Daily Archives: May 3, 2022

MADRID, Spain and CAMBRIDGE, Mass., May 03, 2022 (GLOBE NEWSWIRE) -- Oryzon Genomics, S.A. (ISIN Code: ES0167733015, ORY), a clinical-stage biopharmaceutical company leveraging epigenetics to develop therapies in diseases with strong unmet medical need, announced today the start of a preclinical collaboration on Kabuki Syndrome with researchers from Kennedy Krieger Institute and Johns Hopkins University led by Dr. Jacqueline Harris, Director of the Epigenetics Clinic at Kennedy Krieger Institute and an assistant professor in pediatrics, neurology and genetics at the Johns Hopkins University School of Medicine and Dr. Hans Bjornsson, Founder of the Epigenetic and Chromatin Clinic and associate professor of pediatrics and genetics at the Johns Hopkins University School of Medicine.

Kabuki syndrome (KS) is an autosomal dominant/X-linked disorder that affects multiple organ systems including neuro, immune, auditory and cardiac systems. Patients show characteristic distinctive facial features, growth retardation, and mild to moderate intellectual disability and autoimmune disorders. The majority (>70%) of molecularly confirmed cases of KS have loss-of-function variants in KMT2D gene. This gene, aka MLL2, catalyzes the addition of methyl groups to lysine 4 of histone 3, which are marks associated with open chromatin, thus regulating the expression of critical target genes.

About OryzonFounded in 2000 in Barcelona, Spain, Oryzon (ISIN Code: ES0167733015) is a clinical stage biopharmaceutical company considered as the European leader in epigenetics. Oryzon has one of the strongest portfolios in the field, with two LSD1 inhibitors, iadademstat and vafidemstat, in Phase II clinical trials, and other pipeline assets directed against other epigenetic targets. In addition, Oryzon has a strong platform for biomarker identification and target validation for a variety of malignant and neurological diseases. For more information, visit http://www.oryzon.com

About Vafidemstat Vafidemstat (ORY-2001) is an oral, CNS optimized LSD1 inhibitor. The molecule acts on several levels: it reduces cognitive impairment, including memory loss and neuroinflammation, and at the same time has neuroprotective effects. In animal studies vafidemstat not only restores memory but reduces the exacerbated aggressiveness of SAMP8 mice, a model for accelerated aging and Alzheimers disease (AD), to normal levels and also reduces social avoidance and enhances sociability in murine models. In addition, vafidemstat exhibits fast, strong and durable efficacy in several preclinical models of multiple sclerosis (MS). Oryzon has performed two Phase IIa clinical trials in aggressiveness in patients with different psychiatric disorders (REIMAGINE) and in aggressive/agitated patients with moderate or severe AD (REIMAGINE-AD), with positive clinical results reported in both. Additional finalized Phase IIa clinical trials with vafidemstat include the ETHERAL trial in patients with Mild to Moderate AD, where a significant reduction of the inflammatory biomarker YKL40 has been observed after 6 and 12 months of treatment, and the pilot, small scale SATEEN trial in Relapse-Remitting and Secondary Progressive MS, where antiinflammatory activity has also been observed. Vafidemstat has also been tested in a Phase II in severe Covid-19 patients (ESCAPE) assessing the capability of the drug to prevent ARDS, one of the most severe complications of the viral infection, where it showed significant anti-inflammatory effects in severe Covid-19 patients. Currently, vafidemstat is in two Phase IIb trials in borderline personality disorder (PORTICO) and in schizophrenia patients (EVOLUTION). The company is also deploying a CNS precision medicine approach with vafidemstat in genetically-defined patient subpopulations of certain CNS disorders and is preparing a clinical trial in Kabuki Syndrome patients that is expected to start in 1H 2022. The company is also exploring the clinical development of vafidemstat in other neurodevelopmental syndromes.

FORWARD-LOOKING STATEMENTS This communication contains, or may contain, forward-looking information and statements about Oryzon, including financial projections and estimates and their underlying assumptions, statements regarding plans, objectives and expectations with respect to future operations, capital expenditures, synergies, products and services, and statements regarding future performance. Forward-looking statements are statements that are not historical facts and are generally identified by the words expects, anticipates, believes, intends, estimates and similar expressions. Although Oryzon believes that the expectations reflected in such forward-looking statements are reasonable, investors and holders of Oryzon shares are cautioned that forward-looking information and statements are subject to various risks and uncertainties, many of which are difficult to predict and generally beyond the control of Oryzon that could cause actual results and developments to differ materially from those expressed in, or implied or projected by, the forward-looking information and statements. These risks and uncertainties include those discussed or identified in the documents sent by Oryzon to the Spanish Comisin Nacional del Mercado de Valores (CNMV), which are accessible to the public. Forward-looking statements are not guarantees of future performance and have not been reviewed by the auditors of Oryzon. You are cautioned not to place undue reliance on the forward-looking statements, which speak only as of the date they were made. All subsequent oral or written forward-looking statements attributable to Oryzon or any of its members, directors, officers, employees or any persons acting on its behalf are expressly qualified in their entirety by the cautionary statement above. All forward-looking statements included herein are based on information available to Oryzon on the date hereof. Except as required by applicable law, Oryzon does not undertake any obligation to publicly update or revise any forwardlooking statements, whether as a result of new information, future events or otherwise. This press release is not an offer of securities for sale in the United States or any other jurisdiction. Oryzons securities may not be offered or sold in the United States absent registration or an exemption from registration. Any public offering of Oryzons securities to be made in the United States will be made by means of a prospectus that may be obtained from Oryzon or the selling security holder, as applicable, that will contain detailed information about Oryzon and management, as well as financial statements.

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ORYZON Starts Preclinical Collaboration on Kabuki Syndrome with Kennedy Krieger Institute and Johns Hopkins University - GlobeNewswire

BOSTON, May 02, 2022 (GLOBE NEWSWIRE) -- Decibel Therapeutics (Nasdaq: DBTX), a clinical-stage biotechnology company dedicated to discovering and developing transformative treatments to restore and improve hearing and balance, announced today that it will present at the American Society of Gene and Cell Therapy (ASGCT) 25th Annual Meeting, being held virtually and in Washington D.C. May 15-19, 2022.

The Company will present on its lead investigational gene therapy, DB-OTO, being developed to restore hearing to individuals with a mutation in the otoferlin gene. Decibel will also present two posters featuring its AAV.104 program, a gene therapy designed to restore hearing to individuals with a mutation in the stereocilin gene, and its AAV.103 program, a gene therapy designed to restore hearing to individuals with a GJB2 deficiency, the most common cause of congenital hearing loss.

Details for the oral presentation are as follows:

Development of an AAV-Based Gene Therapy for Children with Congenital Hearing Loss Due to Otoferlin Deficiency (DB-OTO)Oral Abstract Session: Pharmacology/Toxicology Studies or Assay Development IIPresenter: Orion Keifer Jr, M.D., Ph.D., Senior Medical Director, Decibel TherapeuticsDate & Time: Thursday, May 19, 2022 at 10:45 am ET

Details for the poster presentations are as follows:

M-185 | Dual Vector Mediated Gene Therapy for Restoration of STRC-Related Hearing LossPoster Session: Ophthalmic and Auditory DiseasesDate & Time: Monday, May 16, 2022 at 5:30 pm ET

M-183 | Identification of GJB2s Upstream Regulatory Elements Facilitates Design of Safe, Precision AAVs and Recovery of Hearing in a GJB2-Deficient Mouse ModelPoster Session: Ophthalmic and Auditory DiseasesDate & Time: Monday, May 16, 2022 at 5:30 pm ET

About Decibel TherapeuticsDecibel Therapeutics is a clinical-stage biotechnology company dedicated to discovering and developing transformative treatments to restore and improve hearing and balance, one of the largest areas of unmet need in medicine. Decibel has built a proprietary platform that integrates single-cell genomics and bioinformatic analyses, precision gene therapy technologies and expertise in inner ear biology. Decibel is leveraging its platform to advance gene therapies designed to selectively replace genes for the treatment of congenital, monogenic hearing loss and to regenerate inner ear hair cells for the treatment of acquired hearing and balance disorders. Decibels pipeline, including its lead gene therapy product candidate, DB-OTO, to treat congenital, monogenic hearing loss, is designed to deliver on our vision of creating a world of connection for people with hearing and balance disorders. For more information about Decibel Therapeutics, please visit http://www.decibeltx.com or follow us on Twitter.

Investor Contact:Julie SeidelStern IR, Inc.212-362-1200Julie.seidel@sternir.com

Media Contact:Chris RaileyTen Bridge Communications617-834-0936chris@tenbridgecommunications.com

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Decibel Therapeutics to Present at the American Society of Gene and Cell Therapy (ASGCT) 25th Annual Meeting - GlobeNewswire

WASHINGTON, D.C. (May 2, 2022)Gene L. Dodaro, Comptroller General of the United States and head of the U.S. Government Accountability Office (GAO), today announced the appointment of four new members to the Medicaid and CHIP Payment and Access Commission (MACPAC). He also reappointed two members.

MACPAC is an important source of information and advice on Medicaid and the Childrens Health Insurance Program (CHIP), Dodaro said. Once again, a number of outstanding individuals expressed an interest in serving on the Commission, and Im very pleased to announce todays four new appointments and two reappointments.

