The Problem With Current PD Therapy

As Parkinson's Disease progresses, patients taking initially respond very well to the drug. Over some years on this efficacious therapy, however, they need more and more of the drug in order to achieve the same clinical effect. Our hypothesis was that the enzyme that converts the precursor, L-dopa, into the active neurotransmitter, , was being depleted as the neurons that made the enzyme, , died off. The loss of this key enzyme makes it harder for the brain to make sufficient amounts of dopamine. The high doses of L-dopa needed by these patients begins to generate serious side effects as parts of the brain that have not lost so much AADC are over stimulated by the high doses of L-dopa.

Our Solution

Over 10 years ago, we began to explore whether replacement of sufficient AADC in those parts of the brain () that did not have enough AADC might normalize response to low doses of L-dopa. In order to do this, we turned to the then new field of gene therapy. By inserting the human AADC gene into a recombinant non-pathogenic virus called AAV (adeno-associated virus), we created AAV-hAADC and recruited a small biotechnology company, Avigen, to help develop this viral vector as a therapy for PD patients whose L-dopa responsiveness was failing. Animal studies showed that the AAV-hAADC vector was safe and effective, driving clinical improvement in Parkinsonian monkeys for over 8 years. This work culminated in a clinical trial now in progress at UCSF.

The concept of AAV-hAADC therapy is deceptively simple. Make a , inject it into the brain, and that's it. But, in order to make sure that the vector could be delivered to exactly the right part of the brain, we had to learn a huge amount about how AAV moves through brain tissue. A special delivery cannula had to be invented. An imaging technology () had to be developed, so we could visualize and measure the amount of AADC enzyme that the viral vector was generating in the striatum. Finally, we had to convince the Food and Drug Administration that we were ready to try this therapy out on some courageous PD patients to whom we owe a great debt of gratitude. All of these challenges required an ability to recruit collaborators, both academic and corporate, to make this therapy a reality. As we have developed over the last decade, we have learned many lessons, often hard-won, about what it takes to push cutting-edge therapies forward into clinical practice. Of course, we did not do all this on our own. We are indebted to our colleagues at Avigen Inc who supported much of the pre clinical development for this project. Colleagues at UCSF have now taken the lead on managing the Phase 1 study at UCSF. Dr. Michael Aminoff of the Movement Disorders Clinic in the Department of Neurology is the Clinical Principal Investigator for the study. Dr. Philip Starr of the department of Neurological Surgery performs the surgical infusion of the vector. The study is currently sponsored by Genzyme Inc.