All of our projects depend on the creation and advancement of direct infusion of drugs and therapies into the brain.
We have developed a technique in which lipid-like nanoparticles and other therapeutic agents can be infused directly into brain tumors to give enhanced drug efficacy with reduced side effects.
For many years, and continuing still, we have been working on development of direct drug delivery into the brain including cell transplantation, gene transfer and growth factor infusions for Parkinson's disease.
Through gene therapy, we are working to eliminate this inherited lipid storage disorder by restoring the activity of the gene responsible for Niemann-Pick disease, acid sphingomyelinase.
Prolonged treatment of Parkinson’s disease with L-DOPA may result in a characteristic movement disorder known as dyskinesia. By studying the effects of L-DOPA on the brain, we are developing gene therapy solutions to treat L-DOPA-induced dyskinesias.
Using our image-guided delivery techniques AADC activity in the brain, important in the synthesis of several neurotransmitters, may be restored by gene therapy in patients lacking the gene for AADC.
1 Month After
PET image from a human subject after receiving a low dose of AAV2-hAADC gene therapy bilaterally.
The warm colors indicate successful AADC gene transfer.
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.
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 the 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 AAV2 (adeno-associated virus), we created AAV2-hAADC and developed this viral vector as a therapy for PD patients whose L-DOPA responsiveness was failing. Animal studies showed that the AAV2-hAADC vector was safe and effective, driving clinical improvement in Parkinsonian monkeys for over 8 years. With the help of industry partners including Avigen and Genzyme, this work culminated in a clinical trial at UCSF.
The concept of AAV2-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 is delivered to exactly the right part of the brain, we had to learn a huge amount about how AAV2 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 undertaken this development path 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 who supported some of the preclinical development for this project, and our partners at Genzyme who have moved the project through its initial clinical trial. Colleagues at UCSF completed the Phase 1 study at UCSF [see the CBS news story on the Phase 1 trial
]. 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 and Dr. Paul Larson of the Department of Neurological Surgery perform the surgical infusion of the vector. The study is currently sponsored by Genzyme Inc.
A follow-up clinical trial is set to commence in 2012-2013.
A Promising New Drug
In addition to supplementing neurons with the enzyme hAADC, we have researched methods to preserve dying neurons associated with Parkinson's disease. Glial-derived neurotrophic factor (GDNF) is a protein that promotes the survival of these neurons. By injecting GDNF into the putamen, previously dying cells stay alive. Furthermore, using gene therapy, we can produce the GDNF protein locally within the putamen via an AAV2-GDNF vector delivered in the same way we deliver our AAV2-AADC vector, but now with the added control and precision of our MRI-guided convection enhanced delivery system. Our preclinical studies show that GDNF induces a restoration of the dopamine system and has significant impact in improving motor function in Parkinsonian subjects. We plan to extend these primate studies into a clinical trial starting in 2012.