Gene Therapy for Parkinson's Disease: The Next Generation of Therapy?

Abstract & Commentary

By Claire Henchcliffe, MD, DPhil, Assistant Professor, Department of Neurology, Weill Medical College, Cornell University. Dr. Henchcliffe reports no financial relationship to this field of study.

Synopsis: This is the first ever published phase I clinical trial testing gene therapy in Parkinson's disease( PD). Unilateral introduction of AAV-GAD into the subthalamic nucleus of advanced PD patients was safe and well tolerated up to ≥ 1 year.

Source: Kaplitt MG, et al. Lancet. 2007;369:2097-2105.

This phase I open label safety and tolerability trial enrolled 12 patients with idiopathic Parkinson's disease (PD), for infusion of the human glutamic acid decarboxylase gene (GAD), in an adeno-associated virus (AAV) vector, into the subthalamic nucleus (STN). All subjects had disease of at least 5 years' duration, with motor complications of levodopa therapy. Inclusion criteria were Unified Parkinson Disease Rating Scale (UPDRS) motor score of ≥ 30, and Hoehn and Yahr score ≥ 3 (ie, bilateral symptoms with postural instability) off medication, and absence of significant medical or psychiatric illness. Eleven men and 1 woman aged 51-63 years (mean 58.2 ± 5.7 years) entered the study. Disease duration ranged from 6-13 years, and baseline levodopa equivalents ranged from 250-2300 mg daily. Subjects underwent surgical infusion of low, medium, or high dose AAV-GAD into the STN contralateral to the most impaired side of the body. All patients were discharged home after 2 days, and post-operative MRI revealed no hemorrhage or edema at the infusion site. By 12 months, no adverse events were recorded that were judged related to the gene therapy. There were no deaths, no new neurological deficits, and neuropsychological test results did not change significantly. In the absence of significant changes in daily levodopa equivalents, motor UPDRS scores improved significantly both on and off medications, although there was no relationship to AAV-GAD dose. Improvements were sustained in 10/12 at 12 months (4/12 improved ≥40%). FDG-PET scans at 12 months demonstrated reduced thalamic metabolism in the operated hemisphere, and increased activity in the supplementary motor cortex of the implanted hemisphere, compared to baseline, and compared to the non-operated hemisphere. Titers of anti-AAV2 antibodies did not change significantly from baseline to 12 months, and presence of baseline high titers in 2 subjects did not predict lack of motor improvement.


This ground-breaking trial addresses one of many barriers to bringing gene therapy into the arena of human disease treatment, after promising animal studies. Concerns about potential and actual adverse effects have been well described, including the possibility of immune reaction, cell transformation, and infection. Although preliminary, this careful study convincingly demonstrates safety and tolerability of subthalamic AAV-GAD infusion in a small group of advanced PD patients followed for at least one year. Obviously, longer term data are needed, and Kaplitt and colleagues note at the time of publication that safety and tolerability is sustained in 3 subjects followed ≥ 3 years, and 4 subjects followed for 2-3 years. The rationale behind their innovative choice of gene and tissue target, although oversimplified, is to modulate aberrant excitatory glutamatergic output in PD (that ultimately reduces motor output signaling), by introducing the GAD enzyme to allow production of GABA. The net effect is to convert STN output to an inhibitory signal. Indeed, in a rodent model of PD, AAV-GAD therapy improved motor performance, with increased GABA levels measured in the substantia nigra pars reticulata, a site of STN projection. It is difficult to know how to interpret improvements in motor function observed, and this study, like others in PD, is hampered by lack of established surrogate disease markers. The authors are appropriately cautious, given large placebo effects in prior surgical PD studies. Improvements in bilateral UPDRS scores, as well as improved "best on" scores require further explanation. However, it is encouraging that FDG-PET scans demonstrate region-specific alterations in thalamocortical motor pathway metabolism, as reported after DBS surgery. Other gene therapy trials are currently in progress, investigating the use of neurotrophic factor neurturin (CERE-120) and aromatic amino acid decarboxylase genes in PD. The present study provides an important basis upon which to build experience and further testing of this innovative therapeutic approach.