Delayed gene therapy of glial cell line-derived neurotrophic factor is efficacious in a rat model of Parkinson's disease.
Gene transfer of glial cell line-derived neurotrophic factor (GDNF) in rodent models of Parkinson's disease (PD) has been shown to protect against neurodegeneration either prior to or immediately after neurotoxin-induced lesions; however, the nigrostriatal pathway was largely intact when gene delivery was completed in these models, which may not accurately reflect the clinical situation encountered with Parkinson's patients. In this study, replication-incompetent adenoviral vectors encoding the rat GDNF gene were administered into the striatum 4 weeks following 6-hydroxydopamine (6-OHDA) injection in the unilateral striatum, more closely resembling fully developed PD. Apomorphine-induced rotational behavior testing was performed every week following 6-OHDA injection. At the 10th week after gene transfer, the striatal dopamine concentrations were measured by HPLC with an electrochemical detector and the number of tyrosine hydroxylase (TH)-positive dopamine neurons in the substantia nigra (SN) was determined by immunohistochemistry. Injection of 6-OHDA into the striatum produced stable increases in rotation, which reached a plateau between 4 and 5 weeks post-injection. The number of TH-positive neuron in the SN and dopamine levels in the striatum was significantly lower in the 6-OHDA group compared to the normal group. Gene transfer of GDNF, but not beta-galactosidase, significantly increased the number of TH-positive neurons and dopamine levels, with a subsequent behavioral recovery between 5 and 10 weeks following GDNF transduction. These findings demonstrate that adenovirus-mediated gene transfer of GDNF is efficacious even in the late stages of 6-OHDA-induced PD rats. They also provide further evidence on the effectiveness of GDNF-based gene therapy for experimental Parkinson's disease.
Zheng
Jie-Sheng
JS
Department of Neurosurgery, the First Affiliated Hospital, Zhejiang University College of Medicine, Hangzhou 310003, China.
Tang
Ling-Ling
LL
Zheng
Shu-Sen
SS
Zhan
Ren-Ya
RY
Zhou
Yong-Qing
YQ
Goudreau
John
J
Kaufman
David
D
Chen
Alex F
AF
D000256:Adenoviridae / Q000502:physiology; D018663:Adrenergic Agents / Q000008:administration & dosage; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal; D002452:Cell Count / Q000379:methods; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000502:physiology; D051100:Glial Cell Line-Derived Neurotrophic Factor; D007150:Immunohistochemistry / Q000379:methods; D008297:Male; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009414:Nerve Growth Factors / Q000235:genetics / Q000627:therapeutic use*; D016627:Oxidopamine / Q000008:administration & dosage; D010300:Parkinson Disease / Q000209:etiology / Q000628:therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D045442:Rotarod Performance Test / Q000379:methods; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D018663:Adrenergic Agents; C495041:Gdnf protein, rat; D051100:Glial Cell Line-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine