Foster City, Calif and Seattle, Wash., January 28, 1999 -- Cell Genesys, Inc. and the University of Washington today published data demonstrating that after a single gene therapy injection, genetically modified mice exhibiting certain symptoms of Parkinson's disease could survive without daily L-dopa treatments for at least one year, the duration of the study. Without L-dopa treatment, these mice die of malnutrition by three weeks of age. An adeno-associated viral (AAV) gene delivery system was used to deliver the genes required for the production of L-dopa to specific regions of the brain where L-dopa production could be detected throughout the observation period. L-dopa is a commonly prescribed drug which is converted to dopamine, the neurotransmitter chemical missing in these mice and in patients with Parkinson's disease. This work was published in the journal, Neuron, by a team of scientists led by Mark Szczypka, Ph.D. and Richard Palmiter, Ph.D. at the University of Washington and Ronald J. Mandel, Ph.D. and Richard O. Snyder, Ph.D. of Cell Genesys.
"A single gene therapy treatment for Parkinson's disease would be a significant improvement over the currently available treatment for this disease," stated Mitchell H. Finer, Ph.D., vice president, research at Cell Genesys. "These studies are among the first observation that gene therapy with AAV vectors can be used to correct a genetic defect in specific regions of the brain."
"The most striking finding in our experiments was the elimination of the need for daily L-dopa treatment in the mice receiving the gene therapy. This represents a remarkable rescue of an otherwise lethal mutation in these genetically modified mice," stated Dr. Richard Palmiter, Investigator of the Howard Hughes Medical Institute and Professor of Biochemistry at the University of Washington. "In the published work, the motivation of the mice to eat and drink was restored following the single administration of gene therapy."
In the published experiments, mice dependent upon daily injections of L-dopa for their survival, were injected with AAV vectors carrying the tyrosine hydroxylase and GTP cyclohydrolase I genes directly to the striatum, one of the principal regions of the brain affected in Parkinson's disease. L-dopa was then produced at therapeutic levels by the genetically modified brain cells for the duration of the study making daily treatment with exogenous L-dopa unnecessary. These data further support previous findings that both of these two genes are required for L-dopa synthesis in the brain and suggest a potential treatment strategy for patients with Parkinson's disease.
The mouse model used in this study was created in Dr. Palmiter's laboratory using gene-targeting techniques. The genetically modified mice are unable to make tyrosine hydroxylase, a critical enzyme for dopamine synthesis in the brain. These mice develop severe movement dysfunction that resembles that of Parkinson's disease patients. The mice also have behavioral defects and will not eat and drink enough to survive without L-dopa therapy.
Gene delivery systems, or vectors, are the means by which therapeutic genes are introduced into target cells or tissues to induce a therapeutic effect and are a critical component of any successful gene therapy. The AAV gene delivery system is one of four vector systems under development at Cell Genesys. Cell Genesys holds a broad U.S. patent covering all gene therapy products that utilize AAV vectors to deliver genes as therapeutic agents.
Journal
Neuron