Potential of gene therapy for Parkinson's disease: neurobiologic issues and new developments in gene transfer methodologies.
Gene transfer techniques have been explored as therapeutic modalities and neurobiologic tools to understand the role of various genes in animal models of Parkinson's disease. The gene for tyrosine hydroxylase, the rate-limiting step of dopamine synthesis, has been transferred into animal models by viral vectors or by implantable cells that have been modified by retrovirus vectors. The role of additional genes such as GTP cyclohydrolase 1 and aromatic L-amino acid decarboxylase in optimal delivery of dopamine in animal models is reviewed. Gene therapy also allows goals beyond replacement of dopamine. Neurotrophic factors such as brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor can be introduced to promote sprouting of neurites and protect the dopaminergic neurons from degeneration. Genes involved in apoptosis, free radical scavenger pathway, or other cell death mechanism could also be used to prevent the degeneration of the neurons. Current technology of gene therapy is limited in its long-term expression and ability to regulate the gene expression. However, recent developments provide better understanding of these limitations and suggest potential solutions to these technical hurdles.
Kang
U J
UJ
Department of Neurology, University of Chicago, Illinois 60637, USA.
D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics; D004298:Dopamine / Q000378:metabolism; D015870:Gene Expression / Q000502:physiology; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D051100:Glial Cell Line-Derived Neurotrophic Factor; D006801:Humans; D009414:Nerve Growth Factors; D009416:Nerve Regeneration / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics; D010300:Parkinson Disease / Q000235:genetics / Q000628:therapy*; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics
D019208:Brain-Derived Neurotrophic Factor; C495039:GDNF protein, human; D051100:Glial Cell Line-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine