Category Archives: Gene Medicine

Yanyi Zhang, Yi Wen, Qiulin Xiao, Wei Zheng, Gao Long, Bo Chen, Xiaoli Shu, Mizu Jiang

Department of Gastroenterology, Childrens Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang, Peoples Republic of China

Correspondence: Mizu JiangDepartment of Gastroenterology, Childrens Hospital, Zhejiang University School of Medicine,National Clinical Research Center for Child Health, Hangzhou 310003, Zhejiang, Peoples Republic of ChinaTel +86-571-86670046Fax +86-571-86658653Email mizu@zju.edu.cn

Purpose: This study aimed to characterize common mutations of antibiotic-resistant gene of clarithromycin, metronidazole and levofloxacin in Helicobacter pylori (H. pylori) and determine their association with antibiotic resistance of H. pylori for providing a strategy for eradication therapy of H. pylori infection in children.Patients and Methods: The antibiotic resistance to clarithromycin, metronidazole and levofloxacin for H. pylori strains isolated from children was determined by E-test. The mutation of domain V of 23S rRNA, rdxA and frxA genes, gyrA and gyrB genes was performed by PCR-based sequencing of DNA fragments.Results: Out of the 79 H. pylori strains examined, 66 (83.5%) were resistant to at least one of the tested antibiotics and 13 (16.5%) were fully sensitive. A total of 29 (36.7%) strains were resistant to clarithromycin. Analysis of the 23S rRNA gene showed that most mutations occurred at the A2143G and T2182C sites, showing a frequency of 82.8% (24/29) and 89.7% (26/29) respectively. In the 11 sensitive strains to clarithromycin, the frequency of A2143G mutation was only 45.5%, which was significantly lower than that in resistant strains (P< 0.05). There were 54 strains (68.4%) resistant to metronidazole, with most mutations occurring at G47A and T184G in the rdxA gene. T184G mutation was recognized in metronidazole-sensitive strains, but no G47A mutation was identified. Twelve strains (15.2%) were resistant to levofloxacin. Position 91 mutation of the gyrA gene occurred only in resistant strains, whereas position 87 mutations were detected in both sensitive and resistant strains to levofloxacin.Conclusion: In H. pylori resistant strains isolated from children in China, most mutations occurred at A2143G of the 23S rRNA gene for clarithromycin; G47A mutation of rdxA gene for metronidazole; and at 91 mutation of gyrA gene for levofloxacin. It is suggested that susceptibility testing together with screening the mutation of antimicrobial-resistant gene prior to treatment is important for the eradication of H. pylori in children.

Keywords: Helicobacter pylori, Metronidazole, Clarithromycin, Levofloxacin, antibiotic resistant, gene

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Mutations in the Antibiotic Target Genes Related to Clarithromycin, Me | IDR - Dove Medical Press

Autism is associated with brilliance as well as cognitive difficulty, but how either scenario plays out in the brain is not clear. Now a study by University of Toronto researchers has found that a tiny gene fragment impacts the brain in a way that could explain swathes of autism cases that come with mental health challenges.

Researchers led byBenjamin Blencowe, a professor of molecular genetics in the Donnelly Centre for Cellular and Biomolecular Research and Faculty of Medicine, andSabine Cordes, a senior investigator at Sinai Health Systems Lunenfeld-Tanenbaum Research Institute (LTRI), have identified a short gene segment that is crucial for brain development and information processing. Writing in the journalMolecular Cell, the researchersdescribe how an absence of this segment is sufficient to induce altered social behaviour a hallmark of autism in mice, as well as learning and memory deficits, which are seen in a subset of autism cases.

Best known for causing difficulties in social interaction and communication, autism is thought to arise from mishaps in brain wiring during development. It can strike in various ways. Those who experience it can have superior mental ability or need full-time care. Where on the autism spectrum a person falls depends in large part on their genetics, but most cases are idiopathic, or of unknown genetic origin.

Its very important to understand the mechanisms that underlie autism, especially in idiopathic forms where it is not clear what the underlying causes are, saysThomas Gonatopoulos-Pournatzis, a research associate in Blencowes lab and lead author of the study. Not only have we identified a new mechanism that contributes to this disorder, but our work may also offer a more rational development of therapeutic strategies.

Blencowes team had previously uncovered a link between autism and short gene segments, known as microexons, that are predominantly expressed in the brain. Through a process known as alternative splicing, microexons are either spliced in or left out from the final gene transcript before it is translated into a protein. Although small, microexons can have dramatic effects by impacting a proteins ability to bind its partners as required during brain development. However, how individual microexons contribute to autism is not clear.

The team focused on a specific microexon located in a gene known as eIF4G, which is critical for protein synthesis in the cell. They found that this microexon is overwhelmingly excluded from eIF4G gene transcripts in the brains of autistic individuals.

Hippocampal neurons from a normal mouse (above) and a mouse bred to lack the eIF4G microexon (below). The latter contains fewer particles that represent paused protein synthesis machineries. In these mice, higher levels of protein synthesis in neurons lead to disrupted brain waves and autistic-like behaviors as well as cognitive deficits down the line.

To test if the eIF4G microexon is important for brain function, Gonatopoulos-Pournatzis, together with Cordess team, bred mice that lack it. These mice showed social behaviour deficits, such as avoiding social interaction with other mice, establishing a link between the eIFG4 microexon and autistic-like behaviours.

A surprise came when the researchers found that these mice also performed poorly in a learning and memory test, which measures the animals ability to associate an environment with a stimulus.

We could not have imagined that a single microexon would have such an important impact not only on social behaviour but also on learning and memory, says Gonatopoulos-Pournatzis.

Further analysis revealed that the microexon encodes a part of eIF4G that allows it to associate with the Fragile X mental retardation protein, or FMRP, which is missing from people affected with Fragile X syndrome, a type of intellectual disability. About a third of individuals with Fragile X have features of autism but the link between the two remained unclear until now.

FMRPandeIF4G work together to act as a brake to hold off protein synthesis until new experience comes along, as the brake is removed by neural activity, the researchers also found.

Its important to control brain responses to experience, says Gonatopoulos-Pournatzis. This brake in protein synthesis is removed upon experience and we think it allows formation of new memories.

Without the microexon, however, this brake is weakened and what follows is increased protein production. The newly made proteins, identified in experiments performed withAnne-Claude Gingras, a senior investigator at LTRI and a professor in the department of molecular genetics, form ion channels, receptors and other signaling molecules needed to build synapses and for them to function properly.

However, making too many of these proteins is not a good thing because it leads to the disruption of the type of brain waves involved in synaptic plasticity and memory formation. This is revealed by electrode recordings of mouse brain slicesin experiments performed by the teams ofGraham Collingridge, a senior investigator at LTRI and a professor in the department of physiology, andMelanie Woodin, a professor of cell and systems biology at U of T and the dean of the Faculty of Arts & Science.

Moreover, an excess of similar kinds of proteins occurs in the absence of FMRP, suggesting a common molecular mechanism for Fragile X and idiopathic autism.

Researchers believe that their findings could help explain a substantial proportion of autism cases for which no other genetic clues are known. The findings also open the door to the development of new therapeutic approaches. One possibility is to increase the splicing of the eIF4G microexon in affected individuals using small molecules as a way to improve their social and cognitive deficits, Blencowe said.

The study would not have been possible without a close collaboration among multiple teams contributing diverse expertise. Blencowe and Gonatopoulos-Pournatzis also worked closely withJulie Forman-Kay, a professor of biochemistry and program head and senior scientist in the molecular medicine program at the Hospital for Sick Children, andNahum Sonenberg, a professor of biochemistry at McGill University.

The research was made possible by grants from the Canadian Institutes of Health Research, Simons Foundation and theCanada First Research Excellence Fund Medicine by Design program, among others.

