Adenovirus-mediated gene transfer of dopamine D2 receptor cDNA into rat striatum.
A robust feature of mammalian aging associated with diminished motor control is the loss of dopamine D2 receptors from the neostriatum. Decline in this neurotransmitter receptor is also observed in neurodegenerative disorders, such as Huntington's disease and late-stage Parkinson's disease. We have constructed a replication-deficient adenoviral vector to transfer rat dopamine D2 receptor cDNA to brain as a possible therapeutic strategy. Using tissue culture cells infected with this vector, we detected dopamine D2 receptor mRNA by Northern analysis and functional receptor protein in membrane preparations as specific binding of the dopamine D2 receptor ligand, [3H]spiperone. In vivo demonstration involved autoradiographic analysis of [3H]spiperone binding in rat striatum following injection of the adenoviral vector. Dopamine D2 receptor expression was amplified markedly above normal concentrations in the injection site, whereas no increased expression was observed in sites receiving control treatments. These results demonstrate the potential of gene therapy using adenoviral vectors to transfer neurotransmitter receptor proteins to the brain to reverse deficiencies in specific neurodegenerative disorders.
Ikari
H
H
Nathan W. Shock Laboratories, National Institute on Aging, NIH, Johns Hopkins Bayview Research Campus, Baltimore, MD 21224, USA.
Zhang
L
L
Chernak
J M
JM
Mastrangeli
A
A
Kato
S
S
Kuo
H
H
Crystal
R G
RG
Ingram
D K
DK
Roth
G S
GS
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D003342:Corpus Striatum / Q000378:metabolism*; D018076:DNA, Complementary / Q000235:genetics*; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D006367:HeLa Cells; D006801:Humans; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000235:genetics*; D014779:Virus Replication / Q000235:genetics*
D018076:DNA, Complementary; D017448:Receptors, Dopamine D2