Progress in direct striatal delivery of L-dopa via gene therapy for treatment of Parkinson's disease using recombinant adeno-associated viral vectors

Viral vectors have recently been used successfully to transfer genes and ex press different proteins in the brain. This review discusses the requiremen ts to consider human clinical trials in which recombinant adeno-associated virus vectors are used to transfer the genes necessary to produce L-dihydro xyphenylalanine (L-dopa) directly into the striatum of Parkinson's patients . Preclinical data that apply to the criteria defined as prerequisite for c linical trials are discussed. Thus, in animal models using recombinant aden oassociated virus vectors it has been demonstrated that L-dopa can be synth esized in the striatum after in vivo transduction. In addition, these L-dop a levels are sufficient to affect behavior in a dopamine-deficient animal m odel, the expression is extremely long-lasting, and the ability to transcri ptionally regulate tyrosine hydroxylase has been demonstrated but not fully characterized. However, while immune responses to recombinant adeno-associ ated virus infection in the periphery have been studied, direct assessment of the potential immune response in the brain has not been sufficiently def ined. Therefore, the rationale for delivering L-dopa directly to the striat um to treat Parkinson's disease is sound and the preclinical data are promi sing but all the issues surrounding this strategy are not resolved. (C) 199 9 Academic Press.