The newly appointed members are Sonja L. Bjork, Jennifer L. Gerstorff, Angelo P. Giardino, and Rhonda M. Medows. Their terms will expire in April 2025. In addition, current members Tricia Brooks and Dennis Heaphy were reappointed to new terms, which will also expire in April 2025.

The Childrens Health Insurance Program Reauthorization Act of 2009 established MACPAC to review Medicaid and CHIP access and payment policies and to advise Congress on issues affecting Medicaid and CHIP. The Act directs the Comptroller General to appoint MACPACs members. Brief biographies of the new commission members and reappointees follow.

New Commission Members:

Sonja L. Bjork, JD, is the Chief Operating Officer of Partnership HealthPlan of California (PHC), a non-profit community based Medicaid managed care plan. PHC provides healthcare to 635,000 members in 14 Northern California counties. During her tenure at PHC, she has overseen multiple benefit implementations and expansion of the Plans service area. Ms. Bjork served on the executive team directing the Plans $280 million strategic investment of health plan reserves for the purpose of addressing social determinants of health. These included medical respite, affordable housing, and substance use disorder treatment options. Before joining PHC, Ms. Bjork worked as a dependency attorney representing youth in the child welfare system. Ms. Bjork received her Juris Doctorate from UC Berkeley School of Law.

Jennifer L. Gerstorff, FSA, MAAA, is a principal and consulting actuary with Milliman's Seattle office. Since joining the firm in 2006, she has served as lead actuary for several state Medicaid agencies. In addition to supporting state agencies through her consulting work, Ms. Gerstorff actively volunteers with the Society of Actuaries and American Academy of Actuaries workgroups, participating in research efforts, developing content for continuing education opportunities, and facilitating monthly public interest group discussions with Medicaid actuaries and other industry experts. She received her Bachelors in Applied Mathematics from Columbus State University.

Angelo P. Giardino, MD, PhD, MPH, is the Wilma T. Gibson Presidential Professor and Chair of the Department of Pediatrics at the University of Utahs Spencer Fox Eccles School of Medicine and Chief Medical Officer at Intermountain Primary Childrens Hospital in Salt Lake City, Utah. Hereceived his medical degree and doctorate in education from the University of Pennsylvania, completed his residency and fellowship training at the Childrens Hospital of Philadelphia, and earned a Masters in Public Health from the University of Massachusetts. He also holds a Masters in Theology from Catholic Distance University and a Masters in Public Administration from University of Texas Rio Grande Valley. Prior to moving to Utah, Dr. Giardino worked at Texas Childrens Health Plan, Inc. and Texas Childrens Hospital from 2005 to 2018.

Rhonda M. Medows, MD, is a nationally recognized expert in population health and health equity. As President of Providence Population Health Management, Dr. Medows uses her platform to change the way health care organizations approach large-scale issues, such as improving equity in the Medicare and Medicaid programs. Before joining Providence, she was an executive vice president and chief medical officer at UnitedHealth. In the public sector, she served as commissioner for the Georgia Department of Community Health, secretary of the Florida Agency for Health Care Administration, and chief medical officer for the Centers for Medicare & Medicaid Services Southeast Region. Dr. Medows is also a Family Medicine Physician who practiced medicine at Mayo Clinic and at Kaiser Permanente. Dr. Medows received her medical degree from the Morehouse School of Medicine.

Reappointments:

Tricia Brooks, MBA, is a research professor at the McCourt School of Public Policy at Georgetown University and a senior fellow at the Georgetown University Center for Children and Families (CCF), an independent, non-partisan policy and research center whose mission is to expand and improve health coverage for children and families. At CCF, Ms. Brooks focuses on issues relating to policy, program administration, and quality of Medicaid and CHIP coverage for children and families. Before joining CCF, she served as the founding CEO of New Hampshire Healthy Kids, a legislatively created non-profit corporation that administered CHIP in the state, and served as the Medicaid and CHIP consumer assistance coordinator. Ms. Brooks holds a master of business administration from Suffolk University.

Dennis Heaphy, MPH, MEd, MDiv, is a health justice advocate and researcher at the Massachusetts Disability Policy Consortium, a Massachusetts-based disability rights advocacy organization. He is also a dually eligible Medicaid and Medicare beneficiary enrolled in One Care, a plan operating in Massachusetts under the CMS Financial Alignment Initiative. Mr. Heaphy is engaged in activities that advance equitable whole personcentered care for beneficiaries in Massachusetts and nationally. He is a cofounder of Disability Advocates Advancing Our Healthcare Rights (DAAHR), a statewide coalition in Massachusetts. DAAHR was instrumental in advancing measurable innovations that give consumers voice in One Care. Examples include creating a consumer-led implementation council that guides the ongoing development and implementation of One Care, an independent living long-term services and supports coordinator role on care teams, and an independent One Care ombudsman. Previously, he worked as project coordinator for the Americans with Disabilities Act for the Massachusetts Department of Public Health. He received his master of public health and master of divinity from Boston University and master of education from Harvard University.

For more information about MACPAC, contact Moira Forbes, MACPACs acting executive director, at (202) 350-2000. Other questions should be directed to Chuck Young in GAOs Office of Public Affairs at (202) 512-4800. The official announcement will be published in the Federal Register.

#####

The Government Accountability Office, known as the investigative arm of Congress, is an independent, nonpartisan agency that exists to support Congress in meeting its constitutional responsibilities. GAO also works to improve the performance of the federal government and ensure its accountability to the American people. The agency examines the use of public funds; evaluates federal programs and policies; and provides analyses, recommendations, and other assistance to help Congress make informed oversight, policy, and funding decisions. GAO provides Congress with timely information that is objective, fact-based, nonideological, fair, and balanced. GAOs commitment to good government is reflected in its core values of accountability, integrity, and reliability.

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GAO Makes MACPAC Appointments and Reappointments | US GAO - Government Accountability Office

Ray Therapeutics a biotechnology company developing optogenetic gene therapies for patients with retinal degenerative conditions announced that the California Institute for Regenerative Medicine (CIRM) has awarded the company a $4 million grant to support the development of Ray-001, an optogenetic therapy for the treatment of retinitis pigmentosa and other inherited retinal diseases.

Retinitis pigmentosa (RP) is known as a heterogeneous group of genetic diseases that cause retinal degeneration leading to near or complete blindness for most patients. And the severe loss of photoreceptor cells that occurs in this genetic degenerative disease leads to partial or complete blindness. At present, no effective treatment is available to restore vision once the photoreceptor cells have been lost.

Ray Therapeutics lead therapy RAY-001 for the treatment of retinitis pigmentosa, delivers light-sensing channelrhodopsin to retinal cells, to potentially restore vision using the power of optogenetics. And based on the durability of treatment demonstrated in preclinical studies RAY-001 is intended to be a one-time treatment via intravitreal injection that is sustainable for a lifetime. Unlike the current RP gene therapies in development, which are targeted to specific genetic mutations or individuals with remaining photoreceptors that only address a small patient population, Ray-001 is mutation-independent.

KEY QUOTES:

Ray-001 has the potential to address a significant unmet need in patients who suffer from retinitis pigmentosa. The funding and strategic support from CIRM will accelerate development of our lead optogenetics candidate into clinical trials for blind and nearly-blind patients in desperate need of new therapies, without the need for supplementary eyewear or devices for additional light stimulation. The unanimous positive vote from CIRMs independent reviewers, and obtaining the highest score in our application cohort, provides strong validation for our scientific rationale, program development and team. We look forward to advancing our candidate into clinical trials in retinitis pigmentosa.

Paul Bresge, Chief Executive Officer, Ray Therapeutics

Our goal is to always move the most promising research forward as fast as we can. A one-time treatment for retinitis pigmentosa such as Ray-001 would have significant impact for patients with this degenerative disorder. This technology also has the potential to serve the needs of underserved communities because RP has high prevalence in underserved, particularly Hispanic, ethnic populations. We look forward to supporting Ray Therapeutics in bringing this life-changing regenerative therapy to patients with genetic blinding disorders.

Dr. Maria T. Millan, President and Chief Executive Officer, California Institute for Regenerative Medicine (CIRM)

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Optogenetic Gene Therapy Company Ray Therapeutics Awarded $4 Million Grant - Pulse 2.0

image:a: Experimental schematic. Cells are isolated from the fetal yolk sac and AGM and their transcripts are sequenced by next-generation sequencing. b: Cell groups from single-cell analysis of AGM progenitor cells are shown. c: Heatmap of top 10 enriched genes in the three cell groups (6, 12, 17) in b. d: Gene enrichment analysis based on protein-protein inter-network of RUNX1, a transcription factor essential for the endothelial-to-hematopoietic transition (EHT), in which vascular endothelial cells give rise to hematopoietic stem cells. view more

Credit: Figure derived from the paper published in Molecular Psychiatry (2022) (DOI10.1038/s41380-022-01566-y)

An international research group led by Professor Toru Takumi (Senior Visiting Scientist, RIKEN Center for Biosystems Dynamics Research) and Researcher Chia-wen Lin at Kobe University Graduate School of Medicine has shown that idiopathic autism*1 is caused by epigenetic*2 abnormalities in hematopoietic cells during fetal development, which results in immune dysregulation in the brain and gut. The results of the study revealed that in autism, there are immune abnormalities which can be seen in the brain and gut.It is hoped that further classification of the pathophysiology of autism will lead to the creation of new treatment strategies for autism and other neurodevelopmental disorders*3.The results of this research will be published in Molecular Psychiatry on Monday May 2, 2022 (1am BST).

Main Points

Research BackgroundAutism (autism spectrum disorder) is a developmental neurological disorder that remains largely unexplored despite the rapidly increasing number of patients. Immune abnormalities, now considered the cause of many diseases, also play an important role in the development of autism. Brain inflammation and disturbances of the peripheral immune system are frequently observed in autistic patients. Furthermore, immune abnormalities are accompanied by abnormalities in the intestinal microbiota, which is also thought to be involved in the pathogenesis of the disease via the brain-gut axis*11. However, the essential mechanisms behind these immune abnormalities have yet to be elucidated.

Given the critical developmental stages of immune insults and the extensive involvement of the immune system in the development of autism, the research team hypothesized that a common etiology underlies the widespread immune dysregulation and originates in different types of progenitor cells. The analysis focused on the hematopoietic cells from which immune cells are derived, as well as on the yolk sac (YS) and the aorta-gonad-mesonephros (AGM), which are involved in hematopoiesis during the fetal stage. These results seek a common ancestor of inflammation in the brain and abnormalities in the peripheral immune system. In this study, BTBR mice were used as an idiopathic model for autism.

Research FindingsSingle-cell RNA sequencing (sc-RNA seq) of BTBR mice traced the origin of immune abnormalities back to the embryonic stages of the yolk sac (YS) and aorta-gonad-mesonephros (AGM) and identified where macrophages (microglia) and peripheral immune cells differentiate. Definitive hematopoiesis*12 in YS and AGM single-cell level analysis successfully identified pathological mechanisms at the molecular level within rare progenitor cells in the early stages of development. Namely, we found a common mechanism of transcriptional regulation through HDAC1, a histone deacetylase, underlying these pathologies (Figures 1 and 2).

We have also shown that manipulating epigenetic mechanisms during specific developmental stages can restore immune abnormalities in the brain and peripheral tissues. Namely, we identified histone deacetylase HDAC1 as a common mechanism. Administrating inhibitors of this histone (sodium butyrate or Romidepsin) during the fetal stage in BTBR mice suppressed elevated inflammatory cytokines*13and microglial activation (Figure 3).

We further demonstrated that dysregulated immunity can determine gut dysbiosis of specific profiles in autistic model mice, which make the potential biomarkers of Treg and gut dysbiosis a means to categorize the immune-dysregulated ASD subtype.From the above, it is clear that the abnormalities in the brain and peripheral organs (such as the intestines) seen in autism are caused by epigenetic abnormalities in the hematopoietic stem cell lineage, the ancestor of immune cells (Figure 4).

PerspectivesOur findings not only provide the missing piece to solve the long-time puzzle of systemic immune dysregulation in autism, but also hint the role of epigenetic disturbance as common etiology among different autism models of environmental risk factors. Furthermore, to develop precision medicine for ASD in the future, ASD subtyping according to the pathogenesis mechanism is a key first step to resolve the heterogeneity of ASD and to open up a new avenue for ASD treatment.

Glossary*1Idiopathic autism: Autism is considered to be a multifactorial disorder that can be caused by genetic and environmental factors. It is understood that genetic factors such as genetic and genomic abnormalities can cause autism, however there are still many cases of autism where the cause is unknown. Autism where the cause cannot be specified (including environmental factors) is called idiopathic autism.*2Epigenetics: The study of inheritance patterns that affect how genes work but do not involve alterations to the DNA sequence. Even though the information in the genome remains the same, biological mechanisms such as DNA methylation and chemical modification of histone proteins can alter genetic expression.*3Neurodevelopmental disorderPreviously called developmental disorders, this is a disorder that occurs in relation to a functional problem with the brain.*4BTBR mouse:A type of cogenic mouse. From analysis of the systemic behavior of this line of mice, it has been reported that BTBR mouse behavior is the closest to autistic behavior. Therefore, it is known as the idiopathic autism mouse model.*5HDAC1:Histone deacetylase 1 regulates gene expression by modifying histone proteins.*6Single-cell RNA-seq:A method of comprehensively investigating the qualitative and quantitative aspects of all mRNA present in individual cells using a next generation sequencer. By combining this with statistical analysis methods such as dimension reduction, it is possible to classify cells based on their genetic expression, and estimate the cell state. Furthermore, performing pseudo-temporal ordering analysis based on changes in the gene expression profile allows for the depiction of the fibers in the cellular state that accompanies development.*7AGM:The Aorta-gonad-mesonephros (AGM) region is a hematopoietic site within the fetus (i.e. where cellular components of the fetuss blood are formed).*8Yolk sac:During pregnancy the sac, which is a membrane that surrounds the egg yolk, is also a hematopoietic site (primary hematopoiesis).*9Microglia: A type of glial cell in the central nervous system responsible for the central immune system. Microglia are also called the resident macrophages of the central nervous system. Unlike other glial cells (such as astrocytes and oligodendrocytes), microglia originate from yolk sac derived precursor cells.*10Intestinal microbiota: clusters of bacteria in the gut that are also called intestinal flora. Recent research advancements using a next-generation sequencer to analyze the metagenome of gut bacteria have shown links to various disorders including autism.*11Brain-gut axis: The relationship between the brain and the gut, also called the brain-gut connection. Two-way communication occurs between the brain and gut through mediums such as the autonomic nervous system and humoral factors (e.g. hormones and cytokines). Recently, this two-way communication system between the gut microbiome (microbiota) and the brain has received much attention.*12Definitive hematopoiesis: During the fetal period, hematopoiesis begins in the yolk sac with primary hematopoiesis and then secondary hematopoiesis occurs in the AGM region. Subsequent hematopoiesis during the fetal period occurs in the liver and lastly in the bone marrow. Hematopoiesis continues throughout a persons life with bone marrow as the main site of this process.*13Inflammatory cytokineA signaling molecule secreted by the immune cells, it causes inflammation.

AcknowledgementsThis research received funding from sources including those listed below:

Journal InformationTitleA common epigenetic mechanism across different cellular origins underlies systemic immune dysregulation in an idiopathic autism mouse modelDOI10.1038/s41380-022-01566-y

AuthorsChia-Wen Lin, Dian E Septyaningtrias, Hsu-Wen Chao, Mikiko Konda, Koji Atarashi, Kozue Takeshita, Kota Tamada, Jun Nomura, Yohei Sasagawa, Kaori Tanaka, Itoshi Nikaido, Kenya Honda, Thomas J McHugh, Toru Takumi

JournalMolecular Psychiatry

Molecular Psychiatry

Experimental study

Animals

A common epigenetic mechanism across different cellular origins underlies systemic immune dysregulation in an idiopathic autism mouse model

2-May-2022

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Does autism begin in the womb? - EurekAlert

Mount Sinai researchers conducting clinical trials of a drug targeting a cancer gene found that it increased metastatic cancer patients survival and was able to work within the brain.

Mount Sinai researchers conducting clinical trials of a drug targeting a cancer gene found that it increased metastatic cancer patients survival and was able to work within the brain, according to a study published in Clinical Cancer Research in February.

The drug entrectinib targets cancers that involve fusions between the cancer gene NTRK and other genes, including certain types of lung, breast, colon, and other cancers. This study looked into the effectiveness of the drug a year after three clinical trials were completed and found patients response rates post-trial were 60 percent.

A significant finding in this study, which was not seen in the initial trials, was that the drug is able to cross the blood-brain barrier effectively. Researchers found evidence that the therapy was working against metastatic cancer that spread to the brain.

This is the largest study evaluating the safety and activity of entrectinib in NTRKfusion-positive solid tumors, said Christian Rolfo, MD, PhD, MBA, Professor of Medicine (Hematology and Medical Oncology) at the Icahn School of Medicine at Mount Sinai and Associate Director for Clinical Research in the Center for Thoracic Oncology at The Tisch Cancer Institute. The confirmation of substantial effect on metastases in the brain suggests that entrectinib could address the unmet need of an effective treatment for patients with NTRK fusion-positive tumors that spread to the central nervous system. Although NTRK fusions are rare, our results should encourage broader screening for these fusions in patients with solid tumors as they may benefit from entrectinib, particularly because the extended life expectancy of these patients may increase the likelihood of metastases in the brain.

Gene fusions involving NTRK can be associated with a large range of tumor types. They occur in 90 percent of rare pediatric tumors and rarer subtypes of breast cancers and salivary cancers.

This international study was conducted in several institutions in collaboration with investigators from Dana Dana-Farber Cancer Institute, Ludwig Center at Harvard Medical School, and other international centers. The research was funded by F. Hoffmann-La Roche Ltd.

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Molecular Treatment Is Able to Control Brain Metastasis of Different Tumors - OncLive

CAMBRIDGE, Mass., May 03, 2022 (GLOBE NEWSWIRE) -- Ring Therapeutics, a life sciences company founded by Flagship Pioneering to revolutionize gene therapy with its AnellogyTM commensal virome platform, today announced two upcoming presentations at the 25th Annual Meeting of the American Society of Gene & Cell Therapy (ASGCT), to be held from May 16-19, 2022 in Washinton, DC. These presentations further demonstrate the potential of Rings AnellogyTM platform in harnessing the unique biology of anelloviruses to engineer the novel precision medicines.

Poster Presentations:

Title: Favorable immune profile of anelloviruses makes them attractive candidates as gene therapy vectorsSession Title: Immunological Aspects of Gene Therapy and Vaccines IAbstract Number: 713Board number: TU-218Presenter: Harish SwaminathanPresentation Date and Time: Tuesday, May 17, 2022, 5:30 - 6:30 p.m. ET

This poster presents data from a study that characterized the immunogenicity of anelloviruses and the antigenic profile of anellovirus proteins. Results showcase the favorable immune profile of anelloviruses.

Title: A novel gene delivery vector with low pre-existing immunity in humansSession Title: Vector Product Engineering, Development or Manufacturing IIIAbstract Number: 1158Board number: W-284Presenter: Dhananjay NawandarPresentation Date and Time: Wednesday, May 18, 2022, 5:30 - 6:30 p.m. ET

Data in this poster show successful vectorization of synthetically produced anelloviruses to produce the first AnelloVectorTM therapeutic. These novel vectors can successfully target a variety of tissues, and no pre-existing immunity in humans is observed.

About Ring TherapeuticsRing Therapeutics is revolutionizing the gene therapy and nucleic acid medicine space by harnessing the most abundant and diverse member of the human commensal virome, anelloviruses. The company developed the Anellogy platform which focuses on anelloviruses to potentially treat a broad range of diseases. Through harnessing the unique properties of these commensal viruses, the Anellogy platform generates diverse vectors that exhibit both tissue-specific tropism and the potential to be re-dosed. Ring Therapeutics, founded by Flagship Pioneering in 2017, aims to develop and further expand its portfolio by leveraging its platform to unlock the full potential of gene therapy and nucleic acid medicines, enabling a variety of mechanisms that successfully deliver therapeutic cargo to unreachable organs and tissues. To learn more, visit https://www.ringtx.com/ or follow us on Twitter at @Ring_tx.

Ring Therapeutics Media:Brittany Leigh, Ph.D.LifeSci Communicationsbleigh@lifescicomms.com+1-813-767-7801

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Ring Therapeutics Announces Two Presentations at the Upcoming 25th Annual Meeting of the American Society of Gene & Cell Therapy (ASGCT) -...

Findings from the BIONIKK study published in The Lancet Oncology suggest that biomarker-driven treatment selection based on tumor molecular phenotype may be on the horizon in the treatment paradigm for metastatic renal cell carcinoma (RCC).1

The study (NCT02960906) specifically examined this precision medicine pathway in the context of treatment selection between nivolumab (Opdivo) with or without ipilimumab (Yervoy) and a VEGFR tyrosine kinase inhibitor (TKI) in the first-line setting for patients with metastatic clear-cell RCC (ccRCC).

Frontline treatment of ccRCC has changed tremendously since 2015, when the immune checkpoint inhibitor (ICI), nivolumab, was granted FDA approval. Since then, ICIs alone and in combinations have entered the space and offer options for patients with RCC subtypes.

Prior research showed that treatment with sunitinib (Sutent) in patients with good response to the agent had molecular and pathological features closest to normal kidney tissue (ccrcc3), investigators hypothesized that immune-high ccrcc4 tumors would respond to nivolumab-based therapy, either with or without ipilimumab (Yervoy), because of theimmune-enriched tumor microenvironment. Moreover, ccrcc1 tumors would have a better response to the combination of nivolumab and ipilimumab compared with nivolumab alone because of the need to recruit antitumor cytotoxic T cells.

To our knowledge, this is the first study to show the feasibility of prospective patient and treatment selection based on tumor gene expression in metastatic renal cell carcinoma. By allocating treatment according to tumor molecular group, we enriched the population who achieved an objective response with nivolumab, nivolumabipilimumab, and VEGFR tyrosine kinase inhibitors (VEGFR-TKIs), wrote the study authors led by Yann-Alexandre Vano, a medical oncologist at the Hpital Europen Georges-Pompidou.

To conduct the biomarker-driven, open-label, noncomparative, randomized, phase 2 BIONIKK trial (NCT02960906), patients with ccRCC from 15 university hospitals and cancer centers in France were enrolled. Those eligible for the study were patients aged 18 years or older who had newly diagnosed or recurrent stage IV RCC, an ECOG performance status of 0-2, 1 or more measurable lesion per RECIST v1.1, and had not received previous systemic therapy for metastatic disease.

In terms of molecular grouping, the presence of a sarcomatoid component and PD-L1 expression was centrally assessed by an expert uropathologist on selected formalin-fixed paraffin-embedded tumor samples for all patients. Samples were selected by certain criteria, which included tumors with 60% of viable tumor cells, 20% of necrosis, of highest grade, and with the highest immune infiltrate. Also, the presence of a sarcomatoid component was identified and PD-L1 expression was assessed using the PD-L1 22C3 antibody. Tumors with TC 1% were PD-L1 positive.

The patients with ccrcc1 and ccrcc4 disease were assigned to receive either nivolumab 3 mg/kg or nivolumab with ipilimumab 1 mg/kg. Those with ccrcc2 and ccrcc3 groups disease were assigned to receive 1 of 2 VEGFR TKIs (sunitinib 50 mg/day for 4 weeks every 6 weeks or oral pazopanib [Votrient] 800 mg daily continuously).

The primary end point of the study was the objective response rate (ORR) by investigator assessment per RECIST v1.1. Secondary end points of the study included ORR at week 22, progression-free survival (PFS), overall survival, duration of response (DOR), duration of treatment, and safety and tolerability.

Overall, there were 61 patients assigned to receive nivolumab monotherapy, 101 assigned to the combination of nivolumab and ipilimumab, and 40 received a VEGFR TKI.

Among patients with ccrcc1, those treated with nivolumab alone had an ORR of 29% (95% CI, 16%-45%) vs 39% (95% CI, 24%-55%) with nivolumab plus ipilimumab (Odds ratio [OR], 0.63; 95% CI, 0.25-1.56). Patients with ccrcc4 disease had an ORR of 44% (95%, 20%-70%) on nivolumab monotherapy vs 50% (95% CI, 26%-74%) in patients treated with nivolumab/ipilimumab (OR, 0.78; 95% CI, 0.20-3.01).

Responses were higher among patients with ccrcc2 compared with other phenotypes and lower in patients with ccrcc3 disease. Specifically, those with ccrcc2 treated with a VEGFR TKI had an ORR of (50% (95%, 33%-67%) vs 51% (95% CI, 34%-68%) with nivolumab plus ipilimumab (OR, 0.95 (0.38-2.37). Among the patients with ccrcc3, the ORR was 0 with VEGFR TKI therapy compared with 20% (95% CI, 1%-72%; OR, not evaluable [NE]).

DORs were not reached (NR) in any treatment arm, but ranged from 6.0 months to 11.8 months, depending on phenotype and the treatment administered. The shortest time to response was observed in patients with ccrcc4 disease treated with nivolumab monotherapy, with a time to response of 2.2 months (range, 2.2-NR). The longest time to response was among patients with ccrcc2 disease treated with a VEGFR TKI at 4.9 months (range, 2.8-16.5).

PFS was assessed in the ccrcc1, ccrcc2, and ccrcc4 groups. In patients with ccrcc1 disease who received the combination of nivolumab and ipilimumab, the median PFS was 7.7 months (95% CI, 5.0-12.9) compared with 5.2 months (95% CI, 2.4-9.1) among those treated with nivolumab alone (hazard ratio [HR] 1.27 (95% CI, 0.77-2.11).

The median PFS in patients with ccrcc4 treated with the ICI combination was 13.0 months (95%CI, 2.5-NE) vs 7.8 months (95% CI, 2.3-NE) with nivolumab alone (HR, 1.37 (95% CI, 0.57-3.29)

Finally, patients in the ccrcc2 group treated with nivolumab plus ipilimumab had a median PFS of 11.1 months (95% CI, 7.7-23.2) vs 14.4 months (10.6-NE) with VEGFR TKI treatment (HR, 0.75; 95% CI, 0.40-1.39).

Safety was assessed based on treatment with the nivolumab monotherapy, nivolumab plus ipilimumab, and VEGFR TKI therapy, and grade 1/2 adverse events (AEs) were observed in 76%, 54%, and 30% respectively. In the nivolumab-only group, the most common low-grade AEs were fatigue (50%), pruritus (24%), and maculopapular rash (17%). For patients treated with the ICI combination, the most common grade 1/2 AEs were fatigue (50%), pruritus (31%), and diarrhea (32%). Lastly, in the VEGFR TKI arms, the most common grade 1/2 AEs were fatigue (65%), diarrhea (53%), and oral mucositis (43%).

Our results confirm that the response to nivolumab alone or with ipilimumab and to VEGFR-TKIs is different depending on the characteristics of the tumor and its microenvironment. The feasibility of prospectively selecting patients by their molecular group for treatment choice opens the way to larger biomarker-based trial designs, wrote Vano et al.

Reference

1. Vano Y, Elaidi R, Bennamoun M, et al. Nivolumab, nivolumabipilimumab, and VEGFR-tyrosine kinase inhibitors as first-line treatment for metastatic clear-cell renal cell carcinoma (BIONIKK): A biomarker-driven, open-label, non-comparative, randomized, phase 2 trial [Published online ahead of print April 04, 2022].Lancet Oncol. doi: 10.1016/s1470-2045(22)00128-0

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Study shows feasibility of mRCC treatment selection based on tumor gene expression - Urology Times