Reversal of dyskinesias in an animal model of Parkinson's disease by continuous L-DOPA delivery using rAAV vectors.
Dyskinesias are a major complication of long-term l-3,4-dihydroxyphenylalanine (L-DOPA) treatment in Parkinson's disease, and are believed to result from the intermittent and pulsatile supply of L-DOPA. Daily injections of L-DOPA can prime similar abnormal involuntary movements of the limb, orolingual and axial muscles in rats rendered parkinsonian by destruction of the nigrostriatal dopamine (DA) neurons. In this study we used 33 rats with severe nigrostriatal dopamine depletion and showed that in vivo gene transfer of the DA-synthetic enzymes tyrosine hydroxylase (TH) and GTP cyclohydrolase 1 (GCH1) using recombinant adeno-associated virus vectors can provide a constant source of DOPA production locally in the striatum, at a level that is effective in reducing L-DOPA-induced dyskinesias by >85%, and reverse lesion-induced motor impairments. Furthermore, the abnormal expression of DeltaFosB, prodynorphin and preproenkephalin mRNA within the striatal projection neurons normally seen in dyskinetic animals was completely reversed by TH-GCH1 gene transfer. These findings form a strong basis for replacing, or supplementing, conventional systemic L-DOPA therapy by continuous intrastriatal DOPA using in vivo gene transfer in the treatment of patients with advanced Parkinson's disease.
Carlsson
Thomas
T
Wallenberg Neuroscience Center, Division of Neurobiology, Lund University, Lund, Sweden. Thomas.Carlsson@mphy.lu.se
Winkler
Christian
C
Burger
Corinna
C
Muzyczka
Nicholas
N
Mandel
Ronald J
RJ
Cenci
Angela
A
Björklund
Anders
A
Kirik
Deniz
D
D000818:Animals; D003342:Corpus Striatum / Q000378:metabolism / Q000473:pathology; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D004409:Dyskinesia, Drug-Induced / Q000209:etiology / Q000517:prevention & control*; D005260:Female; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D007980:Levodopa / Q000008:administration & dosage / Q000009:adverse effects / Q000096:biosynthesis* / Q000235:genetics; D010300:Parkinson Disease / Q000473:pathology / Q000628:therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley
D007980:Levodopa