Spinocerebellar ataxia type 1 (SCA1) is one of nine polyglutamine expansion diseases and is characterized by cerebellar ataxia and neuronal degeneration in the cerebellum and brainstem. Currently, there are no effective treatment strategies for this disease. Previously, we showed that RNA interference (RNAi)-mediated silencing of ataxin-1 mRNA provides therapeutic benefit in mouse models of SCA1. Adeno-associated viral (AAV) delivery of an engineered microRNA (miRNA) targeting ataxin-1 to the cerebellum of well-established SCA1 transgenic mouse models improved motor phenotypes, neuropathology, and transcriptional changes. We now propose to move our lead vector forward by completing a series of milestones that will lead us to a Phase 1 clinical trial in human subjects. In the UH2 phase of this application we will 1) perform comparability testing of the proposed vector in nonhuman primates to confirm our proposed dosing regimen, and 2) hold a Pre-IND Type B meeting with the CBER of the FDA to receive input on the design of the planned GLP tox study and the proposed Phase 1 protocol. In the UH3 phase of this application we will 1) produce GMP- process comparable vector (GLP vector), 2) perform the planned GLP pharm/tox study in nonhuman primates and rodents, 3) produce GMP-grade vector, 4) prepare and file the IND with the FDA, and 5) perform a phase I/II clinical trial in SCA1 subjects.
Spinocerebellar ataxia type I (SCA1) is a fatal, dominantly inherited neurodegenerative disease that affects the cerebellum, with no available disease-modifying therapies. We have developed vectors that correct disease readouts when delivered to mouse models of the disease, through a delivery approach that we show also works in nonhuman primates. In this milestone-driven application, we will move from our final preclinical studies to IND enabling toxicology studies to a phase 1 safety trial.
|Keiser, Megan S; Monteys, Alejandro Mas; Corbau, Romuald et al. (2016) RNAi prevents and reverses phenotypes induced by mutant human ataxin-1. Ann Neurol 80:754-765|