AAV-LRRK2 Gene Therapy IND-Enabling Study Design

SUMMARY

# AAV-LRRK2 Gene Therapy IND-Enabling Study Design ## Background and Rationale Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra, leading to motor dysfunction and eventual disability. Mutations in the LRRK2 gene are the most common genetic cause of familial PD, accounting for up to 40% of cases in certain populations. The G2019S mutation in LRRK2 results in increased kinase activity, leading to neuronal

METHODOLOGY NOTES

Phase 1: Manufacturing and analytical development (Months 1-6). Produce clinical-grade AAV-LRRK2 vector using established GMP protocols. Conduct comprehensive analytical characterization including vector genome titer, infectious unit determination, residual host cell protein analysis, and endotoxin testing. Develop and validate potency assays measuring LRRK2 knockdown efficiency in relevant cell lines. Phase 2: Pharmacology studies (Months 4-12). Conduct dose-ranging studies in non-human primates (n=24, 4 groups of 6) using stereotactic injection into substantia nigra. Test doses of 1×10^11, 5×10^11, 1×10^12, and 5×10^12 vector genomes. Assess LRRK2 protein reduction, dopaminergic neuron preservation, and motor function using standardized behavioral assessments at 1, 3, 6, and 12 months post-injection. Phase 3: Safety and toxicology (Months 6-18). Perform GLP toxicology studies in non-human primates (n=32) and rodents (n=64) with 6-month treatment and 6-month recovery periods. Monitor

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