Smooth as SILK: Translating Discoveries to New Therapies in Amyotrophic Lateral Sclerosis

No effective therapies exist for the treatment of patients suffering from amyotrophic lateral sclerosis, a devastating neurodegenerative disease characterized by motor neuron loss, paralysis, and death on average 3 Р5 years after diagnosis. Although multiple promising candidates have emerged from preclinical experiments in disease models, failure rates of randomized control trials assessing efficacy in humans are over 95%, demonstrating a need to improve the translation of preclinical findings to human biology. In this dissertation, I present original work investigating amyotrophic lateral sclerosis caused by mutations in SOD1 (ALSSOD1) for the successful translation of SOD1-targeting strategies into meaningful treatment options for patients. Through a retrospective study of ALSSOD1 natural history, my research showed that the most common mutation causing ALSSOD1 in North America, Alanine\u3eValine (A4V), is rapidly progressing, while different mutations show a wide range of variability in clinical outcomes. I then describe initial characterization of SOD1 protein half-life in the cerebrospinal fluid (CSF) of ALSSOD1 patients. Similar to healthy control subjects, I found SOD1 is a long-lived protein in ALS patient CSF, with a half-life on the order of weeks. Moreover, A4V SOD1 mutant protein showed differential behavior compared to wild type SOD1 in CSF in one ALS participant, preliminarily suggesting that CSF SOD1 measures may implicate the pathogenic state of SOD1 protein. Finally, I show that measures of CSF SOD1 protein production serve as a pharmacodynamics biomarker for Antisense Oligonucleotides (ASOs) treatment targeting SOD1 mRNA transcripts in the central nervous system (CNS). Lowering of new SOD1 protein production after ASO treatment preceded lowering of total SOD1 protein concentration, suggesting measures of new protein production are more sensitive for mRNA-targeting therapies and are translatable to human trials to assay drug target engagement. Taken together, these data provide insights that contribute to a further understanding of ALS biology, in addition to the study design and interpretation of randomized control trials in ALS