Neuroprotective gene therapy for the treatment of inherited retinal degeneration.
Buch PK., MacLaren RE., Ali RR.
Inherited retinal degeneration (IRD) affects around 1/3000 of the population in Europe and the United States. It is a diverse group of conditions that results from mutations in any one of over 100 different genes. Many of the genes have now been identified and their functions elucidated, providing a major impetus to develop gene-based treatments. Whilst gene replacement and gene silencing strategies offer prospects for the treatment of specific inherited retinal disorders, other disorders may be less amenable to these corrective approaches. These conditions include, in particular, those associated with abnormal retinal development and those in which retinal degeneration is advanced at birth. Furthermore, the development of individualized corrective gene therapy strategies for patients with disorders due to very rare mutations may be unfeasible. However, generic gene therapy strategies that aim not to correct the gene defect but to ameliorate its consequences offer the possibility of therapies that are widely applicable across a range of conditions. One potential strategy in these cases is to halt or delay the process of cell death, so that useful visual function can be maintained throughout the lifetime of an affected individual. It has been shown in variety of experimental models over the last three decades, that neurotrophic factors have the potential to delay neuronal apoptosis. Neurotrophic factors are small proteins which have relatively short half lives and a requirement for repeated administration has limited their clinical application. Since these proteins do not ordinarily cross the blood-brain barrier, previous approaches have relied upon intrathecal infusion pumps or similar complex devices to sustain elevated neurotrophin levels within the central nervous system (CNS). However, sustained delivery through viral vector mediated expression of genes encoding neurotrophic factors may circumvent the potential side effects of repeated administration. In this review we shall explore some of the concepts of neurotrophic gene therapy and how this might be applicable to preserving vision in inherited retinal degenerations.