Phase I Study of AAV2-hAADC Administered by MRI-guided Real-time Convective Infusion

Objective/Rationale:
The purpose of this study is to provide safety data related to enhancements in the clinical delivery procedure for administering Adeno-Associated Virus Encoding Human Aromatic L-Amino Acid Decarboxylase (AAV2-hAADC) gene therapy in Parkinson’s disease (PD) patients. A previous clinical study investigated low and moderate doses of AADC gene therapy. Safety end points were achieved and modest signs of clinical efficacy were observed, however, imaging data revealed that AADC gene transfer only covered 25 percent of the target structure in the brain. Development of an image-guided brain delivery platform enables delivery of higher vector doses and substantially increased coverage of target structures.

Project Description:
A Phase I safety study will be conducted in PD patients using real-time image-guided delivery to administer a moderate or high dose of AADC gene therapy. An initial cohort of five subjects will receive a gene therapy dose equal to the high dose in the previous clinical study. A second cohort of five subjects will receive a higher dose. For all subjects, the administration of AADC gene therapy will be performed with real-time MRI imaging to monitor and optimize delivery to the dopamine-depleted putamen. Patients will be evaluated for any adverse events and signs of clinical efficacy. A specialized clinical assessment will be performed to assess any change in responsiveness to levodopa administration after AADC gene therapy.

Relevance to Diagnosis/Treatment of Parkinson’s Disease:
In Parkinson’s disease, the progressive loss of dopamine-producing neurons in the substantia nigra leads to symptoms including tremor, bradykinesia, rigidity and postural instability. These symptoms arise due to loss of the enzyme AADC as the dopamine neurons die off, resulting in a reduction in the conversion of levodopa into dopamine. Gene therapy to replace AADC should provide significant clinical benefit to Parkinson’s disease patients by potentially reducing the required levodopa dose level and dyskinesias associated with high levodopa administration.

Anticipated Outcome:
Administration of AADC gene therapy via the enhanced real-time MRI-guided delivery platform is anticipated to increase the potential effectiveness of the treatment while maintaining the safety profile established in the prior clinical study. Successful completion of this Phase I bridging study is expected to enable a multi-center, randomized, sham surgery-controlled Phase II safety and efficacy trial in PD patients.