Neurotrophic factors are polypeptides that regulate the proliferation, survival, migration, and differentiation of cells in the nervous system. Neurotrophic factor therapy is based on the evidence that these factors stimulate the survival of degenerating neurons. This article reviews the role of neurotrophic factors for therapy of neurodegenerative disorders. Delivery to the CNS is a problem because the large neurotrophic molecules cannot cross the blood-brain barrier, and methods to overcome this are described. Several clinical trials have failed, but others are in progress. Gene therapy with stereotactic implantation into the putamen of the gene for neurturin, a member of the same family as glial cell line–derived neurotrophic factor, is in phase II clinical trials for Parkinson disease. A similar gene therapy approach for Alzheimer disease using nerve growth factor has shown neuroprotective effect in phase I clinical trials. Vascular endothelial growth factor, delivered by an intracerebroventricular pump, is in phase II/III clinical trials for amyotrophic lateral sclerosis.
• Neurotrophic factor therapy is based on the evidence that growth factors stimulate the survival of neurons that degenerate in neurologic disorders.
• Most of the clinical trials of neurotrophic factors in neurodegenerative disorders have not been successful.
• Delivery of neurotrophic factors to the brain has been improved by cell and gene therapies.
Historical note and terminology
A trophic factor can be generally defined as any molecule that supports the survival of neurons. Nerve growth factors are polypeptides that regulate the proliferation, survival, migration, and differentiation of cells in the nervous system. Most of the studies have focused on the effect of growth factors on neuronal survival and maintenance, hence, the term neurotrophic factors. A neurotrophic factor is synthesized by and released from target cells of the neurons bound to specific receptors, and then it is internalized and transported by retrograde axonal transport to the cell soma where multiple survival-promoting effects are initiated.
Growth factors termed cytokines have also been found to modulate neuronal processes. Originally, cytokines were thought to be derived solely from the cells of the immune system, but now they are known to be produced by the cells of the CNS also. In this article, the term neurotrophic factors will be used in a broad sense to cover neurotrophins (nerve growth factor, brain-derived neurotrophic factor, and neurotrophins), growth factors, and other substances that promote survival and repair of the cells of the nervous system.