknell and Adams, CU Orthopedics is at the forefront of the effort nationally and globally to understand and develop disease modifying approaches to address bone loss in osteoporosis patients. These projects are just part of a growing portfolio of research activity in the Department of Orthopedics, which has seen a greater than 10-fold increase in extramural grant support since the departments leadership committed to expand its research mission in 2018.

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CU Researcher Awarded NIH Grant to Study Genetics of Bone Density - CU Anschutz Today

LentiMutate identified a mutation that changes an amino acid of KRAS G12C at position 96 from tyrosine (Y) to histidine (H). This change impairs the binding of the novel lung cancer drug LUMAKRAS/AMG 510 (depicted in green) to KRAS G12C (depicted by greyscale). Credit: Kenneth D. Westover

DALLAS Aug. 10, 2021 Using a virus to purposely mutate genes that produce cancer-driving proteins could shed light on the resistance that inevitably develops to cancer drugs that target them, a new study led by UTSouthwestern scientists suggests. The findings, published online in Cancer Research, could help researchers develop drugs that circumvent resistance, validate new drug targets, or better understand the interaction between drugs and their target proteins.

Ralf Kittler, Ph.D.

We believe this approach will be a very useful tool in the fight against cancer therapeutic resistance and could have potential in a variety of other areas of drug development, said study leader Ralf Kittler, Ph.D., Associate Professor of Pharmacology in the Eugene McDermott Center for Human Growth and Development and the Harold C. Simmons Comprehensive Cancer Center. Dr. Kittler co-led the study with John D. Minna, M.D., Professor of Internal Medicine and Pharmacology, Director of the Hamon Center for Therapeutic Oncology Research and member of the Simmons Cancer Center.

Targeted therapies represent a major advance in cancer treatment for multiple tumor types, comprising drugs that specifically alter the function of oncoproteins that drive tumors to grow and spread. They are often oral agents with low toxicity that provide symptom relief and prolong survival. However, explained Dr. Kittler, these drugs have a marked drawback: they lose effectiveness over time as tumors become resistant because the genes responsible for the targeted oncoproteins inevitably mutate, producing proteins that no longer bind the drugs. For example, patients with non-small cell lung cancer are often treated with drugs that inhibit a protein known as the epidermal growth factor receptor (EGFR), providing great clinical benefit; unfortunately, most of these tumors develop resistance to the treatment within about a year. This response has led to second-, third-, and even fourth-generation versions of such EGFR-targeting drugs to try to overcome this resistance.

Although methods exist to predict mutations that will develop in cancer target genes an important step toward developing drugs that can attack the resulting mutant proteins these methods are cumbersome, expensive, time-consuming, or can only predict a limited type of mutation known as a point mutation, Dr. Kittler explained.

Looking for a better way to predict therapeutic resistance, the researchers developed a technique they call LentiMutate. This approach relies on a class of viruses called lentiviruses to cause mutations. In contrast with human cells and many other viruses, lentiviruses take RNA and convert it to DNA while infecting its target cells to eventually produce proteins; however, this process is inherently error-prone, producing mutant mistakes in the resulting DNA.

Working with a lentivirus engineered to make it even more error-prone, Dr. Kittler and his colleagues used the vector to insert EGFR RNA in human cells, causing the cells to produce mutant versions of this protein. They then dosed the cells with a commonly used inhibitor for EGFR called gefitinib to search for resistant cells. By sequencing the introduced single gene in the resistant cells, the researchers were able to identify several mutations that made EGFR resistant to gefitinib, a first-generation anti-EGFR drug, including those previously identified in human patients.

Further experiments showed that LentiMutate was able to identify mutations that conferred resistance to the fourth-generation anti-EGFR drug osimertinib, which is now the standard of care for EGFR mutant non-small cell lung cancer. The approach also identified mutations that cause resistance to imatinib, a drug that targets the BCR-ABL1 protein, which drives chronic myelogenous leukemia, and AMG 510, a drug that targets a specific mutant form of the KRAS protein, which drives non-small cell lung cancer.

Dr. Kittler noted that identifying these mutations through LentiMutate can greatly speed up the process of developing new drugs that can bind to the drug-resistant mutant proteins so that it takes weeks rather than years. LentiMutate could also be used in different ways in drug development: to confirm that new drugs are acting on the target protein and not a different one, to help researchers gain a better understanding of how drugs are interacting with their targets, or to develop new types of drugs for a variety of other diseases beyond cancer.

Precision medicine that comes from sequencing a patients tumor to identify specific proteins to target for therapy has revolutionized cancer treatment. However, we need patients to be cured and not just benefit for 10 to 15 months from such targeted therapy, said Dr. Minna. To do this, we need to deal with drug resistance mutations, including by developing new drugs, and LentiMutate gives us an important new tool in our research armamentarium to help solve this pressing problem.

Other UTSW researchers who contributed to this study include Paul Yenerall, Rahul K. Kollipara, Kimberley Avila, Michael Peyton, Yan Liu, and Kenneth D. Westover.

A patent pending for LentiMutate lists Yenerall, Dr. Minna, and Dr. Kittler as inventors. Dr. Minna receives licensing royalties from the National Cancer Institute and UTSouthwestern for cell lines.

