Gene Therapy for Parkinson's Disease: An Approach to the Prevention or Palliation of Levodopa-Associated Motor Complications
Identifieur interne : 002025 ( Main/Exploration ); précédent : 002024; suivant : 002026Gene Therapy for Parkinson's Disease: An Approach to the Prevention or Palliation of Levodopa-Associated Motor Complications
Auteurs : M. Maral Mouradian ; Thomas N. ChaseSource :
- Experimental Neurology [ 0014-4886 ] ; 1997.
Abstract
Gene therapy holds considerable potential for the treatment of central nervous system disease. The introduction of functional genes into the brain of patients with Parkinson's disease may, for example, prove useful as a means to replace a defective gene, introduce a potentially neuroprotective or neurorestorative protein, or permit the physiological delivery of a deficient neurotransmitter. Recent observations suggest that the oral administration of currently available dopaminomimetics to relatively advanced parkinsonian patients leads to nonphysiologic intermittent stimulation of striatal neurons that express dopamine receptors. Resultant activation of signal transduction pathways from these dopaminergic receptors on medium-sized GABAergic neurons apparently induces long-term potentiation of adjacent glutamatergic receptors of theN-methyl-d-aspartate subtype. The effects of dopaminergic drugs thus become modified in ways that favor the clinical appearance of response fluctuations and peak-dose dyskinesias. In parkinsonian models as well as in patients with Parkinson's disease, continuous dopaminergic replacement tends to prevent or alleviate these adverse effects. By continuously maintaining appropriate cerebral dopamine concentrations, molecular techniques which stimulate an increase in the intrastriatal activity of tyrosine hydroxylase, the rate-limiting enzyme for dopamine synthesis, might be expected to palliate parkinsonian symptoms with less risk of the disabling consequences of current therapy. Clinical study of these approaches could also serve as initial, relatively simple, proof-of-principle evaluations of the safety and efficacy of genetic approaches to the treatment of basic disease processes in Parkinson's disease and related neurodegenerative disorders.
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DOI: 10.1006/exnr.1996.6388
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