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Gene fragment could explain link between autism and cognitive difficulties: U of T study - News@UofT

Decibel Therapeutics Industry veteran Laurence Reid has been tapped to serve as Boston-based Decibels acting chief executive officer. Current CEO Steven Holtzman is retiring and will become a strategic business advisor to the company. Reid is an entrepreneur-in-residence at Third Rock Ventures and has held numerous leadership positions in the biotech industry. Most recently, he served as the CEO of Warp Drive Bio, a drug discovery company advancing novel oncology and anti-infective medicines, and where he ultimately negotiated the successful merger of the company with Revolution Medicines in 2018. In his previous role as chief business officer of Alnylam Pharmaceuticals, he led business development, finance and legal functions.

Passage Bio Bruce Goldsmith was named CEO of Passage Bio. He succeeds Stephen Squinto, who co-founded Passage Bio and served as interim chief executive officer since 2018. Goldsmith joins Passage Bio from Deerfield Management where he was a venture partner responsible for early-stage investments and served as interim chief executive officer of Civetta Therapeutics. Previously, Goldsmith was chief operating officer at Lycera, a company developing first-in-class small molecules for immuno-oncology and autoimmune disease. Goldsmith also held senior positions at Allos Therapeutics and GPC Biotech as well as various strategic marketing and business development roles at Johnson & Johnson focused on oncology and virology.

Century Therapeutics -- Former Novartis CEO Joseph Jimenez joined the board of directors of Century Therapeutics. Jimenez joins Centurys board with more than 20 years of experience as a senior leadership executive in the pharmaceutical and consumer products industries. He retired in 2018 as the CEO of Novartis. Also, the company tapped Celgene veteran Greg Russotti as its chief technology officer. Russotti brings more than 25 years of industrial experience in bioprocess development and implementation, including extensive knowledge in cell therapy technical operations. Most recently, he was vice president of cell therapy technical development at Celgene, where he guided CMC efforts for five different cell therapy products to IND and clinical-stage development. Before Celgene, Russotti spent 12 years at Merck Research Laboratories with roles in cell culture development, downstream purification, pilot plant operations, and manufacturing facility startup.

H.E.L. Group -- H.E.L Group announced the appointment of three new members to its senior team, who will focus primarily on strengthening production and service support for its scientific instrumentation and software. The company appointed Roy Eggleston to the newly created role of Global Quality Manager, while Tony Heywood from AB Turnkey Solutions takes over Roys previous position as Production Manager. John Forbes, formerly a senior manager at Thermo Fisher Scientific, joins as Global Service Manager.

ImageOne Medical Former U.S. Olympian Tuesday Middaugh Slomovitz was named COO of Florida-based ImageOne Medical.

Verrica Pharmaceuticals Pennsylvania-based Verrica named two new vice presidents in its commercial operations group. Gerard DiGirolamo joins as head of sales and Sheila Kennedy has been appointed head of marketing. Prior to Verrica, DiGirolamo spent over 16 years with Stiefel, currently a GSK company, in roles of increasing and varying responsibilities, spanning multiple brands within the dermatology space. Kennedy joins Verrica with over 20 years of success as a biopharmaceutical marketing strategist. In her most recent role, Kennedy directed global and U.S. marketing for the dermatology medication Rhofade. In a prior role, Kennedy served as head of marketing for Onset Dermatologics.

TELA Bio Peter Murphy was named to the newly created role of chief commercial officer. In this position, Murphy will be responsible for the companys continued strategic expansion of its commercial operations. Murphy joins TELA with more than 20 years of commercial sales and marketing. Most recently, he was head of sales at Pacira Pharmaceuticals, where he led the development, management, expansion and execution of a product sales team in the U.S.

NuHope -- Jeff Dunkel assumes the role of NuHope CEO following his position as head of strategy at TITAN SPINE.NuHope is a San Antonio-based outpatient opioid and pain treatment center focused on taper effectiveness, which specificallyreduces controlled substance use in those dependent on opioids.

ValueHealth, LLC William J. Hozack was named medical director. In this new role, Hozack will oversee ValueHealth's clinical protocols, quality outcome measures, patient care pathways, and bundled payments with warranty programs. He will also serve as a liaison to ValueHealth's Advisory Board and provide strategic guidance to the company.

Enzychem Lifesciences Liver disease specialist Michael Charlton joined the companys scientific advisory board. Charlton is currently director of the Center for Liver Diseases at University of Chicago School of Medicine. He has served as president of the International Liver Transplant Society.

Disc Medicine John Quisel was named president and CEO of Disc Medicine. Quisel joins Disc Medicine after more than a decade at Acceleron Pharma where he most recently was CBO. In this planned transition, co-founder and interim CEO Brian MacDonald, will continue to serve as a senior advisor and director of the company.

NeoImmuneTech, Inc. -- Gene Namgoong was named COO of Maryland-based NeoImmuneTech, a T cell-focused immunotherapeutics company. As COO, Namgoong will play a key role in advancing its business operations and shaping its corporate culture. Namgoong joined NeoImmuneTech in 2014 as a legal advisor, later assuming the critical role of general counsel in 2016.

SutroVax Jim Wassil was named COO of California-based SutroVax, Inc. Wassil will lead clinical development, regulatory affairs, medical affairs, quality assurance and program management activities. He spent the past three decades in positions of increasing responsibility in the vaccine divisions of Merck, Novartis, and Pfizer. Most recently, he was responsible for market access, policy, pricing, tender negotiations, epidemiology and health outcomes as the business unit lead for Pfizer Vaccines.

Insmed Incorporated -- Sara Bonstein was named CFO of New Jersey-based Insmed. Bonstein will assume responsibility for leading the company's global financial operations. She most recently served as CFO and COO of OncoSec Medical Incorporated. Prior to joining OncoSec, Bonstein served as the CFO at Advaxis, Inc.

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Movers and Shakers, Jan. 31 | BioSpace - BioSpace

A new study from New York might completely change how breast cancer is classified and treated. Researchers have discovered, in a study of triple negative breast cancer in black women, that the molecular mechanisms involved are more closely related to non-breast cancers, and two specific gene mutations may be responsible for the tumor development.

This study would signal a potential treatment breakthrough for patients with this form of breast cancer, which disproportionately affects and tends to develop more aggressively in black women. Triple negative breast cancer is a form of breast cancer that is not hormone driven, and it does not express the estrogen receptor, progesterone receptor, or HER2/neu genesunlike other forms of the disease, which rely on hormone-driven therapies to control the cancer.

The paper, authored by researchers at The Graduate Center of The City University of New York, Hunter College, Memorial Sloan Kettering Cancer Center, and the University of Chicago, details findings about the interaction between two specific genes during DNA replication that appear to drive growth of malignant cells in patients with triple negative breast cancer.

The research team found the presence of a mutated p53 (a tumor suppressor gene whose mutation often leads to cancer development) and a mutated PARP (a gene that maintains DNA integrity) in a large majority of patients with triple negative breast cancer. Specifically, they found that p53 would interact with replicating DNA and PARP, driving cell growth and division.

This information would suggest that if drugs could specifically target these two mutated genes and the proteins they produce, it would be possible to suppress their actions and slow or stop tumor growth, so the researchers tested this in lab, using drugs developed for other types of cancer.This was indeed the case.

Our new findings suggest that the presence of both [p53] and PARP could serve as a good identifier of breast cancers that would respond to combined treatment with talazoparib a PARP inhibitor that was developed to treat breast cancers with the BRCA mutation and temozolomide a chemotherapy agent that is used to treat some brain cancers, said Professor Jill Bargonetti, whose lab conducted the research. This is an exciting finding because it could lead to the first targeted therapy for triple negative breast cancer, enabling more precise and effective treatment of a very aggressive form of the disease.

To conduct this study, researchers investigated a variety of breast cancer cell lines, patient-derived xenographs, tissue microarray samples, and data from The Cancer Genome Atlas to tease out the association and interaction between p53 and PARP in triple negative breast cancer.

Our findings that mutant p53 and PARP participate in the DNA replication pathway will provide mechanism-derived dual biomarkers that aid in the diagnosis and treatment of these therapeutically elusive subsets of breast cancer, said Gu Xiao, a research associate with Bargonettis lab and the papers first author.

The scientists had discovered that high levels of these proteins are present on replicating DNA in these types of tumors, suggesting that the unusual presence and levels of these proteins may drive tumor growth. When these researchers reviewed the therapeutic mechanisms of existing cancer drugs, it led the research team to identify talazoparib and temozolomide as existing drugs that could potentially be combined to create a targeted therapy that could effectively suppress the growth of triple negative breast cancer tumors.

Looking to the future, this group plans to test if this combination of drugs can successfully block replication of triple negative breast cancer cells in xenographed animal models. If the therapy can prove to be successful, it would very likely lead to the reclassification of triple negative breast cancer to a category of cancers called mutant p53/PARP1 positive cancers, which are treatable with a combination PARP inhibitor therapies.

With so little in positive news for this particular subset of breast cancer, and many previous clinical trials being disappointing, these new findings are both welcome news to the scientific community, as well as a good explanation as to why this disease has been so hard to treat compared to other forms of breast cancer.

This study gives doctors two new biomarkers to test for in patients, and many new potentials in clinical trials, which can be fast tracked since so many drugs already exist that target these specific genes. While this study only tested out two drugs, there are many other drugs that specifically target p53 and PARP, and many more which can be developed, which may give even better results. Hopefully, there will be many new, positive developments for this disease following this discovery.

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Triple negative breast cancer might not actually be 'breast cancer' - Clinical OMICs News

For Immediate Release: January 28, 2020

This is a pivotal time in the field of gene therapy as the FDA continues its efforts to support innovators developing new medical products for Americans and others around the world. To date, the FDA has approved four gene therapy products, which insert new genetic material into a patients cells. The agency anticipates many more approvals in the coming years, as evidenced by the more than 900 investigational new drug (IND) applications for ongoing clinical studies in this area. The FDA believes this will provide patients and providers with increased therapeutic choices.

In that spirit, today, the FDA is announcing the release of a number of important policies: six final guidances on gene therapy manufacturing and clinical development of products and a draft guidance, Interpreting Sameness of Gene Therapy Products Under the Orphan Drug Regulations.

The growth of innovative research and product development in the field of gene therapy is exciting to us as physicians, scientists and regulators, said FDA Commissioner Stephen M. Hahn, M.D. We understand and appreciate the tremendous impact that gene therapies can have on patients by potentially reversing the debilitating trajectory of diseases. These therapies, once only conceptual, are rapidly becoming a therapeutic reality for an increasing number of patients with a wide range of diseases, including rare genetic disorders and autoimmune diseases.

As the regulators of these novel therapies, we know that the framework we construct for product development and review will set the stage for continued advancement of this cutting-edge field and further enable innovators to safely develop effective therapies for many diseases with unmet medical needs, said Peter Marks, M.D., Ph.D., director of the FDAs Center for Biologics Evaluation and Research. Scientific development in this area is fast-paced, complex, and poses many unique questions during a product review; including how these products work, how to administer them safely, and whether they will continue to achieve a therapeutic effect in the body without causing adverse side effects over a long period of time.

One of the most important steps the FDA can take to support safe innovation in this field is to create policies that provide product developers with meaningful guidance to answer critical questions as they research and design their gene therapy products.

The six final guidances issued today provide the agencys recommendations for product developers on manufacturing issues and recommendations for those focusing on gene therapy products to address specific disease areas. The six guidance documents incorporate input from many stakeholders and take a significant step toward helping to shape the modern structure for the development and manufacture of gene therapies. The agency is issuing this suite of documents to help advance the field of gene therapy while providing recommendations to help ensure that these innovative products meet the FDAs standards for safety and effectiveness.

The scientific review of gene therapies includes the need to evaluate highly complex information on product manufacturing and quality. In addition, the clinical review of these products frequently poses more challenging questions to regulators than reviews of more conventional drugs, such as questions about the durability of response, and these questions often cant be fully answered in pre-market trials of reasonable size and duration. For some gene therapy products, therefore, although they have met the FDAs standards for approval, we may need to accept some level of uncertainty around questions of the duration of the response at the time of marketing authorization. Effective tools for reliable post-market follow up, such as post-market clinical trials, are going to be key to advancing this field and helping to ensure that our approach fosters safe and innovative treatments.