This study was supported by funding from the Simmons Cancer Center at UTSouthwestern (P30CA142543), the Cancer Prevention and Research Institute of Texas (CPRIT) (RP120732-P3, RP160652, RP170373), the National Institutes of Health (NCI SPORE in lung cancer 5P50CA070907, R01CA200787, R01CA244341, and R01CA065823), the Margot Johnson Foundation, and the Howard Hughes Medical Institute.

Dr. Kittler is a John L. Roach Scholar in Biomedical Research and a CPRIT Scholar in Cancer Research. Dr. Minna holds the Sarah M. and Charles E. Seay Distinguished Chair in Cancer Research and the Max L. Thomas Distinguished Chair in Molecular Pulmonary Oncology.

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. UT Southwestern 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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Hunting down the mutations that cause cancer drug resistance - UT Southwestern

Introduction

The overuse of antibiotics and the widespread development of antibiotic resistance genes have facilitated the evolution of multidrug-resistant (MDR) Gram-negative bacteria.1 Owing to its toxicity and narrow therapeutic window, colistin has been approved for treatment only for infections in certain patients, including those with cystic fibrosis.2,3 However, the increased incidence of infections with MDR pathogens has led to increased interest in the use of colistin as a last-resort option in a larger number of patients.

Colistin is a positively charged, polypeptide drug that exerts a strong bactericidal effect against a broad-spectrum of Gram-negative bacteria by integration into the negatively charged lipid A, thereby destabilizing the outer membrane lipopolysaccharide (LPS) and leading to cell death.3 However, exposure of Enterobacterales to colistin both in vivo and in vitro has been reported to induce the emergence of colistin resistance in these strains.4,5 The main mechanism of colistin resistance occurs via the addition of cationic groups (ie, phosphoethanolamine [PEtN] or 4-amino-4-deoxy-L-arabinose [L-Ara4N]) to the LPS on bacterial membranes, preventing the high-affinity binding of colistin to LPS.3 The two-component system (TCS) of pmrAB and phoPQ, and the regulator of TCS (ie, mgrB), are primarily responsible for the development of colistin resistance in Enterobacterales.3,6 Moreover, a recently identified plasmid carrying mcr-1 resulted in the addition of PEtN to lipid A.7 Studies have assessed the development of high-level colistin-resistant mutants (HLCRMs) in MCR-1-producing Escherichia coli (MCRPEC). It is not known whether the mcr-1 gene has effects similar to those of plasmid-mediated quinolone resistance genes, which promote the evolution of strains with higher quinolone resistance.8,9 The aim of this study was to determine the impact of chromosomal modifications in pmrAB, phoPQ, and mgrB, combined with mcr-1, on colistin resistance in E. coli.

Six E. coli isolates, five mcr-1-positive clinical strains of E. coli and E. coli ATCC25922, obtained from the American Type Culture Collection (ATCC; Manassas, VA, USA) were used in this study. Isolates were re-identified as E. coli by matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS).10 The mcr-1 gene was amplified by PCR, and its DNA sequence was determined (Table S1). Multi-Locus Sequence Typing (MLST) was performed by comparing sequences of the seven housekeeping genes adk, fumC, gyrB, icd, mdh, purA and recA (https://enterobase.readthedocs.io/en/latest/mlst/mlst-legacy-info-ecoli.html) with the E. coli MLST database (https://enterobase.warwick.ac.uk/species/ecoli/allele_st_search) to determine the allelic types and STs of the tested isolates. None of the data in this study were linked to clinical information.

Plasmid eradication for mcr-1-positive E. coli was performed as previously described.11 Briefly, 5 mL aliquots of LuriaBertani (LB) medium were inoculated with 50 L of a suspension of wild-type E. coli. To each suspension was added 7.5 L, 15 L, or 30 L 10% SDS, and the cultures were incubated with shaking at 37C for 12 h. Subsequently, 50 L of these bacterial suspensions was inoculated into 5 mL fresh LB medium, and the cultures were incubated at 43C for 8 h. Both steps were repeated, and the incubation at 37C was performed a third time. These plasmid-cured derivative strains were plated onto MuellerHinton agar (MHA) plates with and without 4 mg/L colistin. The elimination of the mcr-1-bearing plasmid was confirmed by pulsed-field gel electrophoresis (PFGE), S1-nuclease PFGE (S1-PFGE), and Southern blotting, as described.12,13

Antibiotic susceptibility, except for colistin, was evaluated by Vitek2 (bioMrieux, Marcy-lEtoile, France). The results were in accordance with Clinical and Laboratory Standards Institute (CLSI) guidelines.14 The minimum inhibitory concentrations (MICs) of colistin against the tested strains were determined using the broth microdilution according to CLSI. In addition, the MICs of colistin against the multi-stepwise solutions were determined using the agar dilution method.

The parental and plasmid-curing strains were grown in antibiotic-free MuellerHinton broth at 37C for 68 h, and ~1010 CFU/mL of each strain was spread onto MHA in the presence or absence of colistin. The colistin concentrations used for mutant induction ranged from 1MIC to the concentration at which growth of the parental strain or a sub-parental mutant strain isolated from the prior induction step was fully inhibited. After 4872 h incubation at 37C, colonies growing on the plates were randomly selected, and their MICs of colistin were determined using both the broth microdilution and agar dilution methods. Isolates with the highest MIC were subjected to next-step induction. These induction/selection cycles were terminated when mutants with significantly high MIC were selected, or when their growth on plates with 1MIC colistin concentration was completely inhibited.

The TCS of pmrAB and phoPQ, the negative regulator of the phoPQ system (mgrB) and mcr-1 in parental strains, and their respective mutants, were PCR amplified using primers (listed in Table S1) and 2X A9 LongHiFi PCR MasterMix (Aidlab Biotechnologies Co., Ltd.). Following DNA sequencing, the presumed amino acid sequences of the mutants were compared with those of parental strains using the web platforms of the NCBI (National Center for Biotechnological Information) and ORF Finder (https://www.ncbi.nlm.nih.gov/orffinder/). Sorting Intolerant From Tolerant (SIFT) scores were calculated (http://sift.jcvi.org) to evaluate whether amino acid alterations in PmrAB and PhoPQ affected protein function. Moreover, the TCS domains of PmrA/PmrB and PhoP/PhoQ were subjected to SMART analysis (http://smart.embl.de/).

To determine the effect of mcr-1-bearing plasmids on the evolution of HLCRMs, conjugation experiments were performed as previously described.15 Briefly, a culture of mcr-1-producing isolates was mixed 1:9 with a culture of the recipient strain E. coli C600 in LB broth, followed by overnight incubation on LB agar plates. The resulting transconjugants were selected on MHA plates containing 150 g/mL sodium azide and 2 g/mL colistin. The colonies were identified as E. coli via MALDI-TOF MS, and the DNA of these colonies were sequenced to determine the presence of the mcr-1 gene. Plasmid sizes and numbers were determined using S1-nuclease PFGE. The colonies containing only mcr-1-bearing plasmids (E63-C600 and E66-C600) and E. coli C600 were used to select for colistin-resistant mutants (MuC600, MuE63-C600, and MuE66-C600). Total RNA was extracted from cells grown to mid-log phase in drug-free MHB using the TaKaRa RNAiso Plus (TaKaRa, Japan), according to the manufacturers instructions. The RNA was reverse transcribed to cDNA using PrimeScriptTM RT Reagent kits (TaKaRa). Transcripts of the pmrABC, phoP, mgrB, and mcr-1 genes were quantified by RT-PCR using SYBR Green PCR Master Mix (Applied Biosystems, Foster City, CA, USA) on an ABI7300 Sequence Detection System (Applied Biosystems), using the primers listed in Table S1. Transcription abundance was calculated by the 2CT method16 using gapA as the internal control, and the respective wild-type pmrABC, phoP, mgrB, and mcr-1 genes as references.

Four MCRPECs were subjected to the plasmid eradication test, which successfully eliminated the mcr-1 gene from strains EC18398 and EC26207 (Figure S1). The MICs and STs of the parental and plasmid-cured strains are shown in Table 1. Loss of the mcr-1 gene had little effect on the susceptibility of plasmid-curing strains to other antimicrobial agents, but reduced colistin MIC 416 fold, resulting in MICs of 0.5 and 2 mg/L for strains EC18398E and EC26207E, respectively. In addition, the strains EC1002 and EC2474, co-harboring the mcr-1, blaNDM-1, and blaCTX-M genes, were resistant to colistin, carbapenems, and cephalosporins.

Table 1 Antimicrobial Susceptibility of the E. coli Strains Used in This Study

Following a series of in vitro colistin selection steps, all the tested strains, including MCRPEC and non-MCRPEC strains, successfully evolved to HLCRMs, with MICs of 32 and 64 mg/L, respectively, as determined by the broth microdilution method, and 64 and 64 mg/L, respectively, as determined by the agar dilution method (Table 2 and Figure 1). Colistin inhibited first-step mutants at concentrations of 8 to 32 mg/L, resulting in a 16- to 32-fold increase in susceptibility for these non-MCRPEC mutants compared with their parental strains. By contrast, the in vitro first-step induction had little effect on the MCRPECs, which had MICs equal to or 2-fold higher than their parental strains. For the second cycle, the colistin MIC of all mutants was 32 mg/L, as determined by the broth microdilution method. Second-step mutants were subjected to further repeated inductions, while Mu2EC26207, Mu2EC24990, and Mu3EC18398 failed to grow on the plates containing 1MIC (64 mg/L). Interestingly, all three non-MCRPECs successfully grew on plates containing 1MIC (64 mg/L) after in vitro multi-stepwise induction and selection. The MICs of these non-MCRPEC mutants were 64- to 128-fold higher than those of their parental strains (Figure 2 and Table 2). In addition to determining MIC for colistin, the MICs of various antibiotics with diverse modes of action were also evaluated. Compared with their parental strains, the mutants had equivalent MICs for carbapenems, cephalosporins, levofloxacin, and tigecycline.

Table 2 Phenotypic and Genotypic Profiles of the in vitro Selected Mutants of mcr-1-Positive and mcr-1-Negative E. coli

Figure 1 Changes in the colistin susceptibility of selected mutants. Five mcr-1-positive and three mcr-1-negative E. coli strains were exposed to colistin in a multi-stepwise manner. MIC was measured by the broth dilution method. Mutants with the highest MIC were used for next-step induction and selection processes. Mu1, Mu2, Mu3, and Mu4 indicate the first, second, third, and fourth cycles of induction, respectively.

Figure 2 Mutation frequencies of mcr-1-positive and negative strains when cultured with colistin at its MICs for the parent strains and sub-parental mutants. The colistin MICs of the tested strains were determined by the agar dilution method. Solid line, mcr-1-positive strains; dotted line, mcr-1-negative strains.

In the tested E. coli strains, the mutation rates decreased significantly with increasing colistin concentrations on the selection plates (Figure 2). These results revealed that the frequency of mutation of non-MCRPEC strains to colistin resistance ranged from 106 to 102, whereas the frequency of mutation of MCRPEC strains to colistin resistance was 108 to 10.4 The non-MCRPEC strains could grow on plates containing colistin concentrations of 16 or 32 mg/L, and showed higher mutation rates than their parental strains. For example, EC26207E had a mutation rate of 102 to 106 at 1MIC, which was much higher than that of EC26207 (108 to 106). Additionally, the frequency of non-MCRPEC mutants on plates containing 32 or 64 mg/L was higher than that of MCRPEC mutants.

Comparative genomic analysis of parental and mutants strains showed that non-synonymous mutations in the major TCS associated with colistin resistance were more frequent in non-MCRPEC than in MCRPEC strains. None of the TCS mutations were found in any mutants of EC18398 and EC24990, with only single amino acid changes found in PmrA at position 15 (Gly15Arg) in EC26207, and in PmrB at position 86 (Pro86Gln) in EC1002. By contrast, the mutants of non-MCRPEC strains acquired more non-synonymous mutations in the target regions, including in PmrAB, PhoPQ, and MgrB in EC25922; PmrA in EC18398E; and PmrAB and PhoQ in EC26207E (Table 2). No amino acid substitutions were observed in MCR-1, and neither frameshift mutations nor deletions were identified in any of these strains. The alterations in the TCS regions of EC25922 were predicted to have little impact on protein function, as determined by SIFT score. Interestingly, the amino acid substitution in the mutant of EC25922 was also detected in other tested parental strains, including both MCRPEC and non-MCRPEC strains, suggesting that non-synonymous mutations may occur frequently in PmrA at positions 31, 128, and 144; in PmrB at positions 123 and 351; in PhoQ at positions 6 and 482; and in MgrB at position 36. Interestingly, PmrA at position 144 (Ser144Gly) and PhoQ at position 482 (Ala482Thr) could convert to each other when exposed to colistin plates (Table 2 and S2). The non-synonymous mutations in the plasmid-curing isolates were easily detected when compared with their parental strains. Amino acid alterations were observed in PmrA Gly144Ser, PmrB Pro94Gln, Asn358Tyr, and PhoQ Thr482Ala in the EC26207E mutant, and in PmrA Gly53Arg in the EC18398E mutant. The EC26207 and 18398 mutants had 1 or 0 amino acid variations, respectively. However, the second- and third-step mutants showed no further mutational changes in PmrAB, PhoPQ, and MgrB, except for those in EC26207E and EC25922.

SMART analysis revealed the major domains of the PmrA/PmrB and PhoP/PhoQ TCS, and the positions of all the mutations in colistin-resistant mutants (Figure 3). Our results showed that non-synonymous mutations were mainly found in the HAMP and ATPase domains of PmrB and PhoQ, and in the receiver domain of PmrA and PhoQ. SIFT analysis predicted that the PmrA Gly15Arg, Gly53Arg, PmrB Pro94Gln, and PhoP Asp86Gly mutations would affect protein function.

Figure 3 Domains of the PmrA/PmrB and PhoP/PhoQ two-component system and the positions of all mutations in colistin-resistant mutants. *These substitutions are predicted to affect protein function by SIFT. #These substitutions are predicted to affect protein function by SIFT because the sequences used were not sufficiently diverse. Red, EC18398E; Fuchsin, EC26207; Blue, EC26207E; Black, EC25922; Green, EC1002; Brown, EC2474. Domains of PmrA/PmrB and PhoP/PhoQ are indicated as REC, CheY-homologous receiver domain; Trans_reg_c, transcriptional regulatory C-terminal domain; TM1, first transmembrane domain; TM2, second transmembrane domain; HAMP, histidine kinases, adenylyl cyclases, methyl-binding proteins, and phosphatases domain; HisKA, histidine kinase domain; HATPase_c, histidine kinase-like ATPase C-terminal domain.

To better understand the impact of mcr-1-bearing plasmids on the evolution of HLCRMs, E63-C600, E66-C600, and E. coli C600 were used for the selection of HLCRMs. Transcription of the pmrCAB, phoP, mgrB, and mcr-1 genes in HLCRMs was evaluated by qRTPCR. The levels of expression of pmrCAB and phoP were higher in MuC600 than in E. coli C600, with the level of expression of pmrA being 200-fold higher in MuC600 than in E. coli C600 (Figure 4). Moreover, the magnitude of pmrCAB up-regulation was higher than that of phoP and mgrB, indicating that pmrCAB may play more important roles in the evolution of HLCRMs than phoPQ and mgrB. However, the levels of expression of the pmrCAB, phoP, mgrB, and mcr-1 genes in MuE63-C600 and MuE66-C600 were not significantly higher than those in their parental strains.

