Safety Study of Subthalamic Nucleus Gene Therapy for Parkinson's Disease

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Phase I Study of Subthalamic GAD Gene Transfer in Medically Refractory Parkinson's Disease Patients

Conditions
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Parkinson's Disease

Intervention / Treatment
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* Genetic: Surgical infusion of AAV-GAD into the subthalamic nucleus


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 25 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Intervention/Treatment |
| --- |
|Genetic: Surgical infusion of AAV-GAD into the subthalamic nucleus|nan|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety |  |  | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Improvement in brain metabolism measured by PET scans |  |  | 
| Improvement in standard clinical rating scales |  |  | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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AAV, Parkinson's disease, GABA, Subthalamic nucleus, Adeno-associated virus, Gene therapy