Safety Study of Subthalamic Nucleus Gene Therapy for Parkinson's Disease
Safety Study of Subthalamic Nucleus Gene Therapy for Parkinson's Disease
The purpose of this study is to determine the safety of using a modified virus to transfer a
 gene called GAD into a region of the brain called the subthalamic nucleus in patients with
 advanced Parkinson's disease. The overall goal of this approach is to ultimately normalize
 the flow of information in several brain regions responsible for movement, to ultimately
 improve function in patients with this disorder. The current study is primarily designed to
 evaluate the safety of this approach, but patients are also being monitored for possible
 signs of effectiveness as well.
This study involves treatment of patients with medically refractory Parkinson's disease (PD)
 with gene therapy. The patients are chosen from a population of patients who would normally
 be candidates for standard deep brain stimulation (DBS) surgery for PD. These patients
 respond to medical therapy, but develop substantially reduced responses over time, often with
 severe fluctuations in their condition between a functional and severely non-functional
 state. Some patients also develop dose-limiting side effects from medication, including
 involuntary movements called dyskinesias and nightmares. When there are no medical
 contraindications, DBS is often performed in these patients to try to quiet hyperactive brain
 regions such as the subthalamic nucleus (STN). In PD, the STN is overactive due to a loss of
 GABA inputs to this region, which normally reduces neuronal firing. In turn, the STN drives
 other brain regions, including the globus pallidus (GPi) and substantia nigra (SNr), which
 are also hyperactive and which also have reduced GABA inputs. The goal of this gene therapy
 trial is to introduce the gene for glutamic acid decarboxylase (GAD) into the STN using an
 adeno-associated virus (AAV) vector, in order to permit the STN to produce it's own GABA, as
 well as release GABA into the GPi and SNr targets, which also have reduced GABA inputs. This
 is anticipated to restore a more normal pattern of information flow from this basal ganglia
 circuit to the thalamus and higher cortical structures in order to reduce the motor symptoms
 of PD, while eliminating complications arising from inserting DBS electrodes and batteries
 into the human body.
Inclusion Criteria:

 -  Duration of disease: Greater than 5 years

 -  Idiopathic Parkinson's disease

 -  Parkinson's medication stable for 3 months

 -  Absence of dementia

 -  Hoehn and Yahr rating: 3 or greater and/or UPDRS: 30 or more in "off" state and/or
 Complications of l-dopa therapy limiting effective use

 Exclusion Criteria:

 -  Poor candidate for any surgery

 -  Significant dementia

 -  Secondary parkinsonism

 -  Severe autonomic symptoms

 -  Atypical Parkinson's disease

 -  History of substance abuse