A two-center human clinical trial is proposed 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. LCA from RPE65 mutations is incurable but proof-of-concept studies in animals with RPE65 deficiency indicate there is potential for treatment success given delivery of 11-cis retinal to remaining photoreceptors. LCA patients with RPE65 mutations were recently proven to have sufficient similarity to the animal models in retinal structure-function relationships to warrant this phase I trial. Preclinical safety studies and regulatory approvals are ongoing and planned for completion as part of a U10 (EY13729) multi-center research/clinical grant.
Four specific aims are proposed: 1) a phase I clinical trial of uniocular single dose per patient rAAV2-RPE65 in 6 subjects 18 years and older with retinopathy due to RPE65 mutations;2) a phase I clinical trial of uniocular single dose per patient rAAV2-RPE65 in 6 subjects 13-18 years of age with retinopathy due to RPE65 mutations;3) a phase I clinical trial of serial redosing of rAAV2-RPE65 in 6 adult and younger subjects with retinopathy due to RPE65 mutations;a single dose in one eye will be followed after an interval of 3 months by a single dose to the contralateral eye;and 4) study of newly-identified patients with RPE65 mutations of all ages to determine retinal structure-function relationships, thereby identifying further candidates for the other 3 aims and for future studies. Before and at regularly-scheduled time points after subretinal administration of the vector, ocular-retinal and systemic clinical assessments will be performed to evaluate toxicity. The clinical trials, which will be performed under the guidelines of Good Clinical Practice and within a General Clinical Research Center, are sequential and involve a dose escalation plan with appropriate intervals to allow safety analysis and conference with all regulatory bodies before proceeding. cGMP-grade vector production will be performed under appropriate FDA guidelines. Data generated from the proposed studies should test the hypothesis that this vector in these patients is safe and warrants consideration of use in further phases of clinical trials of gene therapy for LCA associated with RPE65 mutations.

National Institute of Health (NIH)
National Eye Institute (NEI)
Cooperative Clinical Research--Cooperative Agreements (U10)
Project #
Application #
Study Section
Special Emphasis Panel (ZEY1-VSN (06))
Program Officer
Redford, Maryann
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Pennsylvania
Schools of Medicine
United States
Zip Code
Cideciyan, Artur V; Roman, Alejandro J; Jacobson, Samuel G et al. (2016) Developing an Outcome Measure With High Luminance for Optogenetics Treatment of Severe Retinal Degenerations and for Gene Therapy of Cone Diseases. Invest Ophthalmol Vis Sci 57:3211-21
Jin, Minghao; Li, Songhua; Hu, Jane et al. (2016) Functional Rescue of Retinal Degeneration-Associated Mutant RPE65 Proteins. Adv Exp Med Biol 854:525-32
Cideciyan, Artur V; Swider, Malgorzata; Jacobson, Samuel G (2015) Autofluorescence imaging with near-infrared excitation:normalization by reflectance to reduce signal from choroidal fluorophores. Invest Ophthalmol Vis Sci 56:3393-406
Jacobson, Samuel G; Cideciyan, Artur V; Aguirre, Gustavo D et al. (2015) Improvement in vision: a new goal for treatment of hereditary retinal degenerations. Expert Opin Orphan Drugs 3:563-575
Jacobson, Samuel G; Cideciyan, Artur V; Roman, Alejandro J et al. (2015) Improvement and decline in vision with gene therapy in childhood blindness. N Engl J Med 372:1920-6
Li, Songhua; Hu, Jane; Jin, Robin J et al. (2015) Temperature-sensitive retinoid isomerase activity of RPE65 mutants associated with Leber Congenital Amaurosis. J Biochem 158:115-25
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; Aguirre, Geoffrey K; Jacobson, Samuel G et al. (2014) Pseudo-fovea formation after gene therapy for RPE65-LCA. Invest Ophthalmol Vis Sci 56:526-37
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

Showing the most recent 10 out of 22 publications