The draft guidance on interpreting sameness of gene therapy products under the orphan drug regulations provides the FDAs proposed current thinking on an interpretation of sameness between gene therapy products for the purposes of obtaining orphan-drug designation and eligibility for orphan-drug exclusivity. The draft guidance focuses on how the FDA will evaluate differences between gene therapy products when they are intended to treat the same disease. As laid out in the draft guidance and our regulations, the agencys determination will consider the principal molecular structural features of the gene therapy products, which includes transgenes (the transferred gene) and vectors (the vehicle for delivering the transgene to a cell).

With the large volume of products currently being studied, gene therapy product developers have asked the agency important questions about orphan-drug designation incentives to develop products for rare diseases with very small patient populations. The draft guidance has potential positive implications both for product developers and patients by providing insight into the agencys most current thinking on the sameness of products, and thus, not discourage the development of multiple gene therapy products to treat the same disease or condition. For patients, this policy could help lead to the development and approval of multiple treatments, creating a more competitive market with choices. We encourage stakeholders to provide their comments.

In sum, these policy documents are representative of efforts to help advance product development in the field of gene therapy. We will continue to work with product innovators, sponsors, researchers, patients, and other stakeholders to help make the development and review of these products more efficient, while putting in place the regulatory controls needed to ensure that the resulting therapies are both safe and effective. We also encourage developers of new gene therapy products to make full use of our expedited programs available for products intended to address unmet medical needs in the treatment of serious or life-threatening conditions. These programs include breakthrough therapy designation, regenerative medicine advanced therapy designation, and fast track designation, as well as priority review and accelerated approval. Developers should pursue these programs whenever possible to help bring the benefits of important advances to patients as soon as possible. We believe our work will help advance innovations in a way that assures their safety and effectiveness, provides new therapeutic choices to patients and providers and continues to build confidence in this novel and emerging area of medicine.

The FDA is an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nations food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.

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FDA Continues Strong Support of Innovation in Development of Gene Therapy Products - FDA.gov

REDWOOD CITY, Calif., Jan. 28, 2020 (GLOBE NEWSWIRE) -- Adverum Biotechnologies, Inc. (Nasdaq: ADVM), a clinical-stage gene therapy company targeting unmet medical needs in ocular and rare diseases, today announced the presentation of 24-week data from the second cohort of patients (n=6; 2 x 1011 vg/eye) as well as an update from the first cohort of patients (n=6; 6 x 1011 vg/eye) in the OPTIC Phase1 clinical trial of ADVM-022 intravitreal gene therapy in wet AMD at the Angiogenesis, Exudation, and Degeneration 2020 Meeting.

Adverum plans to issue a press release relating to the presentation and post the presentation on Adverums website at http://www.adverum.com in the Investors section under the Events and Presentations page at the beginning of the data presentation at Angiogenesis.

KOL Event Details:In addition, Adverum will host an event with expert retinal specialists to discuss the OPTIC data presented at Angiogenesis and the potential opportunity for ADVM-022. The discussion will be held on Sunday, February 9, 2020 beginning at 10:00 am EST. The event will be webcast live from Adverums website at http://www.adverum.com in the Investors section under the Events and Presentations page. A replay of the webcast will be archived and available for replay following the event.

About Adverum BiotechnologiesAdverum Biotechnologies (Nasdaq: ADVM) is a clinical-stage gene therapy company targeting unmet medical needs in serious ocular and rare diseases. Adverum is evaluating its novel gene therapy candidate, ADVM-022, as a one-time, intravitreal injection for the treatment of its lead indication, wet age-related macular degeneration. For more information, please visit http://www.adverum.com.

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Adverum Biotechnologies to Present Additional Data from the OPTIC Phase 1 Trial with ADVM-022 Intravitreal Gene Therapy in Wet AMD at the...