Grafts and Growth Factors in CNS

Abstract

In 1979, we presented the first evidence that grafts of fetal brain tissue to the adult central nervous system could counteract an experimentally induced neurological deficit. Using the unilaterally dopamine-denervated rat model of Parkinson's disease, it was first shown that fetal substantia nigra grafts were effective and, later, that adult adrenal medullary chromaffin tissue might be used as a possible substitute for fetal brain tissue. These observations led to the first clinical trials with chromaffin autografting in severe cases of Parkinson's disease, which were initiated at the Karolinska Hospital in 1982, and several years later to clinical trials with grafts of fetal dopamine neuroblasts obtained after early elective abortions. In parallel with the ongoing intense basic research aimed at optimizing grafting procedures and finding new possible clinical applications, there are now worldwide clinical trials of grafting procedures involving a large number of neurosurgical centers and a large number of patients. Here, I shall review our recent studies of grafts and growth factors as they relate to possible new therapeutic principles applicable not only to Parkinson's disease, but also to Alzheimer's senile dementia and possibly to spinal cord injury and other afflictions. Recent evidence suggests that cholinergic neurons in the brain, known to degenerate in Alzheimer's disease, depend on nerve growth factor. In one approach we have grafted genetically modified cell lines, designed to secrete large amounts of nerve growth factor, and demonstrated that they can rescue lesioned cholinergic neurons that would otherwise die. Nerve growth factor can also serve to enhance survival of, and promote fiber formation by, chromaffin grafts in experimental parkinsonism. Interestingly, a series of other growth factors, such as IGF-1, bFGF, aFGF, BDNF, TGF's, as well as their receptors, are now being cloned and in several cases shown to have interesting temporal and regional distributions as well as effects in the central nervous system. Our own studies using intraocular grafts suggest potent effects on fetal brain tissue growth of truncated IGF-1, bFGF, and aFGF. It thus appears as if neurosurgery is on the verge of entering a new era in which repair in the adult brain and spinal cord, once thought impossible in mammals, will become possible using growth factors and grafts.