[Gene therapy to treat Parkinson's disease].
One recent strategy of gene therapy is to have cells express the lacking substances. Decline in dopamine D2 receptors (D2R) is observed in late-stage Parkinson's disease. We have constructed a replication-deficient adenovirus vector to transfer rat D2R cDNA (AdCMV.DopD2R) to the brain as a possible therapeutic strategy and a replication-deficient adenovirus vector to express nothing (AdCMV.Null) as a control. Using tissue culture cells infected with this vector, we detected D2 R cDNA by Northern analysis and receptor protein in membrane preparations as specific binding of the D2R ligand, [3H] spiperone. In vivo demonstration involved autoradiographic analysis of [3H] spiperone binding in rat striatum, D2R expression was amplified above normal concentrations in the injection site. We investigated the expression and functionality of the adenoviral vector. Comparative analysis of the autoradiographic images from the striatum injected with AdCMV.DopD2R and the contralateral striatum injected with a control vector, AdCMV. Null, in male rats indicated that D2R binding was increased by 40-60% on days 3 and 5 after injection, but then declined to baseline levels by day 21. When injected with apomorphine on days 3 and 7 after vector injection, experimental groups that had received unilateral striatal injections of AdCMV. DopD2R exhibited a distinct and significant laterality in rotational behavior. These results provide the first demonstration of an adenovirally mediated, intracerebral delivery of a functional neurotransmitter receptor.
Ikari
H
H
Department of Geriatrics, Nagoya University School of Medicine.
Umegaki
H
H
Iguchi
A
A
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001921:Brain / Q000378:metabolism*; D015316:Genetic Therapy; D005822:Genetic Vectors; D008297:Male; D010300:Parkinson Disease / Q000503:physiopathology / Q000628:therapy*; D051381:Rats; D017448:Receptors, Dopamine D2 / Q000096:biosynthesis / Q000502:physiology
D017448:Receptors, Dopamine D2