Retinal gene therapy: current progress and future prospects

Abstract

Clinical trials treating inherited retinal dystrophy caused by RPE65 mutations had put retinal gene therapy at the forefront of gene therapy. Both successes and limitations in these clinical trials have fueled developments in gene vectors, which continue to further advance the field. These novel gene vectors aim to more safely and efficiently transduce retinal cells, expand the gene packaging capacity of adeno-associated virus, and utilize new strategies to correct the varying mechanisms of dysfunction found with inherited retinal dystrophies. With recent clinical trials and numerous pre-clinical studies utilizing these novel vectors, the future of ocular gene therapy continues to hold vast potential.

Keywords:

• adeno-associated virus
• equine infectious anemia virus
• gene therapy
• inherited retinal dystrophies
• RPE65

Financial & competing interests disclosure

M Pennesi received funding from Research to Prevent Blindness, Foundation Fighting Blindness and the National Eye Institute. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Inherited retinal dystrophies (IRDs) are genetically heterogeneous and show diverse mechanisms of disease and inheritance, such as autosomal dominant, X-linked and digenic inheritance requiring more complex treatment than gene replacement therapy for autosomal recessive diseases. Novel gene therapy strategies are required to address these additional and more complex IRDs.

• The translational pathway exemplified by RPE65-LCA studies included a thorough understanding of the mechanism of dysfunction in animal models, pre-clinical treatment in these animal models and detailed characterization of patient phenotype. This pathway greatly contributed to the success of RPE65 clinical trials and would serve well to be modeled in the treatment of additional IRDs.

• Despite promising improvements in retinal sensitivity, foveal thinning occurred following subfoveal delivery of adeno-associated virus (AAV2) in Phase I/IIa RPE65-LCA clinical trials in three patients. The cause of foveal thinning remains unclear, and may be attributed to the location of subretinal administration or viral vector toxicity.

• Assessment of risks and benefits of foveal inclusion are important in future studies.

• An alternate intravitreal route of foveal transduction is in development.

• Optimizing transduction efficiency may minimize viral vector toxicity.

• The limited 4.7 kb packaging capacity of adeno-associated virus requires alternative strategies to target large gene mutations causing IRDs, including expansion of the AAV capacity, use of other viral vectors and non-viral vectors.

• Current clinical trials are using AAV2 to treat autosomal recessive RP associated with MERTK mutations and X-linked recessive choroideremia associated with CHM mutations.

• Current clinical trials are treating large gene targets ABCA4 and MYO7A associated with Stargardt dystrophy and Type 1B Usher syndrome with EIAV, a non-AAV viral vector.

• Application of gene therapy for stable expression of anti-VEGF compounds in the treatment of age-related macular degeneration.

• Mutation-independent gene therapy strategies may be required to aid vision rescue.

Notes