GAD Gene Therapy for Parkinson’s Disease

Abstract

The ability to directly modulate intracellular processes through genetic manipulation has long been felt to have great potential for treating intractable neurological and psychiatric diseases. To date, the largest number of clinical trials of central nervous system gene therapy has been in patients with Parkinson’s disease (PD). Most of these have used adeno-associated virus (AAV) as a vehicle, which we demonstrated to be safe and effective for stable gene therapy in the brain more than 20 years ago. Here, we describe the development and results of the first human gene therapy for PD, which used AAV to transfer the gene for glutamic acid decarboxylase (GAD) into the subthalamic nucleus (STN). The STN is in the basal ganglia circuitry which is dysfunctional in PD, and human therapy for drug resistant PD has focused upon either lesioning or electrical stimulation of the STN for many years. In an initial open label pilot study, unilateral injection of AAV-STN into the STN of the more symptomatic hemisphere demonstrated safety and suggested evidence of efficacy based upon both motor improvements and reversal of functional imaging abnormalities up to 1 year. This led to a randomized, double-blind phase II clinical trial of bilateral AAV-GAD into the STN compared with patients receiving bilateral sham surgery. This confirmed the effectiveness of AAV-GAD, as the treated patients showed significantly greater improvements than the sham patients throughout both the 6-month blinded phase and full 12-month study phase, again with a very good safety profile. Functional imaging further supported these findings and identified a pattern of changes unique to the sham patients with improvement which was not seen in either the AAV-GAD patients or sham non-responders. These combined data support ongoing development of AAV-GAD as the only gene therapy in the CNS to date to demonstrate efficacy compared with contemporaneous sham controls and provide a stronger foundation for the further development of CNS gene therapy for a variety of disorders.