Gene therapy in a rodent model of Parkinson's disease using differentiated C6 cells expressing a GFAP-tyrosine hydroxylase transgene.
Cells expressing a tyrosine hydroxylase (TH) cDNA under control of the promoter of the human glial fibrillary acidic protein (GFAP) gene were tested for therapeutic efficacy in a rat model of Parkinson's disease. The GFAP gene encodes an intermediate filament protein found almost exclusively in astrocytes. Its promoter is of interest for gene therapy as it is expressed in astrocytes throughout postnatal life and is upregulated in response to almost any damage to the central nervous system, including Parkinson's disease. We previously showed that a line of C6 rat glioma cells that expresses a GFAP-TH transgene, C6-THA, displays increased transgene activity when differentiated by forskolin treatment. Accordingly, the effects were investigated of implantation of both undifferentiated and differentiated C6-THA cells into the striatum of rats that had been lesioned with 6-hydroxydopamine. Implantation of either cell type produced significant behavioral recovery one week after transplantation, as judged by the turning response to apomorphine. At two and three weeks after transplantation, the behavioral effect of the undifferentiated cells was no longer statistically significant, whereas that for the forskolin-differentiated cells remained robust. Transgenic TH mRNA and protein could be detected in implants of both cell types, and in agreement with the behavioral results, levels were higher for the differentiated C6-THA cells than for the undifferentiated cells. These results indicate that the GFAP promoter is sufficiently active to enable production of therapeutic levels of dopamine from a GFAP-TH transgene, and suggest the use of astrocytes for gene therapy for Parkinson's disease. They also show that beneficial modifications of cells produced by treatment while in culture may be maintained following implantation.
Trejo
F
F
Programa Multidisciplinario de Biomedicina Molecular, Biofisica y Neurociencias del Centro de Investigación y de Estudios Avanzados del IPN, México, D.F.
Vergara
P
P
Brenner
M
M
Segovia
J
J
D000818:Animals; D017690:Cell Transplantation; D015316:Genetic Therapy; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics*; D005910:Glioma / Q000235:genetics; D006801:Humans; D008297:Male; D016627:Oxidopamine / Q000633:toxicity*; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000235:genetics / Q000628:therapy*; D051381:Rats; D017208:Rats, Wistar; D014407:Tumor Cells, Cultured; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics*
D005904:Glial Fibrillary Acidic Protein; D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase