The first human clinical trial has been performed to assess the safety of recombinant adeno-associated virus (rAAV) vector-based gene delivery to the retina of patients with blindness from Leber congenital amaurosis (LCA) and mutations in the RPE65 (retinal pigment epithelium-specific protein 65-kDa) gene. Vision was safely restored in RPE65-LCA, a previously untreatable and incurable human retinal degenerative disease. At the end of the current grant period, we will have treated 15 patients representing two age groups: 8-17 (n=7) and >18 years (n=8), using 4 different doses and two approaches: a single injection site in one eye (Cohorts 1-3, n=9) and two injection sites in one eye at the same surgical session (Cohorts 4 and 5, n=6).
Five specific aims are now proposed to complete this early phase trial.
Aim 1 - Evaluate the long-term safety of subretinal rAAV2-hRPE65 gene therapy in all 15 subjects with the FDA-mandated three years of follow- up.
Aim 2 - Evaluate the efficacy of gene therapy to restore vision by determining: a) if the early improvement in vision persists by 3 years post-treatment;b) whether pre-treatment photoreceptor-RPE structure predicts the improvement in visual sensitivity in the post-treatment period;and c) if there are visual changes that emerge over a longer time course following treatment.
Aim 3 - Evaluate whether gene therapy alters the natural history of retinal degeneration by determining: a) the natural history of retinal degeneration in human RPE65-LCA in the cone-only fovea and in rod-dominated extrafoveal retina;and b) if treated retinal regions have a different natural history of photoreceptor loss.
Aim 4 - Study the properties of the restored visual cycle in treated patients using dark adaptometry and determine: a) if there is a dose-response function for the adaptation defect;b) the resulting rate kinetics for rods and cones as a function of remaining photoreceptor architecture and retinal location, pre-treatment visual function and the extent of improvement post-treatment;and c) if the dark adaptation defect changes with time after treatment.
Aim 5 - Assess whether mobility performance is affected by the gene therapy intervention and what quantified visual parameters make a difference in mobility. Answers will thus be sought to the many scientific and medical questions that have arisen from the procedures in these 15 patients. These answers should refine the approach and clarify expectations of gene therapy in this disease and lead to better approaches to other human genetic retinal diseases that are queuing up as future candidates for this type of therapy.

Public Health Relevance

The current proposal dovetails with the ongoing clinical trial. Many unanswered questions remain about the detailed results of this first human gene therapy for a genetic retinal disease. The five aims of this grant are both regulatory and scientific and will seek answers to questions critical to further development of this clinical trial and future gene therapy trials of retinal degenerative disorders.

National Institute of Health (NIH)
National Eye Institute (NEI)
Cooperative Clinical Research--Cooperative Agreements (U10)
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Special Emphasis Panel (ZEY1-VSN (02))
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Redford, Maryann
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University of Pennsylvania
Schools of Medicine
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Li, Songhua; Izumi, Tadahide; Hu, Jane et al. (2014) Rescue of enzymatic function for disease-associated RPE65 proteins containing various missense mutations in non-active sites. J Biol Chem 289:18943-56
Cideciyan, Artur V; Jacobson, Samuel G; Beltran, William A et al. (2013) Human retinal gene therapy for Leber congenital amaurosis shows advancing retinal degeneration despite enduring visual improvement. Proc Natl Acad Sci U S A 110:E517-25
Roman, Alejandro J; Cideciyan, Artur V; Schwartz, Sharon B et al. (2013) Intervisit variability of visual parameters in Leber congenital amaurosis caused by RPE65 mutations. Invest Ophthalmol Vis Sci 54:1378-83
Jacobson, Samuel G; Cideciyan, Artur V; Ratnakaram, Ramakrishna et al. (2012) Gene therapy for leber congenital amaurosis caused by RPE65 mutations: safety and efficacy in 15 children and adults followed up to 3 years. Arch Ophthalmol 130:9-24
Cideciyan, Artur V (2010) Leber congenital amaurosis due to RPE65 mutations and its treatment with gene therapy. Prog Retin Eye Res 29:398-427
Maeda, Tadao; Cideciyan, Artur V; Maeda, Akiko et al. (2009) Loss of cone photoreceptors caused by chromophore depletion is partially prevented by the artificial chromophore pro-drug, 9-cis-retinyl acetate. Hum Mol Genet 18:2277-87
Cideciyan, Artur V; Hauswirth, William W; Aleman, Tomas S et al. (2009) Human RPE65 gene therapy for Leber congenital amaurosis: persistence of early visual improvements and safety at 1 year. Hum Gene Ther 20:999-1004
Cideciyan, Artur V; Hauswirth, William W; Aleman, Tomas S et al. (2009) Vision 1 year after gene therapy for Leber's congenital amaurosis. N Engl J Med 361:725-7
Jacobson, Samuel G; Aleman, Tomas S; Cideciyan, Artur V et al. (2009) Defining the residual vision in leber congenital amaurosis caused by RPE65 mutations. Invest Ophthalmol Vis Sci 50:2368-75
Jacobson, Samuel G; Cideciyan, Artur V; Aleman, Tomas S et al. (2008) Photoreceptor layer topography in children with leber congenital amaurosis caused by RPE65 mutations. Invest Ophthalmol Vis Sci 49:4573-7

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