Figure 4 Transcriptional activities of pmrABC, phoP, mgrB, and mcr-1 in wild-type isolates and their derivative colistin-resistant mutants (MuC600, MuE63-C600, and MuE66-C600) grown in drug-free MHB. The fold change in transcription was calculated as 2CT. Means and standard deviations were determined for three independent replicates.

The clinical use of colistin is being re-evaluated because of the increasing prevalence of infections caused by MDR organisms.17 Plasmid-mediated colistin resistance via the mcr-1 gene was found to provide a horizontal transfer mechanism for rapid dissemination.7 The prevalence of colistin resistance has become of great concern because of the location of the mcr-1 gene on highly mobile genetic elements and its coexistence with other resistance determinants. However, the phenotype of HLCRMs in mcr-1-harboring E. coli is not fully understood. Moreover, the impact of chromosomal modifications in TCS combined with mcr-1 on colistin resistance has not been determined.1820

The present study found that HLCRMs could be successfully isolated from MCRPEC and non-MCRPEC strains by multi-stepwise induction under conditions of colistin exposure. Unexpectedly, the absence of the mcr-1 gene from E. coli resulted in higher mutation rates and facilitated the selection of HLCRMs, in contrast to the role of plasmid-mediated quinolone resistance genes in Enterobacteriae. Quinolone resistance may be due to the presence of a plasmid-carried quinolone resistance determinant Qnr, which has been shown to bind to and protect both DNA gyrase and topoisomerase IV from inhibition by ciprofloxacin. In addition, because of their additive nature, the concentration required for mutant prevention is increased.8,21,22 Conversely, mcr-1, which encodes a pEtN transferase, confers colistin resistance via the addition of pEtN to LPS, similar to the chromosomal colistin resistance mechanism that constitutively activates PhoPQ and PmrAB.19,23 Thus MCR-1-associated LPS modifications may impair the role of TCS in the evolution of HLCRMs. These findings demonstrated that non-synonymous mutations by TCS were more easily observed in non-MCRPECs than in MCRPECs. Furthermore, pmrABC and phoP expression levels were higher in non-MCRPECs. Taken together, these findings indicated that the presence of mcr-1 limited the up-regulation of TCS genes related to colistin resistance. Usually, the MIC of colistin against MCRPECs is 2 to 8 mg/L, whereas the MIC of colistin mediated by chromosomal resistance mechanisms, such as mutations in pmrAB or phoPQ, is 16 to 256 mg/L.3,23 Because chromosomal resistance mechanisms, rather than mcr-1, may have an important impact on the evolution of HLCRMs, HLCRMs in the present study were more easily generated by non-MCRPECs. The presence of the mcr-1 gene may, however, facilitate the selection of HLCRMs. These findings suggest that the dilution of overnight cultures was too low (105 CFU/mL) to prevent E. coli TOP10 from generating HLCRMs.24

Mutations related to colistin resistance in PmrAB and PhoPQ TCS play crucial roles in the development of MCRPEC and non-MCRPEC into HLCRMs, as mutations in these systems can cause their constitutive overexpression, resulting in the activation of arnBCADTEF and pmrCAB and the modification of lipid A.23 Various genetic alterations have been associated with an increased MIC of colistin, including Ser39Ile and Arg81Ser in PmrA; Glu375lys in PhoQ; several mutations in PmrB, including Leu10Gly, Glu, 41::Tn5 (insertion of Tn5 at nucleotide 41), Cys84Tyr, a 12 bp deletion from nucleotide 258 to nucleotide 269 (GlnAlaValArgArg), Ile91Thr92 ins Ile (an insertion of isoleucine at position 92), Asp149Tyr, Thr156Lys, Ala159Val, and Val161Gly.3,4,25 Although none of these non-synonymous mutations were detected in the present study, SIFT determined that the Gly15Arg and Gly53Arg mutations in PmrA, the Pro94Gln mutation in PmrB, and the Asp86Gly mutation in PhoP affect protein function. Except for PmrA Gly15Arg, which was found in MCRPEC strains, these mutations were found in non-MCRPEC strains. The Gly15Arg and Gly53Arg mutations in PmrA, and the Pro94Gln mutation in PmrB, were found to be involved in colistin resistance in Salmonella enterica.6 Position 53 in the PmrA has also been described as being responsible for acquired colistin resistance in Klebsiella pneumoniae and Enterobacter aerogenes.3 Gly53 of PmrA is located in its phosphate receiver domain, close to the active site at Asp51.26 An amino acid substitution at Gly53, whether to Arg or Ala, prevented the Asp active site from being dephosphorylated by the phosphatase activity of PmrB. Pro94 of PmrB is located in its HAMP domain, which is crucial for signal transduction from the periplasmic input to the kinase domain.27 A mutation in the HAMP domain might therefore lead to constitutive activation of PmrA. In addition, several non-synonymous mutations were identified in PmrAB and PhoPQ, especially in non-MCRPEC strains, but SIFT showed that these mutations had little impact on protein function.

