A permanent, immortalized human fetal astrocyte cell line (SVG) which maintains the phenotypic characteristics of fetal astrocytes is being studied as a candidate for CNS engraftment. This cell line has been found to constitutively express NGF, BDNF, GDNF and active D1 and D2 dopamine receptors, which suggest that the SVG cell line could act as a vehicle for multiple neurotrophin delivery in an engraftment paradigm. The cDNA for human tyrosine hydroxylase, type 2, has been stably transfected into the SVG cell line, establishing a second cell line, SVG-TH, which secretes L- dopa demonstrating that this cell line could potentially act as a drug delivery vehicle as well. When grafted subcutaneously or within the cranium of nude mice, the SVG and SVG-TH cell lines survive without leading to tumor formation, consistent with their non-transformed behavior in vitro. When the SVG-TH cells were grafted to the lesioned striatum of 6-OHDA-treated rats, rotational behavior of the rat decreased by 50% initially, then slowly returned to baseline over the next four weeks, paralleling graft rejection. In contrast, the SVG cell line has been successfully engrafted and survived in the striatum of the rhesus macaque for up to 18 months, immunologically acting as an allograft. MPTP-lesioned macaques are currently undergoing engraftment with both the SVG and SVG-TH cell lines to determine whether the Parkinsonian symptoms can be reversed via the production of L-dopa and secretion of neurotrophic factors by the grafted cells. Several cell-specific promoters are also being investigated to optimize transgene expression in the SVG cells. The Parkinsonian monkeys have all shown recovery of neurologic symptoms to a lesser or greater degree. Necropsy of the animal indicates graft survival; there was neither nodule formation nor inflammation at the graft site.
