Establishing a genetic diagnosis system for the era of gene therapy

Abstract

Amyotrophic lateral sclerosis (ALS) is a refractory neurological disease that predominantly affects individuals in middle age or later, causing progressive motor neuron degeneration. Currently, riluzole, edaravone, and intramuscular injection of mecobalamin are the only disease–modifying treatments. Approximately 5–10% of ALS cases are familial, and over 30 related genes have been identified. In 2023, tofersen, an antisense oligonucleotide (ASO) therapy for SOD1–ALS, received accelerated approval in the US and obtained Japanese approval in December 2024. Gene therapy is now a practical option, marking a major shift in treatment approaches. ASO targets include SOD1 (around 30% of Japanese familial cases) ; the RNA–binding proteins FUS and TARDBP ; and the C9orf72 gene with hexanucleotide repeat expansion, which is common in Europe and the US. To actively facilitate gene therapy research and clinical trials in Japan, we have collaborated with five domestic institutions to establish and launch the Japan Familial ALS Trial–ready registry (J–FAST). The registry's purpose is to systematically identify and characterize patients eligible for gene therapy trials, and to provide a platform for evaluating new interventions. Targeting familial ALS and sporadic cases with onset under age 40, we screen for SOD1, FUS, TARDBP, and C9orf72, adding exome or whole–genome sequencing when needed. We also record the natural history of each case to confirm their clinical details. Ongoing registry enrollment will identify clinical trial candidates and gather data to assess the efficacy of new treatments. We will validate biological samples to explore surrogate pathogenic markers. This will enable earlier intervention and help turn the registry into a key resource for ALS clinical practice and new therapies.