A Phase I/II Open-label Intrathecal Administration of MELPIDA to Determine the Safety and Efficacy for Patients with Spastic Paraplegia Type 50 (SPG50) caused by a Mutation in the AP4M1 gene.

AAV9-based AP4M1 gene therapy has promise to treat SPG50 disease, but as with any other new modality, it has some development challenges. Preclinical safety studies in mice, rats, and NHPs demonstrate a favorable safety profile of MELPIDA, at up to twice the proposed human dose of 1E15 vg (doses extrapolated across species by CSF volume, Table 2). Pharmacology studies in the AP4M1 KO mouse model demonstrated a dose-dependent benefit of MELPIDA, with the greatest benefit seen at a dose of 5E11 vg in mice (scaled to approximately 1E15 to 2E15 vg in humans by CSF volume). Importantly, the safety concerns noted in the toxicology studies are balanced against the severe unmet medical need of this patient population and the potential benefit of intrathecal administration of MELPIDA.