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.