Search

Over the last 20 years it has been recognized that neurotrophic factors profoundly influence the development of the nervous system and have the potential to modify disease processes in the adult nervous system. The ability of nervous system growth factors to prevent or reduce neuronal degeneration in animal models of neurodegenerative diseases has led to several clinical trials. One of the main obstacles to the success of these trials has been the method of growth factor delivery: sufficiently high doses of neurotrophic factors must be achieved in the target region of the brain to efficiently modify disease processes, but delivery must be restricted to specific brain regions to prevent adverse effects. Recent advances in molecular medicine have made gene therapy in the nervous system a potentially realistic approach for the delivery of therapeutic molecules such as growth factors. As an alternative to conventional drug delivery, several gene therapy trials for the treatment of central nervous system diseases have started or will start in the near future. This chapter reviews the development of neurotrophic factor gene therapy for neurodegenerative diseases focusing on the therapeutic potential of nerve growth factor in Alzheimer's disease, currently the subject of a phase I clinical trial.

Grafting cells to the CNS has been suggested and applied as a potential approach to CNS therapy through the selective replacement of cells lost as a result of disease or damage. Independently, studies aimed at direct genetic therapy in model systems have recently begun to suggest conceptually new approaches to the treatment of several kinds of human genetic disease, especially those caused by single gene enzyme deficiencies. We suggest that a combination of these two approaches, namely the graftment into the CNS of genetically modified cells, may provide a new approach toward the restoration of some functions in the damaged or diseased CNS. We present evidence for the feasibility of this approach, including a description of some current techniques for mammalian cell gene transfer and CNS grafting, and several possible approaches to clinical applications. Specifically, we report that fibroblasts, genetically modified to secrete NGF by infection with a retroviral vector and implanted into the brains of rats with a surgical lesion of the fimbria-fornix, prevented the degeneration of cholinergic neurons that would die without treatment.