GDNF

Gene therapy AB-1005 being developed to locally increase glial cell line-derived neurotrophic factor (GDNF) levels in the brain for the treatment of MSA-P Phase 1 randomized, controlled trial to assess safety of AB-1005 delivered to the putamen in patients with MSA-P RESEARCH TRIANGLE PARK, N.C., Nov. 17, 2023 /PRNewswire/ -- Asklepios BioPharmaceutical, Inc. (AskBio), a gene therapy company wholly owned and independently operated as a subsidiary of Bayer AG, today announced that the first patient has been randomized at the Ohio State University Wexner Medical Center in the Phase 1 REGENERATE MSA-101 clinical trial of AB-1005, a gene therapy being developed as a treatment for multiple system atrophy-parkinsonian type (MSA-P).1 This marks a significant milestone in the development of AB-1005 gene therapy, an adeno-associated viral vector encoding for glial cell line-derived neurotrophic factor (AAV2-GDNF) that is delivered to the putamen, and brings this therapeutic one step closer to potentially reaching patients. AB-1005 is also currently being investigated for the treatment of mild to moderate Parkinson's disease with the enrollment of the Phase 1b study having now been completed.2 "It means a lot to the MSA community to know that the first patient has been enrolled in the Phase 1 REGENERATE MSA-101 trial," said Philip M. Fortier, MA, President and Executive Director, Defeat MSA Alliance. "There is no cure for MSA, and there are currently no treatments to stop or slow the progression of the disease. This makes it especially hard for patients, given the rapid decline many will experience. Today's milestone hopefully brings us one step closer to potentially changing the outcome for MSA patients." MSA-P, which can initially be difficult to distinguish from Parkinson's disease, is marked by slow movement, lack of coordination, imbalance, and dizziness, among other symptoms, as individuals experience increasing difficulty with movement.3 This is the result of a progressive loss of nerve cells in the brain and spinal cord. Affecting an estimated 100,000–500,000 worldwide, MSA is a rare disease that in most cases seems to occur at random.3,4,5 Symptoms tend to appear in people during their 50s, followed by a rapid progression within 5–10 years.3 "In those with MSA-P, the loss of dopamine producing neurons leads to markedly disabling symptoms, such as profound motor impairment throughout the hands, legs, and trunk. Previous experience with a similar approach in a population of Parkinson's disease patients has been very encouraging and supported the consideration of this approach in MSA-P. The intent is for GDNF levels in the brain to help preserve dopamine neurotransmission, which is noticeably reduced in MSA-P," said Nicolas M. Phielipp, MD, University of California Irvine, REGENERATE MSA-101 Principal Investigator. "We're including a genetic sequence in the AAV2 vector that codes for the GDNF protein and are delivering this to the putamen. In this way, we're targeting local brain cells and adjacent brain tissue that can benefit from the protein's growth properties. This trial marks the first step toward understanding the potential that GDNF gene therapy might have for patients with MSA-P." "Enrolling the first patient in our REGENERATE MSA-101 trial is an important step in AskBio's ongoing work to advance GDNF gene therapy" said Krystof Bankiewicz, MD, PhD, Scientific Chair, Parkinson's and MSA, AskBio. "The clinical advancement of AB-1005 for the treatment of MSA-P comes as we are gathering the results of our Phase 1 programs in Parkinson's. Taken together we expect the outcomes of these trials to meaningfully contribute to the body of scientific knowledge related to the potential of GDNF gene therapy in the treatment of these debilitating central nervous system diseases. We believe these data, combined with our exploration of AAV-based intracranial gene delivery and our close collaborations with clinical neurosurgical centers of excellence, will support our goal of successfully developing and eventually delivering to patients these much-needed treatments." About the Phase 1 REGENERATE MSA-101 Trial The Phase 1 REGENERATE MSA-101 trial is a randomized, double-blind, placebo-controlled trial designed to determine the safety of AB-1005 (also known as AAV2-GDNF), a gene therapy delivered to the putamen in patients with multiple system atrophy-parkinsonian type (MSA-P).1 The trial will include adults aged 35 to 75 years, with a clinical diagnosis of MSA-P (as defined by current consensus criteria), who are suitable surgical candidates. The trial is expected to enroll up to 