Molecular Anthropology Meets Genetic Medicine to Treat Blindness in the North African Jewish Population: Human Gene Therapy Initiated in Israel

Abstract

The history of the North African Jewish community is ancient and complicated with a number of immigration waves and persecutions dramatically affecting its population size. A decade-long process in Israel of clinical-molecular screening of North African Jews with incurable autosomal recessive blindness led to the identification of a homozygous splicing mutation (c.95-2A > T; IVS2-2A > T) in RPE65, the gene encoding the isomerase that catalyzes a key step in the retinoid-visual cycle, in patients from 10 unrelated families. A total of 33 patients (four now deceased) had the severe childhood blindness known as Leber congenital amaurosis (LCA), making it the most common cause of retinal degeneration in this population. Haplotype analysis in seven of the patients revealed a shared homozygous region, indicating a population-specific founder mutation. The age of the RPE65 founder mutation was estimated to have emerged 100-230 (mean, 153) generations ago, suggesting it originated before the establishment of the Jewish community in North Africa. Individuals with this RPE65 mutation were characterized with retinal studies to determine if they were candidates for gene replacement, the recent and only therapy to date for this otherwise incurable blindness. The step from molecular anthropological studies to application of genetic medicine was then taken, and a representative of this patient subgroup was treated with subretinal rAAV2-RPE65 gene therapy. An increase in vision was present in the treated area as early as 15 days after the intervention. This process of genetically analyzing affected isolated populations as a screen for gene-based therapy suggests a new paradigm for disease diagnosis and treatment.

The Status ofRPE65Gene Therapy Trials: Safety and Efficacy

“…This describes the short-term results of one subject who received injection of a vector that was slightly different than that injected in the UPENN/UFL study ( Table 1). In that subject, there was an increase in vision present in the treated area as early as 15 d after the intervention (Banin et al 2010).…”

The human visual cortex responds to gene therapy–mediated recovery of retinal function

“…LCA2 patients are good candidates for gene transfer therapy, as the degeneration of retinal cells is delayed several years after initial symptoms. Studies in animal models of LCA2 (6)(7)(8)(9)(10) and, more recently, in humans (11)(12)(13)(14)(15)(16)(17) using adeno-associated virus-mediated (AAV-mediated) retinal gene delivery have demonstrated success in restoring retinal and visual function using one or more measures, including visual acuity (VA), visual fields (VFs), light sensitivity, pupillary light reflex, and/or mobility. Of all sensory systems, vision is processed by the largest brain area.…”

Human retinal gene therapy for Leber congenital amaurosis shows advancing retinal degeneration despite enduring visual improvement

“…Patients with RPE65-LCA show a substantial loss of light sensitivity unexplained by the amount of underlying photoreceptors (3,6,10,22,27). It is important to emphasize, however, that the patients do not lose all visual function.…”

“…Gene augmentation therapy for human RPE65-LCA, as performed in four independent clinical trials, has resulted in substantially improved visual function within days to weeks after treatment (7)(8)(9)(10), and the functional gain has been durable for as long as 3 y (11,36) (Fig. 2C).…”

“…RPE65-associated LCA (RPE65-LCA) is a complex disease in which vision loss results from two pathological mechanisms-dysfunction and degeneration of photoreceptors (3)(4)(5)(6). RPE65-LCA has been proclaimed to be the first successfully treated inherited retinopathy using gene augmentation therapy (7)(8)(9)(10), and the treatment has resulted in substantial improvement in vision that endures at least 3 y (11).…”