Kaplitt MG et al. (2007) Safety and tolerability of gene therapy with an adeno-associated virus (AAV) borne GAD gene for Parkinson's disease: an open label, phase I trial. Lancet 369: 2097–2105

The increase in subthalamic nucleus activity seen in Parkinson's disease (PD) is largely attributable to a reduction in inhibitory gamma-aminobutyric (GABA)ergic input. In a phase I trial, Kaplitt et al. examined the safety and tolerability of transferring the gene encoding glutamic acid decarboxylase (GAD)—the enzyme responsible for the synthesis of GABA—into the subthalamic nucleus of patients with PD by use of an adeno-associated virus (AAV) vector.

The study involved 12 patients (mean age 58.2 years) with Hoehn and Yahr stage 3 or greater PD, all of whom underwent unilateral subthalamic AAV–GAD gene therapy. Baseline assessments were conducted within a week of the intervention, and patients were reassessed at 1, 3, 6 and 12 months after therapy. During follow-up, none of the patients had any adverse events related to gene therapy. At 3 months, significant improvements relative to baseline were seen in Unified Parkinson's Disease Rating Scale motor scores for both the off and on states (P = 0.0015 and P = 0.01, respectively). These improvements were observed primarily on the side of the body contralateral to surgery and persisted up to 12 months. Furthermore, comparison of baseline and 12-month PET scans revealed a marked reduction in thalamic metabolism in the treated hemisphere.

Although not designed to test the efficacy of AAV–GAD gene therapy in PD, the results of this study are encouraging, and indicate that AAV-mediated gene transfer to the brain is safe and well-tolerated.