9 participants who will be randomized on the day of surgery to receive either the AAV2-GDNF investigational medicinal product or a control surgery. The first patient in the REGENERATE MSA-101 trial was randomized at the Ohio State University Wexner Medical Center, and the trial is currently enrolling patients at the University of California Irvine and the Quest Research Institute, Michigan. Brain Neurotherapy Bio, Inc., an AskBio subsidiary, is the sponsor for REGENERATE MSA-101.For more information, visit clinicaltrials.gov (NCT#04680065), visit askbio.com, or send an email to [email protected]. About GDNF & AB-1005 (AAV2-GDNF) Glial cell line-derived neurotrophic factor (GDNF) is a homodimer that is a distantly related member of the transforming growth factor-β superfamily. In midbrain cultures, recombinant human GDNF promoted the survival and morphological differentiation of dopaminergic neurons and increased their high-affinity dopamine uptake. GDNF has long been suspected to be a potential treatment for diseases, such as Parkinson's, marked by progressive degeneration of midbrain dopaminergic neurons.6 It has been found that there is around 76% less GDNF and 96% loss of dopamine content in postmortem putamen tissue from MSA patients compared to matched controls.7AB-1005 is an adeno-associated viral vector serotype 2 (AAV2) containing the human GDNF transgene, which allows for stable and continuous expression of GDNF in localized regions of the brain after direct neurosurgical injection with MRI-monitored convection enhanced delivery.8,9 About AskBio Asklepios BioPharmaceutical, Inc. (AskBio), a wholly owned and independently operated subsidiary of Bayer AG, is a fully integrated gene therapy company dedicated to developing life-saving medicines and changing lives. The company maintains a portfolio of clinical programs across a range of neuromuscular, central nervous system, cardiovascular and metabolic disease indications with a clinical-stage pipeline that includes therapeutics for congestive heart failure, Huntington's disease, limb-girdle muscular dystrophy, multiple system atrophy, Parkinson's disease, and Pompe disease. AskBio's gene therapy platform includes Pro10™, an industry-leading proprietary cell line manufacturing process, and an extensive capsid and promoter library. With global headquarters in Research Triangle Park, North Carolina, and European headquarters in Edinburgh, Scotland, the company has generated hundreds of proprietary capsids and promoters, several of which have entered pre-clinical and clinical testing. An early innovator in the gene therapy field, with over 900 employees in five countries, the company holds more than 800 patents and patent applications in areas such as AAV production and chimeric capsids. Learn more at or follow us on LinkedIn. About Bayer Bayer is a global enterprise with core competencies in the life science fields of health care and nutrition. Its products and services are designed to help people and the planet thrive by supporting efforts to master the major challenges presented by a growing and aging global population. Bayer is committed to driving sustainable development and generating a positive impact with its businesses. At the same time, the Group aims to increase its earning power and create value through innovation and growth. The Bayer brand stands for trust, reliability and quality throughout the world. In fiscal 2022, the Group employed around 101,000 people and had sales of 50.7 billion euros. R&D expenses before special items amounted to 6.2 billion euros. For more information, go to . AskBio Forward-Looking Statements This press release contains "forward-looking statements." Any statements contained in this press release that are not statements of historical fact may be deemed to be forward-looking statements. Words such as "believes," "anticipates," "plans," "expects," "will," "intends," "potential," "possible" and similar expressions are intended to identify forward-looking statements. These forward-looking statements include without limitation statements regarding AskBio's clinical trials. These forward-looking statements involve risks and uncertainties, many of which are beyond AskBio's control. Known risks include, among others: AskBio may not be able to execute on its business plans and goals, including meeting its expected or planned clinical and regulatory milestones and timelines, its reliance on third-parties, clinical development plans, manufacturing processes and plans, and bringing its product candidates to market, due to a variety of reasons, including possible limitations of company financial and other resources, manufacturing limitations that may not be anticipated or resolved in a timely manner, potential disagreements or other issues with our third-party collaborators and partners, and regulatory, court or agency feedback or decisions, such as feedback and decisions from the United States Food and Drug Administration or the United States Patent and Trademark Office. Any of the foregoing risks could materially and adversely affect AskBio's business and results of operations. You should not place undue reliance on the forward-looking statements contained in this press release. AskBio does not undertake any obligation to publicly update its forward-looking statements based on events or circumstances after the date hereof. _______________________________ 1 GDNF Gene Therapy for Multiple System Atrophy. Available at: . Accessed November 2023. 2 GDNF Gene Therapy for Parkinson's Disease. Available at: . Accessed: November 2023 3 NIH – Multiple System Atrophy. Available at: . Accessed November 2023. 4 Vanacore N, Bonifati V, Fabbrini G, et al. Epidemiology of multiple system atrophy. ESGAP Consortium. European Study Group on Atypical Parkinsonisms. Neurol Sci. 2001;22(1):97-99. 5 Bower JH, Maraganore DM, McDonnell SK, Rocca WA. Incidence of progressive supranuclear palsy and multiple system atrophy in Olmsted County, Minnesota, 1976 to 1990. Neurology. 1997;49(5):1284-1288. 6 Lin LF, Doherty DH, Lile JD, Bektesh S, Collins F. GDNF: a glial cell line-derived neurotrophic factor for midbrain dopaminergic neurons. Science. 1993;260(5111):1130-1132. 7 Goldstein, DS, Sullivan, P,Holmes, C Bankiewicz, K. Post-mortem and in vivo evidence for ''sick but not dead'' central dopaminergic neurons in multiple system atrophy: implications for neurotrophic factor gene enhancement therapy. Poster #7. Clin Auton Res (2019) 29:479–546. 8 Heiss JD, Lungu C, Hammoud DA, Herscovitch P, Ehrlich DJ, Argersinger DP, Sinharay S, Scott G, Wu T, Federoff HJ, Zaghloul KA, Hallett M, Lonser RR, Bankiewicz KS. Trial of magnetic resonance-guided putaminal gene therapy for advanced Parkinson's disease. Mov Disord. 2019 Jul;34(7):1073-1078. doi: 10.1002/mds.27724. Epub 2019 May 30. PMID: 31145831; PMCID: PMC6642028... 9 Kells AP, Eberling J, Su X, Pivirotto P, Bringas J, Hadaczek P, Narrow WC, Bowers WJ, Federoff HJ, Forsayeth J, Bankiewicz KS. Regeneration of the MPTP-lesioned dopaminergic system after convection-enhanced delivery of AAV2-GDNF. J Neurosci. 2010 Jul 14;30(28):9567-77. doi: 10.1523/JNEUROSCI.0942-10.2010. PMID: 20631185; PMCID: PMC2914692. SOURCE AskBio

Researchers found that using a gene therapy to elevate levels of GDNF, a brain protein, could keep alcohol cravings in monkeys at bay. Humans—and our ancestors—have been drinking alcohol for thousands of years, and likely becoming addicted to it for just as long. Yet, even as our understanding of the biological underpinnings of addiction has progressed enough for scientists to develop effective drugs, many people with alcohol use disorder, or AUD, still find themselves trapped in a loop of abstinence and relapse. But if results in monkeys bear out in humans, a new gene therapy might be able to interrupt the cycle. In the results of a study published Aug. 14 in Nature Medicine, scientists from Ohio State University Wexner Medical Center and School of Medicine, Oregon Health and Science University, the Oregon National Primate Center and the University of California, San Francisco reported that they were able to halt AUD in primate models by expressing a key brain chemical called glial cell line-derived neurotrophic factor, or GDNF, which suppressed their desire to consume large amounts of alcohol for months at a time. “Overall, our findings indicate that GDNF gene therapy could diminish reintroduction-associated alcohol intake in our primate model,” co-corresponding author Krystof Bankiewicz, M.D., Ph.D., a researcher at Ohio State, said in a press release. “We believe this approach shows merit for further study as a promising therapy for AUD and possibly other substance-abuse disorders.” GDNF is found in several regions of the adult brain containing neurons that secrete the neurotransmitter dopamine, where it protects them from damage—including the kind caused by alcoholism. Its potential to curb alcohol consumption has been investigated for more than a decade; other compounds studied as a treatment for AUD, like the hallucinogen ibogaine, may work at least in part by upregulating GDNF. Previous studies suggested that alcohol consumption directly downregulates the gene responsible for encoding GDNF. Additionally, these studies demonstrated that overexpressing this gene can attenuate alcohol cravings in mice. Such findings led Bankiewicz’s team to investigate whether a gene therapy that upregulates the GDNF gene in the mesolimbic reward pathway—a dopamine-rich tract through several brain regions that is well known for its role in addiction—could be a practical way to treat AUD in primates without the risk of relapse. To do that, the scientists first habituated eight macaque monkeys to alcohol. Next, they infused an adeno-associated virus vector that encoded the GDNF gene into the brains of four of them, doing so directly into the brain’s ventral tegmental area, or VTA. The VTA is a key player in the mesolimbic reward pathway, as it’s the site of dopaminergic neurons that send signals to other regions downstream. The other four primates, serving as controls, received a saline solution. The researchers then exposed the primates to alcohol in cycles, mirroring the effects of abstinence and relapse. They withheld alcohol for four weeks at a time, then offered it to them for another four weeks. This continued for multiple rounds. The scientists tested the monkeys’ blood alcohol levels throughout the experiment. They found that while the controls had consistently higher blood alcohol levels, indicating that they were “relapsing” during exposure periods, they were undetectable most weeks in the treated primates. That suggests that by elevating GDNF, the gene therapy was indeed keeping their alcohol cravings at bay. This is far from the first gene therapy for substance abuse. One of the earliest examples is a gene therapy that increased the number of dopamine receptors in the brains of mice, which decreased their interest in the drug. A little over a decade later, the Mayo Clinic’s anti-cocaine gene therapy—which works by a different mechanism—is recruiting for a phase 1 clinical trial. Researchers from the University of Arkansas have encoded anti-meth genes into mice that made it so the drug was less rewarded, reducing the amount of it in their brains.

Dr. Barbara Waszczak, Professor of Pharmacology at Northeastern University's Bouvé College of Health Sciences, and collaborators from Cummings School of Veterinary Medicine at Tufts University and Tufts University School of Medicine, are Principal Investigators. Copernicus Therapeutics, Inc. supplied the DNA nanoparticles that are the basis for the gene therapy approach used in the study. Northeastern University and Copernicus Therapeutics, Inc. receive second year of Phase 1 funding through a grant from the National Institute on Drug Abuse (NIDA), part of the National Institutes of Health (NIH) through the Helping to End Addiction Long-term Initiative, or NIH HEAL Initiative to develop a gene therapy approach for treating opioid use disorder. With these data and further proof-of-concept studies underway, Copernicus will be commercializing its technology for additional diseases, including rare targets, with the goal of advancing gene therapy treatment. CLEVELAND, OH / ACCESSWIRE / May 18, 2023 / Copernicus Therapeutics, Inc., today announced preliminary data, in collaboration with Northeastern University and Tufts University, that demonstrated plasmid GDNF DNA nanoparticles (pGDNF NPs) delivered intranasally bypass the blood-brain barrier to allow gene expression in brain cells, which ultimately results in a reduction in drug-seeking behaviors in rats. With further study, this novel approach, which utilizes proprietary DNA nanoparticles as the basis for a non-viral technology platform, is expected to restore normal functioning of the brain's reward system, reduce drug craving, and thus enable people in recovery from opioid use disorder to avoid relapse. Intranasal testing of these pGDNF NPs in primates is currently underway with results expected in early 2023. "These data take us one step closer to being able to show that we can deliver therapeutic doses of gene therapy into the brain in a non-invasive way," said Dr. Barbara Waszczak, Professor of Pharmacology at Northeastern University's Bouvé College of Health Sciences, a Principal Investigator in the study. "We are encouraged that this approach could be part of a solution to this significant global health crisis and look forward to further study in this area and in other brain disorders." Opioid use disorder is a serious public health issue in the United States and throughout the world with 5.6 million people in the United States experiencing opioid use disorder in 2021 according to the Substance Abuse and Mental Health Services Administration. The Centers for Disease Control and Prevention estimates that the total "economic burden" of opioid misuse in the United States was $1.02 trillion in 2017, with Forbes updating that figure to $1.3 trillion in February 2022. Although opioid use disorder prevalence has increased significantly in the past decade, few seek treatment or maintain their recovery. "These data further illustrate a path to a new gene therapy approach to treat opioid use disorder, as well as a template for exploring gene therapy approaches for other substance use disorders, and the cellular and molecular mechanisms that are involved in this novel and promising approach," said Mark J. Cooper, MD, Senior VP of Science and Medical Affairs at Copernicus. "We are pleased to continue to work with these talented academic scientists and believe this is a critical proof point toward moving our patented nanoparticle platform forward into human trials for opioid use disorder as well as other indications in the brain, lung and eye." About the Study One of the neuroadaptive changes associated with repeated drug use is a neural dopamine (DA) deficiency in the brain's reward circuit, which has been long recognized as a significant underlying mechanism of drug craving and seeking behaviors. Targeting this mechanism, a gene therapy for OUD utilizing glial cell line-derived neurotrophic factor (GDNF) was designed based on the hypothesis that GDNF treatment can correct the DA deficiency induced by chronic opioid use, thereby attenuating drug-seeking behaviors during abstinence. For the current application, plasmid GDNF DNA nanoparticles were delivered intranasally, bypassing the blood-brain barrier to allow GDNF transcription and translation in dopamine-containing brain regions. The main goal was to determine whether intranasal infusion of pGDNF NPs could reduce drug-seeking behavior in a robust animal model of opioid addiction. The newly presented results confirmed their ability to significantly reduce relapse-like behavior in both male and female rats. A second aim, currently underway, will assess whether these effects are associated with correction of the neural DA deficiency following chronic opioid self-administration. The study was recently presented at the 2022 Society for Neuroscience annual congress by co-Principal Investigators, Dr. Barbara Waszczak, Professor of Pharmacology in the Bouvé College Department of Pharmaceutical Sciences at Northeastern University, and Drs. Elizabeth Byrnes, Professor of Comparative Pathobiology at Cummings School of Veterinary Medicine at Tufts University, and Emmanuel Pothos, Associate Professor of Immunology at Tufts University School of Medicine. Isgate SB et al, The impact of intranasal administration of GDNF plasmid DNA nanoparticles on cue-induced opioid reinstatement and central dopamine pathways in male and female rats. Abstract, Society for Neurosciences, 2022 About the NIDA/NIH Grant The Phase 1 segment of the NIDA grant, through the Helping to End Addiction Long-term Initiative, or NIH HEAL Initiative, awarded $6.7 million to Northeastern University, to fund the first two years of this research project. Upon successful completion of Phase 1, Northeastern University will be eligible to receive an additional approximate $7.5 million in funding from NIDA to further advance this therapeutic approach towards human clinical trials. About Copernicus Therapeutics, Inc. Copernicus Therapeutics, Inc. is a U.S.-based privately held clinical stage company, with a non-viral, nucleic acid gene therapy platform technology enabled by patent protected nanoparticles, which deliver gene therapy directly to target sites to address diseases of the brain, eye, and lung. Pilot data research was done with the support of awards from the Brain Research Foundation and Tufts Clinical Translational Science Institute. This research is supported by the National Institute on Drug Abuse of the National Institutes of Health, through the NIH HEAL Initiative, under award number 1UG3DA050942-01A1. The content presented in this release is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The Helping to End Addiction Long-term® Initiative, or NIH HEAL Initiative®, is an aggressive, trans-NIH effort to speed scientific solutions to stem the national opioid public health crisis. Launched in April 2018, the initiative is focused on improving prevention and treatment strategies for opioid misuse and addiction, and enhancing pain management. For more information, visit: . # # # For More Information, contact: Robert C. Moen, MD. PhD President & CEO Copernicus Therapeutics, Inc (216) 231-0227 ext 026 SOURCE: Copernicus Therapeutics View source version on accesswire.com: