Long term gene therapy of Parkinson's disease using immortalized rat glial cell line with tyrosine hydroxylase gene.
Glial cell is an ideal vehicle for gene therapy of brain diseases. However, there are many limits in using primary glial cells. Therefore, an immortalized rat glial cell line (RGLT) was established by SV40 large T-antigen (LTag) gene from the primary rat fetal glial cells. The RGLT cell was shown to be non-tumorigenic after transplantation to nude mice (up to 4 weeks) and rat striatum (up to 18 months). Rat tyrosine hydroxylase (TH) gene was transfected into RGLT cell to obtain RGLT-TH cell. The TH immunohistochemical staining and HPLC-ECD analysis demonstrated the TH expression and dopamine (DA) production in RGLT-TH cells in vitro. When implanting RGLT-TH cells into the striatum of 6-hydroxydopamine (6-OHDA) lesioned hemiparkinsonism model rats, TH immunohistochemical staining showed the TH presence in striatum and HPLC-ECD analysis held at 6 months after cell implantation showed an increase of DA content in striatum. The asymmetric rotation of rats receiving RGLT-TH cells was reduced by 50%-60% and this reduction persisted stably at least for 18 months. These results suggest that the immortalized glial cell line could serve as an ideal vehicle for therapeutic gene delivery system to achieve a long-term gene therapy of neurodegenerative diseases.
Zhuo
Ming
M
Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, the Chinese Academy of Sciences, Shanghai 200031, China.
Xu
De-Hua
DH
Cao
Lei
L
Xu
Ling-Fei
LF
Yu
Fu-Rong
FR
Zheng
Zhong-Cheng
ZC
Liu
Xin-Yuan
XY
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D002461:Cell Line, Transformed; D003342:Corpus Striatum / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D005333:Fetus; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009457:Neuroglia / Q000166:cytology / Q000201:enzymology* / Q000637:transplantation; D010302:Parkinson Disease, Secondary / Q000235:genetics / Q000503:physiopathology / Q000628:therapy*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014183:Transplantation, Heterologous; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics* / Q000378:metabolism
D015102:3,4-Dihydroxyphenylacetic Acid; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine