Gene therapy of Parkinson's disease: AAV vectors for delivery of therapeutic genes into mammalian brains

Abstract

Motor symptoms in Parkinson's disease (PD) result from severe decreases in the dopamine (DA) content of the striatum, secondary to progressive loss of nigrostriatal dopaminergic neurons. One potential strategy for treating advanced PD is the local production of DA in the striatum by restoring the enzymes for DA synthesis. Injection of recombinant adeno-associated viral (rAAV) vectors expressing enzymes necessary for efficient DA synthesis into the unilateral putamen of Parkinsonian monkeys resulted in amelioration of motor dysfunction with robust transgene expression and elevated DA synthesis in the treated putamen. An alternative strategy for gene therapy of PD is to relieve or reverse the ongoing degenerative processes by delivering genes for molecules that would block further dopaminergic cell loss. Sustained expression of a glial cell line-derived neurotrophic factor gene in the striatum rescued nigral neurons and led to functional recovery in a rat model of PD, even when treatment was delayed until after the onset of progressive degeneration. Gene therapy using rAAV vectors represents a novel and feasible protocol for the treatment of PD.