Gene therapy for Parkinson's disease: now getting closer

BMC A11, Lund, Sweden

Gene transfer in PD is currently pursued along two different lines: either by gene transfer of potential neuroprotective molecules, or as a tool to supply dopamine to the affected striatum by introducing the enzymes responsible for L-DOPA or dopamine synthesis. Promising results have been obtained in the rat 6-OHDA lesion model and the monkey MPTP lesion model by gene transfer using recombinant viral vectors, in particular the new generations of highly efficient adeno-associated virus (AAV) or lentiviral vectors carrying the GDNF or Tyrosine hydroxylase (TH) genes. Nanogram amounts of GDNF expressed by the transduced cells are highly effective in protecting the dopaminergic nigral neurons from the toxic insult and promote substantial functional recovery. This contrasts with the microgram amounts required to achieve a similar magnitude of protection after intracerebral injection or infusion of recombinant GDNF.

Direct in vivo gene transfer of the tyrosine TH gene can provide substantial functional improvement in both drug-induced and spontaneous behavior in rats with either complete or partial 6-OHDA lesions of the nigrostriatal pathway provided that TH is co-expressed with the co-factor synthetic enzyme, GTP-cyclohydrolase. Complete reversal of motor deficits, and almost complete reversal of L-DOPA-induced dyskinesias were obtained in 6-OHDA lesioned animals where part of the striatal dopamine innervation was left intact. Intrastriatal L-DOPA delivery may be a viable strategy for treatment, and for control of adverse side-effects associated with oral L-DOPA therapy, such as on-off fluctuations and drug-induced dyskinesias, in patients with Parkinson's disease.