Gene Therapy for Inherited Retinal Disorders Short Term Results of the First Human Trials in Leber’s Congenital Amaurosis

The principle of gene therapy involves the introduction of exogenous DNA into the host tissue followed by its expression by host transcription-translational system leading to production of RNA, DNA, peptides or proteins.Advances in molecular biology and genetics have revealed the molecular basis of various diseases and developments in gene transfer technology have contributed to recent progress in the field of gene therapy.

Several animal studies have shown the efficacy and safety of gene therapy for inherited retinal disorders. Leber’s congenital amaurosis (LCA) is a heritable retinal disease which has been successfully treated by gene therapy in dogs. However, the first reports on the human phase of gene therapy for LCA were only recently introduced. LCA is typically an autosomal recessive disease with variable expression leading to significant heterogeneity. One form of LCA is caused by mutations in the retinal pigment epithelium specific 65 KD protein (RPE 65) gene. The RPE 65 protein is the isomerase responsible for conversion of alltrans-retinal to 11-cis-retinal and is essential for normal function of the visual cycle. Abnormal function of the RPE 65 gene results in accumulation of all-trans-retinyl esters and reduction of rhodopsin in rod photoreceptor outer segments. In the absence of 11-cis-retinal, the opsins cannot capture light and transduce it into electrical impulses. Despite the severity of LCA, patients with RPE 65 mutations retain some visual function and retinal integrity demonstrated by normal retinal thickness and partially preserved fundus autofluorescence up to the age of 8 to 12 years.

The majority of recent gene therapy studies targeting the retina have used adeno-associated virus (AAV) as the gene transfer vector. For treating LCA, recombinant AAV2 has been developed which is a vector containing complementary DNA that induces production of RPE 65 protein in targeted cells in vitro. Three human clinical trials have recently evaluated the efficacy and safety of subretinal AAV gene replacement in LCA patients with RPE 65 mutations. In the first study at the Institute of Ophthalmology, University College of London,subretinal injections of recombinant AAV vector expressing RPE 65 complementary DNA were administered to three young patients with LCA. The results showed no serious adverse events, however, there was no clinically significant change in visual acuity or in peripheral visual fields on Goldmann perimetry in any of the three patients. Also, no change in retinal responses on electroretinography was detected,but one patient had significant improvement in visual function on microperimetry and on darkadapted perimetry. The same patient also showed improvement in a subjective test of visual mobility. In the second study conducted at Scheie Eye Institute, University of Pennsylvania,the safety of subretinal delivery of recombinant AAV carrying RPE 65 complementary DNA was investigated. The three studied patients with LCA had acceptable local and systemic adverse-event profiles after delivery.All patients had modest improvements in measures of retinal function on subjective visual acuity tests. In one patient, an asymptomatic macular hole developed; although it was considered as an adverse event, the patient demonstrated improved retinal function. In the third trial which was performed at the University of Florida, three eyes of three patients underwent treatment and were followed for 90 days. Visual acuity was not statistically different from baseline, however all patients reported increased visual sensitivity in the treated eye. Dark-adapted full-field sensitivity testing showed significant increase from baseline in the treated eyes, as compared to controls.

All three mentioned reports were safety studies on patients with RPE 65 mutations associated with LCA. Although follow-up was very short and normal vision was not achieved,they provide the basis for further studies on gene therapy in patients with inherited retinal disorders.