Lafora Disease

Scientists have identified new genetic risk factors for two types of non-Alzheimer's dementia. These findings detail how researchers identified large-scale DNA changes, known as structural variants, by analyzing thousands of DNA samples. The team discovered several structural variants that could be risk factors Lewy body dementia (LBD) and frontotemporal dementia (FTD). Scientists at the National Institutes of Health have identified new genetic risk factors for two types of non-Alzheimer's dementia. These findings were published in Cell Genomics and detail how researchers identified large-scale DNA changes, known as structural variants, by analyzing thousands of DNA samples. The team discovered several structural variants that could be risk factors Lewy body dementia (LBD) and frontotemporal dementia (FTD). The project was a collaborative effort between scientists at the National Institute of Neurological Disorders and Stroke (NINDS) and the National Institute on Aging (NIA) at NIH. Structural variants have been implicated in a variety of neurological disorders. Unlike more commonly studied mutations, which often affect one or a few DNA building blocks called nucleotides, structural variants represent at least 50 but often hundreds, or even thousands, of nucleotides at once, making them more challenging to study. "If you imagine that our entire genetic code is a book, a structural variant would be a paragraph, page, or even an entire chapter that has been removed, duplicated, or inserted in the wrong place," said Sonja W. Scholz, M.D., Ph.D., investigator in the neurogenetics branch of NINDS and senior author of this study. By combining cutting-edge computer algorithms capable of mapping structural variations across the whole genome with machine learning, the research team analyzed whole-genome data from thousands of patient samples and several thousand unaffected controls. A previously unknown variant in the gene TCPN1 was found in samples from patients with LBD, a disease, that like Parkinson's disease, is associated with abnormal deposits of the protein alpha-synuclein in the brain. This variant, in which more than 300 nucleotides are deleted from the gene, is associated with a higher risk for developing LBD. While this finding is new for LBD, TCPN1 is a known risk factor for Alzheimer's disease, which could mean that this structural variant plays a role in the broader dementia population. "From a genetics standpoint, this is a very exciting finding," said Dr. Scholz. "It provides a point of reference for cell biology and animal model studies and possibly down the road, a target for intervention." By looking at a group of 50 genes implicated in inherited neurodegenerative diseases, the investigators were able to identify additional rare structural variants, including several that are known to cause disease. The analyses also identified two well-established risk factors for FTD changes in the C9orf72 and MAPT genes. These proof-of-concept findings bolstered the strength of the study's new findings by demonstrating that the algorithms were properly working. Because reference maps for currently-available structural variants are limited, the researchers generated a catalog based on the data obtained in these analyses. The analysis code and all the raw data are now available to the scientific community for use in their studies. An interactive app also allows investigators to study their genes of interest and ask which variants are present in controls vs. LBD or FTD cases. The authors assert these resources may make complex genetic data more accessible to non-bioinformatics experts, which will accelerate the pace of discovery. "Research to unravel the intricate genetic architecture of neurodegenerative diseases is resulting in significant advances in scientific understanding," said Bryan J. Traynor, M.D., Ph.D., senior investigator at NIA. "With each discovery, we shed light on the mechanisms behind neuronal cell death or dysfunction, paving the way for precision medicine to combat these debilitating and fatal disorders." Researchers expect that the dataset will continue to grow as additional data are analyzed. This work was supported in part by the Intramural Research Program at NINDS and NIA.

10 physician-scientists have been selected for drug development grant to advance discoveries into the clinic CLEVELAND, April 26, 2023 /PRNewswire/ -- Harrington Discovery Institute at University Hospitals in Cleveland, Ohio, today announced the 2023 class of Harrington Scholar-Innovators. The scholar awards will support a diverse set of projects including new breakthrough treatments for autoimmune disorders, cancer, heart failure, kidney disease, and severe forms of epilepsy. Harrington Discovery Institute was established in 2012 to accelerate the development of new treatments to address major unmet needs in medicine and society. Harrington Scholar-Innovators are accomplished physician-scientists whose research demonstrates innovation, creativity and potential for clinical impact. In addition to grant funding, Harrington provides guidance and oversight in drug development, while intellectual property is retained by the scholar and their institution. Since its founding, Harrington Discovery Institute has supported 165 drugs-in-the-making, 65 institutions, 36 company launches, 19 clinical candidates, and 13 licenses to pharma. "Now in our second decade, we continue to be inspired by the brilliant science demonstrated in academic labs across the U.S. and Canada. It is an honor to support these extraordinary physician-scientists and their novel medicines-in-the-making that have the potential to significantly improve human health," said Jonathan S. Stamler, MD, President, Harrington Discovery Institute, Robert S. and Sylvia K. Reitman Family Foundation Distinguished Professor of Cardiovascular Innovation and Professor of Medicine and of Biochemistry at University Hospitals and Case Western Reserve University. In addition to grant funding and tailored drug development guidance, Harrington Scholar-Innovators have the opportunity to access acceleration funds up to $300,000 and to qualify for mission-related investment funds typically up to $2 million. Scholars also have facilitated access to Harrington's mission-aligned commercial entities, the Advent-Harrington Impact Fund and BioMotiv, and to its charitable partner Morgan Stanley GIFT Cures. The 2023 Harrington Scholar-Innovator Award recipients, their organizations and fields of research are: Kirk Campbell, MD – Icahn School of Medicine at Mount Sinai Novel therapeutics for proteinuric kidney disease Jacques Galipeau, MD – University of Wisconsin, Madison Curative treatment for type 1 diabetes Won Jin Ho, MD – Johns Hopkins University Novel treatment to enhance antitumor immunity Maximillian Konig, MD – Johns Hopkins University T-cell therapies for antiphospholipid syndrome, a rare autoimmune disorder Berge Minassian, MD – UT Southwestern New therapy for the fatal teenage-onset epilepsy, Lafora disease Michael Pacold, MD, PhD – New York University A drug for pancreatic cancer Anthony Rosenzweig, MD – University of Michigan Nucleic acid therapy for heart failure Jeffrey Schelling, MD – Case Western Reserve University Novel drug to treat diabetic kidney disease Ming-Ru Wu, MD, PhD – Dana-Farber Cancer Institute Treating melanoma via the body's own immune system Timothy Yu, MD, PhD – Boston Children's Hospital Personalized therapies for epileptic encephalopathies Harrington Discovery Institute is now accepting Letters of Intent for the 2024 Harrington Scholar-Innovator Award. The deadline to submit a brief Letter of Intent is June 5, 2023. The full application deadline, for those invited to submit, is August 7, 2023. Learn more and apply to the 2024 Scholar-Innovator Award at HarringtonDiscovery.org/Scholar-Innovators. SOURCE Harrington Discovery Institute

Additional Phase 1 Data with CST-2032/CST-107 Reinforce Potential of Adrenoceptor Agonist Class of Drugs in Patients with Cognitive Impairment GOTHENBURG, Sweden--(BUSINESS WIRE)-- CuraSen Therapeutics, Inc., a clinical-stage company developing small molecule drugs to treat neurodegenerative symptoms and disease progression, announced that it will present Phase 2 clinical data showing improvements in cognition and mood in Parkinson’s disease patients treated with CST-103/CST-107, a novel combination therapy that restores adrenergic stimulus to the brain. Additionally, the company will present promising Phase 1 data with a second program, CST-2032/CST-107, in healthy participants and patients with mild cognitive impairment (MCI). Data will be shared in two oral presentations at the International Alzheimer’s Disease and Parkinson’s Disease (AD/PD’23) conference, being held March 28 - April 1, 2023, in Gothenburg, Sweden. Presentation details are below. CST-103, also known as clenbuterol, and CST-2032 are oral, brain-permeant, beta2 adrenoceptor (β2-AR) agonists, and CST-107, known as nadolol, is a brain-sparing β-AR blocker. In these studies, clenbuterol and CST-2032 are co-administered with nadolol to minimize known peripheral cardiometabolic side effects of β2-AR agonists. The company is developing fixed-dose combinations for both drugs. “For the first time, we have been able to show improved outcomes in cognition and mood with adrenergic agonism in patients with neurodegenerative disease, by safely restoring a stimulus to the brain that is lost early in the pathologic process. With its strong safety pro impressive effect sizes in key domains, we look forward to testing this fast-acting combination treatment in a longer-term study in Parkinson’s patients later this year,” said Anthony Ford, PhD, chief executive officer, CuraSen Therapeutics. “These data, coupled with promising Phase 1 results from our second program, CST-2032/nadolol, validate our novel approach to providing meaningful treatment options to neurodegenerative patients with high unmet needs.” Clenbuterol is an established drug that has been used in pulmonology for decades, while CST-2032 was discovered and developed at CuraSen, with properties providing the ability to differentiate and de-risk the two products in distinct neurodegenerative patient populations and outcome measures. Phase 2 Proof-of-Concept Study with Clenbuterol/Nadolol in Parkinson’s Disease Parkinson’s disease is a progressive, neurodegenerative disease that is associated with slow movement, tremor, rigidity and imbalance, as well as non-motor complications such as cognitive impairment, depression, pain, dysautonomia and sleep disorders. The Phase 2 trial was an exploratory, randomized, double-blinded, crossover study in 25 patients with Parkinson’s disease with cognitive deficits. An additional 13 patients were enrolled with mild cognitive impairment without a PD diagnosis. Patients received either the once-daily clenbuterol (80 µg)/nadolol (1 mg) combination treatment or matched placebo, with 14 days treatment on each period and at least 14 days of washout between periods. All PD subjects had impaired cognition at baseline with evidence of impaired cerebral noradrenergic signaling, as assessed by neuromelanin MRI of the locus coeruleus. The study took place at sites in the UK, Australia, New Zealand and Belgium. Results in PD patients showed: Statistically significant improvements in several quantitative test measures of episodic memory, attentiveness and depressive emotional bias in patients treated with clenbuterol/nadolol, with several effect sizes (Cohen’s d) in the range 0.3-0.6 which are predictive of clinically meaningful results in a larger, longer trial Rapid onset of drug effect - improvements observed as early as one day after treatment and in some cases, persisting beyond the two weeks of daily treatment No serious or severe adverse events attributed to study drug; most adverse events observed were mild CuraSen’s next Phase 2 study with clenbuterol/nadolol is anticipated later this year and will enroll Parkinson’s patients with significant non-motor symptoms with a similar combination dosing plan in a 12-week parallel design. Phase 1 Study with CST-2032/Nadolol in Mild Cognitive Impairment (MCI) The Phase 1 study with CST-2032/nadolol included 79 healthy volunteers and patients with MCI. The study involved single-ascending and multiple-ascending dose cohorts. Results showed that treatment with CST-2032/nadolol: Was safe and well tolerated Increased cerebral blood flow, a biomarker for target engagement, in brain regions involved in memory, alertness and arousal Led to performance changes in cognitive tasks associated with memory Offered clear guidance on optimal combination dose levels of each substance for Phase 2 assessment Based on the strength of these data, CuraSen has initiated a Phase 2a exploratory, randomized, placebo-controlled, double-blinded crossover study with CST-2032/CST-107 in up to 60 patients with MCI or mild dementia due to either Alzheimer’s or Parkinson’s disease. The trial is taking place at 20 centers in the U.S. and New Zealand, with results anticipated later in 2023. Oral Presentation Details Abstract #: 368 Title: “Effects of a Beta-2 Adrenoceptor Agonist on Cognition in Parkinson’s Disease Patients with REM Sleep Behavior Disorder” Date/Time: Sat, April 1, 3:15-3:30 pm CET; 9:15 am-9:30 am ET Session: #4450 - Advances in PD and LBD Diagnosis and Drug Development Presenter: Gabriel Vargas, MD, PhD, chief medical officer, CuraSen Therapeutics Abstract #: 338 Title: "A Phase 1 Safety, Pharmacokinetics and Pharmacodynamic Study of CST-2032: A Novel, Selective, CNS Penetrating Beta-2 Adrenoceptor Agonist for the Treatment of Cognitive Impairment” Date/Time: Sat, April 1, 6:25-6:40 pm CET; 12:25-12:40 pm ET Session: #4540 - SOC Drugs and Other Targeted Therapies in AD Presenter: Professor Thomas Lodeweyckx, MD, KU Leuven, Belgium About CuraSen Therapeutics CuraSen is developing novel treatments for neurodegenerative diseases, including Parkinson’s disease, Alzheimer’s disease and other related orphan conditions. CuraSen’s drugs are designed to activate certain receptor populations in the brain to compensate for critical neuronal and glial functions that have otherwise been lost early in degeneration and represent a unique approach in the field, addressing core symptoms and the progression of pathology. The company is evaluating CST-103 and CST-2032, both selective β2-ARs agonists, in combination with CST-107, a β-AR blocker, in multiple Phase 2 clinical studies. For more information, please visit .