Investigating the mechanisms of retinal degenerations with antisense oligonucleotides.

Utilizing antisense oligonucleotides coupled with an intact Xenopus eye rudiment model, we have effectively demonstrated that we are able to downregulate the expression of a photoreceptor-specific protein, rds/peripherin, and generate a loss-of-function model upon which to further study the function of the rds/peripherin gene. The ultrastructure and protein expression patterns very closely resemble those previously documented in both the rds mouse and in human autosomal dominant retinitis pigmentosa due to peripherin/RDS mutations. An identical strategy can be applied to any gene correlated with a degenerative retinal phenotype. As the entire array of genes is revealed through the various genome projects, including human and mouse, it is becoming increasingly critical to evaluate and determine the function of the corresponding gene products. Discovering which gene is responsible for a particular clinical phenotype is only the first of many steps in the development of a treatment or cure for that particular disease. Using our in vitro model, in which the retina is readily accessible to the antisense oligonucleotide yet the normal three-dimensional ultrastructure of the retina is maintained, we can evaluate the function of virtually any gene as the sequence becomes available. A thorough understanding of the function of individual genes will provide insights on the role of gene product in retinal health and pathophysiology. This experimental approach will also allow for specific therapeutic interventions to be evaluated so that targeted treatments can be designed for individuals with specific genetic mutations.