Pre-clinical testing of a novel gene therapy for pediatric neurodegenerative disease

PROJECT SUMMARY A significant number of pediatric neuromuscular and neurodegenerative conditions are caused by recessive gene mutations resulting in loss of both maternal and paternal copies of a gene. These genes may encode for proteins that play critical roles in cell differentiation, cell survival, and/or cell function(s). Current medical

management strategies attempt to delay disease progression or minimize symptoms of these conditions, yet they do not address the underlying genetic deficiency. Gene replacement therapy is a treatment approach that provides back to cells a functional copy of a gene, thereby overcoming the deficiency caused by genetic

mutations and permanently rescuing cell differentiation, survival, and/or function to a degree that the disease is halted or prevented entirely. This approach utilizes an AAV9 virus to deliver functional copies of a gene to cells of interest based, in part, on how the therapy is administered. Gene therapies have potential to revolutionize

treatment of pediatric diseases, as was demonstrated recently by the FDA approval of a gene therapy for spinal muscular atrophy. As part of this study, we are testing a novel gene therapy for childhood-onset striatonigral degeneration, a severe progressive neurologic disease caused by recessive mutations in the VAC14 gene.

Patients with this condition develop signs of neurodegeneration in the first half-decade of life that progresses rapidly and results in severe neurologic and neuromuscular deficit that is not responsive to current medical treatments. To study this further, we engineered the first viable pre-clinical mouse model of this condition (termed

Vac14ducky). Vac14ducky mice develop neurologic disease associated with accumulation of vacuoles within the brain cortex, spinal cord, and dorsal root ganglia. The vacuolization observed in Vac14ducky mice is similar to vacuole formation previously demonstrated in patient-derived fibroblasts. We developed a novel gene therapy

product (AAV9-hVAC14opt) expressing the human VAC14 gene transcript, and using our novel Vac14ducky mice, we performed preliminary in vivo efficacy and toxicology evaluations. Following a single intrathecal injection at 7 days of age, our results thus far demonstrate that AAV9-hVAC14opt successfully rescues overall health and

motor function in adult Vac14ducky mice. Additionally when treating control mice, AAV9-hVAC14opt showed no detectable toxicities. These preliminary results suggest AAV9-hVAC14opt is a potential novel gene therapy for the pediatric VAC14-associated neurodegenerative disease. The study proposed here will test a dose-response

that is required for an IND application. Aim 1 determines the minimal effective dose of AAV9-hVAC14opt needed to provide therapeutic benefit in Vac14ducky mice as well as in the more severe mouse line Vac14ingls. Aim 2 tests the post-symptomatic treatment efficacy utilizing Vac14ducky mice as well as Vac14ingls mice. The complementary

Aims of this proposal will provide critical evidence demonstrating AAV9-hVAC14opt as a novel gene therapy for this severe pediatric condition. At the completion of this study, we will be prepared to proceed toward an IND application for eventual testing in patients.