ENGINEERING CELLS TO SECRETE GROWTH-FACTORS

The neutrotrophins stimulate survival and differentiation of a range o f target neurons. A wealth of evidence suggests that central cholinerg ic neurons depend on nerve growth factor (NGF) for trophic support. Gr afts of NGF-producing cells rescue axotomized basal forebrain choliner gic neurons and reduce cholinergic cell death in the medial septum. Sk eletal muscle cells, immortalized from embryonic day 15 (E15) rat embr yos for transplantation purposes, were transfected with a human NGF co nstruct and individual clones tested for NGF production by a biologica l assay using embryonic sympathetic ganglia. Clone RM22 showed a consi stent ability to produce human recombinant NGF in high concentration; RM22 cells were grafted to the rat brain, following fimbria-fornix les ions, in order to examine the influence of these cells on basal forebr ain cholinergic neurons. The results suggest that implantation of gene tically modified cells, engineered by the introduction of expression p lasmids or viral constructs to produce NGF or other neurotrophins may have therapeutic applications in rescuing damaged central cholinergic neurons in senile dementia of the Alzheimer type as well as in providi ng trophic support for chromaffin tissue grafts in Parkinson's disease . Moreover, the use of genetically engineered cells may be used to stu dy the effects of administering tailor-made neurotrophins with novel a ctivity profiles.