Treatment of Leber Congenital Amaurosis Due toRPE65Mutations by Ocular Subretinal Injection of Adeno-Associated Virus Gene Vector: Short-Term Results of a Phase I Trial

Abstract

Leber congenital amaurosis (LCA) is a group of autosomal recessive blinding retinal diseases that are incurable. One molecular form is caused by mutations in the RPE65 (retinal pigment epithelium-specific 65-kDa) gene. A recombinant adeno-associated virus serotype 2 (rAAV2) vector, altered to carry the human RPE65 gene (rAAV2-CB SB -hRPE65), restored vision in animal models with RPE65 deficiency. A clinical trial was designed to assess the safety of rAAV2-CB SB -hRPE65 in subjects with RPE65-LCA. Three young adults (ages 21-24 years) with RPE65-LCA received a uniocular subretinal injection of 5.96 ϫ 10 10 vector genomes in 150 l and were studied with follow-up examinations for 90 days. Ocular safety, the primary outcome, was assessed by clinical eye examination. Visual function was measured by visual acuity and dark-adapted full-field sensitivity testing (FST); central retinal structure was monitored by optical coherence tomography (OCT). Neither vector-related serious adverse events nor systemic toxicities were detected. Visual acuity was not significantly different from baseline; one patient showed retinal thinning at the fovea by OCT. All patients self-reported increased visual sensitivity in the study eye compared with their control eye, especially noticeable under reduced ambient light conditions. The dark-adapted FST results were compared between baseline and 30-90 days after treatment. For study eyes, sensitivity increases from mean baseline were highly significant (p Ͻ 0.001); whereas, for control eyes, sensitivity changes were not significant (p ϭ 0.99). Comparisons are drawn between the present work and two other studies of ocular gene therapy for RPE65-LCA that were carried out contemporaneously and reported. 979

High-Efficiency Transduction of Fibroblasts and Mesenchymal Stem Cells by Tyrosine-Mutant AAV2 Vectors for Their Potential Use in Cellular Therapy

“…More recently, nonintegrating adenoviral vectors (Stadtfeld et al, 2008) and plasmid DNAs (Okita et al, 2008) have been used to deliver Klf4, Oct3/4, and Sox2 genes to fibroblasts, but the efficiency of reprogramming is low, ranging between 0.01 and 0.1%. Thus, we believe that further development of alternative vector systems, such as AAV, needs to be pursued for their potential ability to infect MSCs and fibroblasts, as well as to generate iPS cells at high efficiency, given the proven safety of AAV vectors in several clinical trials (Bainbridge et al, 2008;Hauswirth et al, 2008;Maguire et al, 2008).…”

“…Recombinant retro-and lentiviral vectors can also undergo random integration into host chromosome, thereby elevating the risk of insertional mutagenesis (Cockrell and Kafri, 2007;Nair, 2008). Thus, development of alternative vector systems, such as adeno-associated virus (AAV), needs to be pursued, given the proven safety of AAV vectors in several Phase I/II clinical trials (Bainbridge et al, 2008;Cideciyan et al, 2008;Hauswirth et al, 2008;Maguire et al, 2008).…”

Curing blindness: Vision quest

“…The hope is that the working gene will repair malfunctioning cells and keep them alive, preserving and even improving vision. Trials by three different groups [1][2][3][4] have shown not only that the procedure is safe, but also that it boosts vision in most participants -and that most improvements seem to be maintained for up to seven years. The biotechnology company Spark Therapeutics in Philadelphia, Pennsylvania, is now testing gene therapy for LCA2 in an advanced trial, and it hopes to file for regulatory approval in the United States as early as 2016.…”

“To perpetuate blindness!”: attitudes of UK patients with inherited retinal disease towards genetic testing

“…With the progress of molecular genetics increasingly more detailed, genotypes of these conditions are being identified, better predictive testing is becoming available and a more accurate estimation of future vision is possible (Pradhan et al 2009). This has been followed by the start of gene therapy trials in animal models of human retinal degeneration and the early results of gene therapy for RPE65-mediated disease are encouraging (Simonelli et al 2010;Le Meur et al 2007;Hauswirth et al 2008;Bainbridge et al 2008). Stem cell therapy has also shown promise in animal models and clinical trials of stem cell therapy for inherited retinal disease are imminent (Tucker et al 2011;Wong et al 2011).…”