Aromatic l-amino acid decarboxylase (AADC) deficiency is a rare, inherited disorder that appears in the first year of life. Children with the condition may have severe developmental delays, weak muscle tone, problems moving, and uncontrollable movements of the arms and legs. The disease is caused by a genetic defect in the AADC enzyme, which makes chemical messengers that are essential for the brain to work properly. People with the condition do not have enough AADC. The investigators are working on a drug that restores AADC in the brain, treating the symptoms of AADC deficiency. This project’s aim is to further develop and manufacture the drug so that it can be tested in human clinical trials.
The purpose of this project is to manufacture Good Manufacturing Practice (GMP)-grade AAV2-AADC for use in a clinical trial of AADC gene therapy to ameliorate the symptoms of AADC deficiency, a rare genetic disorder in which the AADC enzyme is inactive due to structural mutations in the gene. We have previously shown that AAV2-AADC, when delivered into the putamen of patients with Parkinson’s disease, restores effective levels of the enzyme and enhances dopaminergic function. The investigators plan to use the same strategy to restore AADC function in children with AADC deficiency. The clinical study will take place at NIH Clinical Center. Accordingly, the goal of this BrIDGs project is to manufacture sufficient AAV2-AADC under GMP conditions to initiate the study.
University of California, San Francisco
Krzysztof Bankiewicz, M.D., Ph.D.
Public Health Impact
The proposed gene therapy for AADC deficiency disease, if successful, should lessen many of its central neurological symptoms. The use of a new, advanced targeting and delivery technology also may be applicable to a number of other neurological disorders that would benefit from neurosurgical delivery of therapeutic agents.
Work on this project is complete. The investigators successfully filed an Investigational New Drug (IND) application using BrIDGs data.
- Synthesis of GMP material
- Formulation development
- Pharmacokinetic/absorption, distribution, metabolism, and excretion (PK/ADME) studies
- IND-directed toxicology