These results are in agreement with studies showing that not all the mutations in pmrAB and phoPQ result in colistin resistance.4,28 The MICs of mutants were progressively elevated by in vitro multi-stepwise induction and selection, whereas the second- and third-steps did not yield further mutations in pmrAB, phoPQ, and mgrB. This analysis may have been unable to identify mutations in other regulatory pathways that led to colistin resistance.

Previous genetic analysis revealed that Etk, a tyrosine-kinase, can phosphorylate Ugd, the starting material for L-Ara4N synthesis and can activate the PmrAB system, resulting in colistin resistance and the deletion of mgrR (influenced by the PhoPQ system).2931 Therefore, different mechanisms mediating or contributing to colistin resistance may be responsible for the development of greater resistance to colistin, especially for MCRPEC strains, inasmuch as non-synonymous mutations in pmrAB, phoPQ, and mgrB were not detected in EC24990 or EC18398. Thus, increasing the clinical use of colistin may result in the spread of colistin-resistant organisms. The present findings suggested that acquisition of the mcr-1 gene partly lowered the target mutation to impede the evolution of HLCRMs. The difficulty of a chromosomal mutation related to further colistin resistance in MCRPEC strains may provide further support for the use of colistin-based combination strategies to treat infections caused by MCR-1-producing isolates. Exposure of MCR-1- and NDM-5-producing E. coli to polymyxin B monotherapy did not result in the acquisition of a chromosomal polymyxin resistance mutation, with polymyxin B MIC remaining stable at 4 mg/L in the hollow-fiber infection model.18 The triple combination of polymyxin B, aztreonam, and amikacin resulted in undetectable bacterial counts and suppression of colistin resistance.

The present study had several limitations. First, the number of tested strains in this study was limited. Moreover, our findings showed that the presence of the mcr-1 gene may limit the evolution of MCRPEC strains into HLCRMs. Further investigations are required to determine the effects on colistin resistance of a combination of chromosomal modifications in TCS and the mcr-1 gene. Additionally, the colistin MICs of mutants in this study were further improved by in vitro multi-stepwise induction and selection, with non-synonymous mutations and other resistance mechanisms not detected. Further research is required to determine the internal molecular mechanisms of colistin resistance.

The acquisition by E. coli of the mcr-1 gene usually results in a low-level colistin resistance (28 mg/L), while having a negative impact on the development of HLCRMs. This may support the use of colistin-based combination regimens to combat infections with MCR-1-producing isolates.

The datasets used and analyzed during the current study are available from the corresponding author, Yonghong Xiao, upon reasonable request.

All named authors meet the criteria of the International Committee of Medical Journal Editors (ICMJE) for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.

All authors contributed to the data analysis, and the drafting and revising of the article; agreed on the journal to which the article will be submitted; gave final approval for the version to be published; and agreed to be accountable for all aspects of this work.

This work was supported by the Key research and development program of Zhejiang province (no. 2021C03068) and the Natural Science Foundation of Ningbo (no. 2019A610232).

The authors report no conflicts of interest in this work.

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Acquisition of the mcr-1 gene lowers the target mutation | IDR - Dove Medical Press

When an injury occurs, damaged cells need to be replaced. Stem cells, known as the go-to cells when new specialized cells need to be produced, are rare in adult tissues, so the job often falls to differentiated, or mature, cells.

Dr. Jason Mills and his lab have been working on identifying the genes driving mature cells to return to a regenerative state, a process called paligenosis.

My lab has been promoting the idea that given that cells in all organs use similar functions like mitosis and apoptosis, theres likely to be a conserved genetic program for how mature cells become regenerative cells, said Mills, senior author of the study and professor of medicine gastroenterology,pathology and immunologyandmolecular and cellular biologyat Baylor. The research was conducted while his lab was atWashington University School of Medicine in St. Louis.

To begin paligenosis and reenter the cell cycle, mature cells must first go through the process of autodegredation, breaking down larger structures used in specialized cell function. Mills and his team, led by first author Dr. Megan Radyk, a postdoctoral associate at the Washington University School of Medicine in St. Louis at the time of research, found that the genes Atf3 and Rab7b are upregulated in gastric and pancreatic digestive-enzyme-secreting cells of mice during autodegredation, and return to normal expression before mitosis.

The researchers showed that Atf3 activates Rab7b, which directs lysosomes to begin dismantling cell parts not needed for regeneration. But when Atf3 was not present, Rab7b did not trigger autodegredation.

The team also found Atf3 and Rab7b expression were consistent in paligenosis across other organs and organisms. Similar gene expression also appeared in precancerous gastric lesions in humans. According to Mills, the discoveries in this research are foundational to understanding how repetitive injury and paligenosis may impact cancer.

The more tissue damage you have, the more youre calling mature cells back into regeneration duty, said Mills, co-director of theTexas Medical Center Digestive Disease Center. Theres emerging evidence that, when these cells go through paligenosis, they dont check for DNA damage well. The cells are storing DNA mutations when they return to their differentiated function. Over time, they become so damaged that they cant go back to normal function and instead keep replicating.

Its our belief that paligenosis is at the heart of cancer development.

This research also provides groundwork for potential therapeutic targets. Existing drugs like hydroxychloroquine can be used to inhibit autodegredation, therefore stopping paligenosis.

According to Mills, further study is required to determine whether drugs targeting autodegredation can be used in conjunction with cancer treatments to stop cells from replicating.

The complete study is published in EMBO Reports.

For a full list of authors, their contributions to this work and sources of support, see the publication.

By Molly Chiu

Read the original post:
Atf3 and Rab7b genes drive regeneration in mature cells - Baylor College of Medicine News

2021 UBC Faculty of Medicine recipients of the BC Knowledge Development Fund (clock-wise): Dr. Samuel Aparicio, Dr. Hilla Weidberg, Dr. Nozomu Yachie, Dr. Carl de Boer, Dr. Thibault Mayor, Dr. Vivien Measday, and Dr. Don Sin.

Faculty of medicine members have been awarded more than $6.5 million in funding from the B.C. Knowledge Development Fund (BCKDF) to drive innovation in B.C.

More than $22 million was awarded to 24 projects at UBC. The funding will help provide students and researchers access to the latest technology, tools and equipment to drive research. Past recipients of the BCKDF include faculty of medicine professor Dr. Pieter Cullis, who developed the lipid nanoparticle technology that allows the Pfizer-BioNTech mRNA vaccine to enter human cells.

UBC is home to some of the worlds top researchers, and this investment gives them access to cutting-edge scientific infrastructure that will support breakthroughs in fields like health care, clean technology, quantum science and agriculture, said Santa Ono, UBC president and vice-chancellor in a release. Whether its developing life-saving new drugs, ensuring literacy for all or creating novel technologies that give B.C. companies a competitive edge, this investment will promote a more healthy, innovative and sustainable society for all British Columbians.

The BCKDF enables B.C.s public post-secondary institutions and affiliated research hospitals to compete successfully for federal and private sector funding. This funding matches Government of Canada investments made through the Canada Foundation for Innovation.

The BCKDF plays a crucial role in the modernization of our universities research infrastructure capacity and capabilities, said Anne Kang, Minister of Advanced Education and Skills Training, in a release. By investing in technologically-advanced equipment and buildings, B.C. institutions will be well positioned to develop successful collaborations with industry and other partners.

We are proud to partner with the B.C. Knowledge Development Fund to invest in British Columbias teaching and research facilities, said the Honourable Franois-Philippe Champagne, Minister of Innovation, Science and Industry in a release. This partnership is helping B.C. universities rise to the challenges facing Canadians across the country from combatting climate change to conserving our precious water resources, from fighting cancer to maintaining a high quality of life for our growing senior population all while cultivating the top-notch talent we need to excel on the global stage.

The research projects will contribute to B.C.s economic plan to rebuild and grow the economy by improving B.C.s productivity and competitiveness. Other benefits include potential commercialization, spin-offs and patents, as well as discoveries that directly impact the lives of British Columbians.

The BCKDF funding will accelerate cancer research by providing researchers with specialized technology that analyses the genomes of single cells. This will advance the development of precision oncology, which uses the genomes of the patient and tumour to inform the choice of therapy that is most likely to benefit the patient. The research will provide insight into how cancer changes over time and factors that cause treatment resistance, leading to improved diagnostics and therapeutics for cancer patients in British Columbia.

Principal Investigator: Dr. Samuel Aparicio, department of pathology and laboratory medicine

BCKDF award: $2,396,810

The BCKDF funding will be used to shed light on the complex genetic underpinnings behind common inherited diseases affecting British Columbians, such as autoimmunity and heart disease, which will pave the way for the development of cellular therapies and targeted treatments for patients.

Principal Investigator: Dr. Carl de Boer, School of Biomedical Engineering

BCKDF award: $125,000

The BCKDF funding will support the development of new genetic circuit devices that will advance understanding of complex biological systems and enable the development of innovative cell-based therapies for cancer and cardiovascular diseases.

Principal Investigator: Dr. Nozomu Yachie, School of Biomedical Engineering

BCKDF award: $400,000

The BCKDF funding will help uncover better ways to treat patients with chronic obstructive pulmonary disease (COPD) using new molecular and imaging technologies. The research will support the development of innovative precision therapies that have the potential to improve the lives and enhance the health outcomes of millions of Canadians with COPD.

Principal Investigator: Dr. Don Sin, department of medicine

BCKDF award: $185,935

The BCKDF funding will be used to study the role that mitochondrial damage plays in neurodegenerative diseases such as Parkinsons and Alzheimers. The research will help uncover mechanisms to prevent this damage and develop new therapeutics to fight these otherwise incurable diseases.

Principal Investigator: Dr. Hilla Weidberg, department of cellular and physiological sciences

BCKDF award: $125,000

The BCKDF funding supports the development of new technologies that will expand the use of yeast for bioprocessing applications that benefit the environment, economy and health of British Columbians. These applications include the food and beverage industry (e.g., wine, beer, dough), removal of pollutants from the environment and the production of non-animal proteins, enzymes and new medicines.

Principal Investigator: Dr. Thibault Mayor and Dr. Vivien Measday, department of biochemistry and molecular biology

BCKDF award: $3,276,459

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Faculty of medicine researchers receive more than $6.5M from BC Knowledge Development Fund - UBC Faculty of Medicine

PITTSBURGH, Aug. 12, 2021 (GLOBE NEWSWIRE) -- NeuBase Therapeutics, Inc. (Nasdaq: NBSE) (NeuBase or the Company), a biotechnology platform company Drugging the Genome to address disease at the base level using a new class of precision genetic medicines, today reported its financial results for the three- and nine-month periods ended June 30, 2021.

In June, we presented preclinical in vivo data of novel compounds demonstrating selective silencing of disease-causing mutations at the DNA or RNA level in three diseases, each of which is caused by a different underlying genetic mechanism. These new data further illustrate the broad applicability of our genetic medicine platform, said Dietrich A. Stephan, Ph.D., Founder, CEO, and Chairman of NeuBase. Following intravenous or subcutaneous dosing, these compounds were well tolerated at pharmacologically active doses. In addition, the compounds achieved targeted delivery into brain and muscle, which further support our claim of offering the unique ability to deliver genetic medicines throughout the body.

For our lead program in DM1, recent data support a differentiated therapeutic approach to maintain DMPK function while selectively silencing the disease-driving mutation. With these positive data in hand, we believe we have a clear path towards entering the clinic and are planning for an IND filing in the fourth quarter of calendar year 2022, continued Dr. Stephan. We are continuing to advance our therapeutic program for Huntingtons disease and we believe our proprietary delivery technology will allow our compounds to advance beyond intrathecal delivery, overcoming challenges seen with other programs.

Dr. Stephan concluded, Finally, we have shown that we can silence activating KRAS point mutations in vivo to inhibit protein production, which has the potential to target G12D and G12V, the two most common and historically undruggable KRAS driver mutations that represent the majority of KRAS-driven tumors. This sets the stage for generating new precision genetic medicines capable of selectively targeting mutations at the single-base level to treat both rare and common diseases.

Third Quarter of Fiscal Year 2021 and Recent Operating Highlights

Financial Results for the Third Fiscal Quarter Ended June 30, 2021

Financial Results for the Nine-Month Period Ended June 30, 2021

About NeuBase TherapeuticsNeuBase is accelerating the genetic revolution by developing a new class of precision genetic medicines which can be designed to increase, decrease, or change gene function, as appropriate, to resolve genetic defects that drive disease. NeuBases targeted PATrOL therapies are centered around its proprietary drug scaffold to address genetic diseases at the DNA or RNA level by combining the highly targeted approach of traditional genetic therapies with the broad organ distribution capabilities of small molecules. With an initial focus on silencing disease-causing mutations in debilitating neuromuscular, neurological and oncologic disorders, NeuBase is committed to redefining medicine for the millions of patients with both common and rare conditions. To learn more, visit http://www.neubasetherapeutics.com.

Use of Forward-Looking StatementsThis press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act. These forward-looking statements are distinguished by use of words such as will, would, anticipate, expect, believe, designed, plan, or intend, the negative of these terms, and similar references to future periods. These forward-looking statements include, among others, those related to the prospects of DM1 and the Companys expectation to make an IND filing for DM1 in the fourth quarter of CY 2022, the Companys therapeutic program for Huntingtons disease, the Companys ability to target G12D and G12V and the Companys expectation that its cash will fund currently planned operating and capital expenditures into the first quarter of CY 2023. These views involve risks and uncertainties that are difficult to predict and, accordingly, our actual results may differ materially from the results discussed in our forward-looking statements. Our forward-looking statements contained herein speak only as of the date of this press release. Factors or events that we cannot predict, including those risk factors contained in our filings with the U.S. Securities and Exchange Commission (the SEC), may cause our actual results to differ from those expressed in forward-looking statements. The Company may not actually achieve the plans, carry out the intentions or meet the expectations or projections disclosed in the forward-looking statements, and you should not place undue reliance on these forward-looking statements. Because such statements deal with future events and are based on the Companys current expectations, they are subject to various risks and uncertainties, and actual results, performance or achievements of the Company could differ materially from those described in or implied by the statements in this press release, including: the Companys plans to develop and commercialize its product candidates; the timing of initiation of the Companys planned clinical trials; the risks that prior data will not be replicated in future studies; the timing of any planned investigational new drug application or new drug application; the Companys plans to research, develop and commercialize its current and future product candidates; the clinical utility, potential benefits and market acceptance of the Companys product candidates; the Companys commercialization, marketing and manufacturing capabilities and strategy; global health conditions, including the impact of COVID-19; the Companys ability to protect its intellectual property position; and the requirement for additional capital to continue to advance these product candidates, which may not be available on favorable terms or at all, as well as those risk factors contained in our filings with the SEC. Except as otherwise required by law, the Company disclaims any intention or obligation to update or revise any forward-looking statements, which speak only as of the date hereof, whether as a result of new information, future events or circumstances or otherwise.

NeuBase Investor Contact:Dan FerryManaging DirectorLifeSci Advisors, LLCdaniel@lifesciadvisors.com OP: (617) 430-7576

NeuBase Media Contact:Jessica Yingling, Ph.D.Little Dog Communications Inc.(858) 344-8091jessica@litldog.com

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NeuBase Therapeutics Reports Financial Results for the Third Quarter of Fiscal Year 2021 and Recent Operating - GlobeNewswire