Gene therapy for Leber congenital amaurosis: advances and future directions

Abstract

Background: Leber congenital amaurosis (LCA) is a congenital retinal dystrophy that results in significant and often severe vision loss at an early age. Comprehensive analysis of the genetic mutations and phenotypic correlations in LCA patients has allowed for significant improvements in understanding molecular pathways of photoreceptor degeneration and dysfunction. The purpose of this article is to review the literature on the subject of retinal gene therapy for LCA, including historical descriptions, preclinical animal studies, and human clinical trials.

Methods: A literature search of peer-reviewed and indexed publications from 1996-2011 using the PubMed search engine was performed. Key terms included "Leber congenital amaurosis", LCA, RPE65, "cone-rod dystrophy", "gene therapy", and "human trials" in various combinations. Seminal articles prior to 1996 were selected from primary sources and reviews from the initial search. Articles were chosen based on pertinence to clinical, genetic, and therapeutic topics reviewed in this manuscript. Fundus photographs from LCA patients were obtained retrospectively from the clinical practice of one of the authors (R.A.S).

Results: Herein, we reviewed the literature on LCA as a genetic disease, the results of human gene therapy trials to date, and possible future directions towards treating inherited retinal diseases at the genetic level. Original descriptions of LCA by Theodor Leber and subsequent research demonstrate the severity of this disease with early-onset blindness. Discoveries of the causative heritable mutations revealed genes and protein products involved in photoreceptor development and visual transduction. Animal models have provided a means to test novel therapeutic strategies, namely gene therapy. Stemming from these experiments, three independent clinical trials tested the safety of subretinal delivery of viral gene therapy to patients with mutations in the RPE65 gene. More recently, efficacy studies have been conducted with encouraging results.

Conclusions: Initial safety studies indicated promising results of subretinal delivery of viral vector with subclinical immunologic or surgical sequelae. Overall, these initial studies demonstrate that viral vector gene therapy results are very promising, safe, and effective. Future studies measuring potential improvement in photoreceptor function may rely on recent advances in retinal imaging and electrophysiologic testing.

Conflict of interest statement

Conflict of interest None

Figures

Fig. 1

Various retinal phenotypes among LCA patients. a Focal perimacular atrophy and pigment accumulation. b Fundus hypopigmentation with diffuse RPE granularity. c Macular atrophy and bone spicule pigmentation. d Macular RPE clumping and atrophy accompanying peripheral bone spicule changes

Fig. 2

Schematic illustration of LCA-associated proteins and their location in the photoreceptor-RPE complex. Protein functions are outlined in Table 1. RPE cells (yellow) are in contact with the outer segments of cone (green) and rod (blue) photoreceptors. Proteins altered by LCA-causing mutations affect photoreceptor cells at several levels, including development, outer segment formation, protein trafficking, and photoreceptor-glia connections that form the outer limiting membrane. GUCY2D and AIPL1 participate in necessary machinery for transduction of light into hyperpolarization response. Additionally, genes expressed in RPE cells are affected, including RPE65 and LRAT, which participate in recycling vitamin A analogues in the visual transduction cycle (arrows; for further description, see corresponding text)