Gene therapy progress and prospects: Parkinson's disease

Progress Inhibition of apoptosis by gene delivery prevents development of the disease phenotype in animal models Transgene-mediated expression of glial cell line-derived neurotrophic factor may prevent progression after an initial insult, and may even be restorative in animal models Combination of antiapoptotic and glial cell line-derived neurotrophic factor (GDNF) gene therapy protects dopaminergic neurons against a toxic insult, more effectively than either intervention alone Transgene-mediated production of the inhibitory neurotransmitter gamma-amino butyric acid (GABA) in neurons of the subthalamic nucleus ameliorates the behavioral phenotype and may be neuroprotective, in an animal model Delivery of transgenes encoding enzymes involved in dopamine biosynthesis enhances dopamine production in the striatum Stem cells may be driven to differentiate into functioning dopaminergic cells by genetic modification Isolation of genes implicated in rare genetic forms of Parkinson's disease (PD) has allowed generation of new animal models and identification of new candidate targets for intervention One human gene therapy trial is about to commence in PD The optimal vector remains uncertain Prospects Development of presymptomatic diagnostic tests will facilitate neuroprotective studies Better understanding of the pathogenesis may lead to the development of improved animal models that more closely resemble the human disease Studies may broaden their scope to include the important nonmotor manifestations of PD Further characterization of ES and adult stem cell populations will establish whether ex vivo transduction can drive their differentiation into dopaminergic neurons in a therapeutically useful way Well-designed clinical trials for PD gene therapy may take their lead from cell transplantation trials.