Recent progress in gene therapy for Parkinson's disease

Curr Mol Med. 2012 Dec;12(10):1311-8. doi: 10.2174/156652412803833580.

Abstract

Parkinson's disease (PD) is an age-related and the second most common neurodegenerative disorder beyond Alzheimer's disease. A neuropathological hallmark of PD is a prominent loss of dopaminergic neurons in the substantia nigra projecting into the caudate and putamen. Oral administration of L-dopa and/or dopamine agonists ameliorates cardinal motor symptoms of PD. However, an intermittent and long-term treatment with L-dopa frequently induces adverse side effects such as motor fluctuations and dyskinesia. As alternative therapeutic strategies, the following four approaches are currently under evaluation for clinical gene therapy trials in PD; 1) recombinant adeno-associated virus 2 system encoding aromatic L-amino acid decarboxylase (AADC), 2) glutamic acid decarboxylase (GAD) and 3) Neurturin, and 4) equine infectious anemia virus-based lentiviral system encoding AADC, tyrosine hydroxylase (TH) and GTP cyclohydrolase I (GCH) in a single transcriptional unit. GAD and Neurturin have been assessed in double blind placebocontrolled phase II studies; GAD showed a significant improvement in motor function, and Neurturin, although it failed to show significant effects at 12 months post-treatment, exhibited promising outcomes in additional examinations at 18 months. The other two approaches also represented significant effects in phase I or I/II studies. Adverse side effects due to surgery have not been observed. Here, we review preclinical and clinical trials encouraging further investigations of curative treatment for the patients suffering from PD.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Aromatic-L-Amino-Acid Decarboxylases / genetics
  • Aromatic-L-Amino-Acid Decarboxylases / therapeutic use
  • Dependovirus / genetics
  • Dopamine Agonists / therapeutic use
  • Dopaminergic Neurons / pathology
  • GTP Cyclohydrolase / genetics
  • GTP Cyclohydrolase / therapeutic use
  • Gene Transfer Techniques
  • Genetic Therapy*
  • Genetic Vectors
  • Glutamate Decarboxylase / genetics
  • Glutamate Decarboxylase / therapeutic use
  • Humans
  • Infectious Anemia Virus, Equine / genetics
  • Levodopa / therapeutic use
  • Neurturin / therapeutic use
  • Parkinson Disease / genetics
  • Parkinson Disease / therapy*
  • Tyrosine 3-Monooxygenase / genetics
  • Tyrosine 3-Monooxygenase / therapeutic use

Substances

  • Dopamine Agonists
  • Neurturin
  • Levodopa
  • Tyrosine 3-Monooxygenase
  • GTP Cyclohydrolase
  • Glutamate Decarboxylase
  • Aromatic-L-Amino-Acid Decarboxylases