Viral-vectored ribozymes as therapy for autosomal dominant retinal disease

The design, delivery and preclinical testing of ribozymes specific for opsin mutations are discussed with particular focus on their use in the treatment of dominantly inherited retinal disease. There are several preliminary experimental stages that must be completed in order to maximize the chances for a therapeutic result. The first consideration of critical importance for therapy is the way the therapeutic gene is introduced into the retina and how its expression is controlled. The properties of the adeno-associated virus (AAV) as a viral vector are surveyed with emphasis on those properties best suited for ribozyme-based therapies in the retina. The second key consideration is the design and initial in vitro screening of ribozymes, since we have seen that the behavior of appropriately designed RNA enzymes in cell-free systems is a reasonable predictor of their in vivo activity in the animal. Finally, recent experimental results employing AAV-vectored ribozyme genes are summarized to provide a tangible example of how ribozyme gene therapy for an autosomal dominant retinitis pigmentosa (ADRP)-like disease in a rodent model can be approached. Here, we emphasize the need to analyze effects of the therapy at three levels, biochemical, morphological and electrophysiological, in order to gain a full appreciation of any retinal rescue and to understand the mechanism whereby it was achieved.