U01NS134684

Silence ALS: A platform for the discovery and development of antisense therapeutics for patients with ultra-rare forms of ALS - ALS is a progressive neurodegenerative disease that affects tens of thousands of Americans. Therapeutic options for ALS patients remain severely limited, but for the ~15% of ALS patients with a disease-causing mutation, gene-based therapeutics, including antisense oligonucleotides (ASOs), provide a direct means to engineer a product that specifically targets the molecular mechanism underlying a patient’s ALS and are therefore an important enabling technology for the advancement of individualized therapies.

The ability to target the disease gene or its encoded messenger RNAs (mRNAs) has opened new opportunities for therapy development. Industry-sponsored efforts focused on ALS caused by mutations in C9ORF72, SOD1 and FUS offer hope to ALS patients and families with these relatively common, genetic forms of the disease. Silence ALS is a partnership between Columbia University and the N-LOREM Foundation that aims to extend these gene-based therapeutic strategies to ALS patients with ultra-rare mutations, expanding access to this powerful technology through a non-profit, precision medicine approach.

With support from the NINDS Urgent Network, this initiative will focus on genetic mutations that cause ALS through a dominant mechanism amenable to ASO therapy. In a trailblazing project, Silence ALS will focus on ALS patients with rare pathogenic mutations in TARDBP, with the aim of developing a series of individualized, allele-specific ASOs targeting the mutated TDP-43 transcript. This effort builds on the first successful Silence ALS program that led to first-in-human (FIH) dosing of an ALS patient with an allele-specific TARDBP ASO in October 2022.

A second project of this urgent proposal will focus on the development of a non-allele-specific ASO targeting ultra-rare mutations in CHCHD10 associated with ALS and frontotemporal dementia (FTD). Additional projects will target mutations in other ALS genes, including KIF5A, PFN1 and ANXA11. Silence ALS will take advantage of the robust clinical and research infrastructure of the Columbia University ALS Center and the optimized ASO discovery and development platform at N-LOREM.

Our program will include patient identification and clinical characterization, continuing through ASO design and screening, in vitro and in vivo testing, and GLP toxicity studies of lead candidates mandated by current FDA guidelines. In total, we expect to develop nine different ASOs targeting diverse genes and haplotypes in ultra-rare forms of ALS, through IND submission and readiness for the FIH trials.

In future efforts, Silence ALS aims to follow asymptomatic carriers of ultra-rare ALS mutations and to prepare personalized ASO therapeutics for individuals at risk. Silence ALS is the first initiative of its kind, bringing a disease focus to the broader, non-profit, ASO development platform of N-LOREM. Through this urgent proposal, we aim is to create a paradigm for other ultra-rare disease communities to follow, bringing together academic, non-profit and public stakeholders to develop antisense therapeutics for an underserved patient population, while creating knowledge, experience and efficiencies that will inform our understanding and approach across diseases and treatment modalities.

The Trustees Of Columbia University In The City Of New York

(1) TO SUPPORT EXTRAMURAL RESEARCH FUNDED BY THE NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE (NINDS) INCLUDING: BASIC RESEARCH THAT EXPLORES THE FUNDAMENTAL STRUCTURE AND FUNCTION OF THE BRAIN AND THE NERVOUS SYSTEM, RESEARCH TO UNDERSTAND THE CAUSES AND ORIGINS OF PATHOLOGICAL CONDITIONS OF THE NERVOUS SYSTEM WITH THE GOAL OF PREVENTING THESE DISORDERS, RESEARCH ON THE NATURAL COURSE OF NEUROLOGICAL DISORDERS, IMPROVED METHODS OF DISEASE PREVENTION, NEW METHODS OF DIAGNOSIS AND TREATMENT, DRUG DEVELOPMENT, DEVELOPMENT OF NEURAL DEVICES, CLINICAL TRIALS, AND RESEARCH TRAINING IN BASIC, TRANSLATIONAL AND CLINICAL NEUROSCIENCE. THE INSTITUTE IS THE LARGEST FUNDER OF BASIC NEUROSCIENCE IN THE US AND SUPPORTS RESEARCH ON TOPICS INCLUDING BUT NOT LIMITED TO: DEVELOPMENT OF THE NERVOUS SYSTEM, INCLUDING NEUROGENESIS AND PROGENITOR CELL BIOLOGY, SIGNAL TRANSDUCTION IN DEVELOPMENT AND PLASTICITY, AND PROGRAMMED CELL DEATH, SYNAPSE FORMATION, FUNCTION, AND PLASTICITY, LEARNING AND MEMORY, CHANNELS, TRANSPORTERS, AND PUMPS, CIRCUIT FORMATION AND MODULATION, BEHAVIORAL AND COGNITIVE NEUROSCIENCE, SENSORIMOTOR LEARNING, INTEGRATION AND EXECUTIVE FUNCTION, NEUROENDOCRINE SYSTEMS, SLEEP AND CIRCADIAN RHYTHMS, AND SENSORY AND MOTOR SYSTEMS. IN ADDITION, THE INSTITUTE SUPPORTS BASIC, TRANSLATIONAL AND CLINICAL STUDIES ON A NUMBER OF DISORDERS OF THE NERVOUS SYSTEM INCLUDING (BUT NOT LIMITED TO): STROKE, TRAUMATIC INJURY TO THE BRAIN, SPINAL CORD AND PERIPHERAL NERVOUS SYSTEM, NEURODEGENERATIVE DISORDERS, MOVEMENT DISORDERS, BRAIN TUMORS, CONVULSIVE DISORDERS, INFECTIOUS DISORDERS OF THE BRAIN AND NERVOUS SYSTEM, IMMUNE DISORDERS OF THE BRAIN AND NERVOUS SYSTEM, INCLUDING MULTIPLE SCLEROSIS, DISORDERS RELATED TO SLEEP, AND PAIN. PROGRAMMATIC AREAS, WHICH ARE PRIMARILY SUPPORTED BY THE DIVISION OF NEUROSCIENCE, ARE ALSO SUPPORTED BY THE DIVISION OF EXTRAMURAL ACTIVITIES, THE DIVISION OF TRANSLATIONAL RESEARCH, THE DIVISION OF CLINICAL RESEARCH, THE OFFICE OF TRAINING AND WORKFORCE DEVELOPMENT, THE OFFICE OF PROGRAMS TO ENHANCE NEUROSCIENCE WORKFORCE DEVELOPMENT, AND THE OFFICE OF INTERNATIONAL ACTIVITIES. (2) TO EXPAND AND IMPROVE THE SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. TO UTILIZE THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM, TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.853 - Extramural Research Programs in the Neurosciences and Neurological Disorders

National Institute of Neurological Disorders and Stroke (NNDS) [HHS - NIH]

New York, New York 100323725 United States

Single Zip Code

Translational Efforts to Advance Gene-based Therapies for Ultra-Rare Neurological and Neuromuscular Disorders (U01 - Clinical Trial Optional) (PAR-22-030)

Amendment Since initial award the total obligations have increased 90% from $5,159,965 to $9,796,602.