Thursday, April 25, 2024
4/25/2024
PROJECT SUMMARY Amyotrophic lateral sclerosis (ALS) is a rapidly progressive, paralytic, and ultimately fatal disease that can be caused by gain-of-function mutations in superoxide dismutase 1 (SOD1). Despite its severity, there remains no cure for ALS and current therapies provide only modest benefit to patients, underscoring the critical need for new, effective strategies for treating the disease. We have developed an approach to inactivate the production of the mutant SOD1 protein in vivo using CRISPR base editing, a gene-editing modality capable of introducing precise single-base substitutions in DNA, but without the requirement for a mutagenic DNA break, thus overcoming a major safety hurdle facing the implementation of traditional CRISPR nucleases. Through the support of the CREATE Bio Optimization Track, we have undertaken a milestone-driven research plan that has enabled us to refine not only the editing capabilities but also the specificity of our SOD1-targeting CRISPR base-editing platform. As a next step in this project, we will define the properties of our lead SOD1-targeting platform in cynomolgus macaques, a non-human primate (NHP) model that shares more anatomical, physiological, and immunological similarities with humans than most laboratory animals. However, a worsening shortage of NHPs, alongside increases in their demand for research, has resulted in unanticipated and hefty cost increases for an already limited domestic supply. To this end, this Administrative Supplement will contribute to the acquisition of two adult cynomolgus macaques, their intrathecal dosing with an adeno-associated virus (AAV) vector formulation encoding our CRISPR base-editing platform, their housing, and the isolation of nervous system tissue and peripheral tissues. This Supplement will thus ensure that our study carries sufficient statistical power to most accurately quantify the effects for our therapeutic agent and as such is critical to the completion of the milestones for the project, “Optimization of an in vivo base editing strategy to treat SOD1-linked ALS” (5U01NS122102). In sum, by providing us with the statistical power to most accurately quantify the efficacy, tolerability, and immunological responses of our novel CRISPR gene therapy in the nervous system of a NHP, this Administrative Supplement will ensure that our project exerts a maximum impact on its field and the field of gene therapy at large.
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