Non-viral retinal gene therapy: a review

Abstract

In the developed world, diseases of the retina are common causes of untreatable blindness. In many cases, a genetic component to the aetiology has been identified, making the development of gene-based treatments a logical long-term goal. The clinical strategy for retinal gene therapy broadly encompasses two distinct advantages over systemic drug delivery. First is that gene delivery can limit expression of a therapeutic protein to a specific target cell, which is rarely possible even with local drug delivery methods. Second, by delivering DNA that remains stable and non-degraded, gene expression and hence protein production could in theory be indefinite, obviating the need for repeated tablets or injections. Viruses have evolved distinct mechanisms, such as receptor mediated uptake and genomic integration, which efficiently encompass these two properties. For non-viral gene therapy approaches, however, nuclear localization and stable long-term transgene expression remain significant hurdles that need to be overcome. The challenge of non-viral gene therapy is therefore to harness current laboratory and molecular-based techniques to develop a man-made system that can approach the efficiency of a natural biological process. In the unique environment of the retina, this goal may not be insurmountable and would overcome the major limiting factor of adeno-associated viral vectors, which is the size of gene that can be delivered.