Th170 - Longitudinal Analysis of Immune Cell Changes in FUS-ALS Patients Treated with a FUS Antisense Oligonucleotide

Samuel Levy – Columbia University; Ryan Talcoff – Columbia University; Maedot Yidenk – Columbia University; Neil Shneider – Columbia University; Wassim Elyaman – Columbia University

Abstract Text: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with significant genetic, pathological, and clinical heterogeneity. Individuals with a mutation in the fused in sarcoma (FUS) gene experience one of the most aggressive and early-onset forms of ALS (FUS-ALS), as well as mislocalization and aggregation of FUS protein. To test the therapeutic potential of FUS knockdown, our previous work generated a knock-in FUS-ALS mouse model exhibiting denervation of neuromuscular junctions and glial activation followed by motor neuron death, features which were reduced with a single injection of FUS antisense oligonucleotide (ASO) at birth. Further, in a first-in-human trial, we showed that treatment with FUS ASO slowed the rate of functional decline as measured by the ALS Functional Rating Scale-Revised. Now, the efficacy of FUS ASO (i.e., jacifusen) is being tested further in an expanded access program in which paired blood and CSF samples are collected. Considering the role of the immune system in neuron function and survival, as well as the alterations to gliosis seen in our mouse model, this study sought to characterize immune cell changes in ASO-treated FUS-ALS participant blood and CSF. Analysis of single-cell RNA sequencing and TCR sequencing data revealed significant changes to immune cell frequencies and phenotypes, as well as altered clonal expansion and migration of clones between the blood and CSF, across treatment. These findings were validated further with methods such as flow cytometry and cytokine profiling, and provide important insight into immune-related functional consequences of FUS knockdown and their potential relationship with clinical outcomes.