Reversal of Dyskinesias By in-vivo Gene Transfer of L-DOPA Using Adeno-associated Viral Vectors

Parkinson's disease is a result of an extensive loss of the pigmented neurons located in the brain stem (termed the Substantia Nigra). These nerve cells are the principal neurons producing dopamine in the brain. Typically, symptoms of Parkinson's disease start to appear when about 70-80% of dopamine is lost and about 50% of the neurons in the Substantia Nigra have died. Current pharmacological treatment of the disease is based on providing the precursor of dopamine, L-3,4-dihydroxyphenylalanine (Levodopa), which can be converted to dopamine locally in the brain. Although this treatment can reverse the symptoms initially, it is overshadowed by side effects, such as on-off fluctuations and involuntary movements called dyskinesias. Recent work in specialized clinics have shown that if these patients are given continuous delivery of levodopa instead of intermittent doses, as would be the case when one takes pills every 3-4 hours, the side effects subside. In order to carry this therapy one step forward, we are developing a gene transfer approach using a new generation, high titer recombinant viral vector designed to deliver genes required for local production of levodopa continuously in the brain. Our results are very encouraging and show that this technique may be a viable therapeutic strategy, not only as a strategy to prevent or reverse dyskinesias associated with standard systemic medication but also provide substantial improvement the patients quality of life.