Age-dependent effects of RPE65 gene therapy for Leber's congenital amaurosis: a phase 1 dose-escalation trial

Abstract

Summary Background Gene therapy has the potential to reverse disease or prevent further deterioration of vision in patients with incurable inherited retinal degeneration. We therefore did a phase 1 trial to assess the effect of gene therapy on retinal and visual function in children and adults with Leber’s congenital amaurosis. Methods We assessed the retinal and visual function in 12 patients (aged 8–44 years) with RPE65-associated Leber’s congenital amaurosis given one subretinal injection of adeno-associated virus (AAV) containing a gene encoding a protein needed for the isomerohydrolase activity of the retinal pigment epithelium (AAV2-hRPE65v2) in the worst eye at low (1·5×1010 vector genomes), medium (4·8×1010 vector genomes), or high dose (1·5×1011 vector genomes) for up to 2 years. Findings AAV2-hRPE65v2 was well tolerated and all patients showed sustained improvement in subjective and objective measurements of vision (ie, dark adaptometry, pupillometry, electroretinography, nystagmus, and ambulatory behaviour). Patients had at least a 2 log unit increase in pupillary light responses, and an 8-year-old child had nearly the same level of light sensitivity as that in age-matched normal-sighted individuals. The greatest improvement was noted in children, all of whom gained ambulatory vision. The study is registered with ClinicalTrials.gov, number NCT00516477. Interpretation The safety, extent, and stability of improvement in vision in all patients support the use of AAV-mediated gene therapy for treatment of inherited retinal diseases, with early intervention resulting in the best potential gain. Funding Center for Cellular and Molecular Therapeutics at the Children’s Hospital of Philadelphia, Foundation Fighting Blindness, Telethon, Research to Prevent Blindness, F M Kirby Foundation, Mackall Foundation Trust, Regione Campania Convenzione, European Union, Associazione Italiana Amaurosi Congenita di Leber, Fund for Scientific Research, Fund for Research in Ophthalmology, and National Center for Research Resources.

Massively parallel sequencing for early molecular diagnosis in Leber congenital amaurosis

“…Last but not least, the knowledge of the molecular defect is a prerequisite for gene-specific therapy, as recently established for LCA. [3][4][5][6][7][8] This study appointed mutations in AIPL1, GUCY2D, and RDH12 as the molecular cause of LCA in three patients. For both AIPL1 and GUCY2D, proof-of-concept studies in animal models have shown beneficial effects of subretinal delivery of adeno-associated vectors containing the wild-type coding sequence.…”

“…[3][4][5] A follow-up study including children demonstrated even more beneficial effects at a younger age. 6 The efficacy and safety persisted through up to 2 years. [6][7][8] Despite this tremendous step forward, a major obstacle remains in identifying LCA patients eligible for gene-specific treatment due to a massive genetic heterogeneity.…”

“…6 The efficacy and safety persisted through up to 2 years. [6][7][8] Despite this tremendous step forward, a major obstacle remains in identifying LCA patients eligible for gene-specific treatment due to a massive genetic heterogeneity. Sixteen disease genes are known to account for ~70% of LCA cases, leaving the remaining 30% unexplained (RetNet, http://www.sph.uth.tmc.edu/ massively parallel sequencing for early molecular diagnosis in Leber congenital amaurosis…”

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.…”

Gene-based therapies for dominantly inherited retinopathies

“…Results from recent human clinical trials for a severe recessively inherited retinopathy, retinal pigment epithelium-65-linked Leber congenital amaurosis, have served to highlight the attractive features of AAV as a delivery vector for the human eye. [33][34][35][36][37] Notably, in three Leber congenital amaurosis trials reported to date AAV2/2 vectors have been well tolerated after a single subretinal administration of vector (with doses ranging from 1.5Â10 10 -1.5Â10 11 viral particles per treated eye) and moreover have provided beneficial effects to the function of the treated eye as evaluated by a range of methods including retinal sensitivity to light and patient mobility. The majority of AAV serotypes, while providing many advantageous features, have a limited packaging capacity of approximately 4.5 kb currently restricting their use to therapies requiring a relatively modest cargo size.…”