Results at 2 Years after Gene Therapy for RPE65-Deficient Leber Congenital Amaurosis and Severe Early-Childhood-Onset Retinal Dystrophy.
To provide an initial assessment of the safety of a recombinant adeno-associated virus vector expressing RPE65 (rAAV2-CB-hRPE65) in adults and children with retinal degeneration caused by RPE65 mutations.



Nonrandomized, multicenter clinical trial.



Eight adults and 4 children, 6 to 39 years of age, with Leber congenital amaurosis (LCA) or severe early-childhood-onset retinal degeneration (SECORD).



Patients received a subretinal injection of rAAV2-CB-hRPE65 in the poorer-seeing eye, at either of 2 dose levels, and were followed up for 2 years after treatment.



The primary safety measures were ocular and nonocular adverse events. Exploratory efficacy measures included changes in best-corrected visual acuity (BCVA), static perimetry central 30° visual field hill of vision (V30) and total visual field hill of vision (VTOT), kinetic perimetry visual field area, and responses to a quality-of-life questionnaire.



All patients tolerated subretinal injections and there were no treatment-related serious adverse events. Common adverse events were those associated with the surgical procedure and included subconjunctival hemorrhage in 8 patients and ocular hyperemia in 5 patients. In the treated eye, BCVA increased in 5 patients, V30 increased in 6 patients, VTOT increased in 5 patients, and kinetic visual field area improved in 3 patients. One subject showed a decrease in BCVA and 2 patients showed a decrease in kinetic visual field area.



Treatment with rAAV2-CB-hRPE65 was not associated with serious adverse events, and improvement in 1 or more measures of visual function was observed in 9 of 12 patients. The greatest improvements in visual acuity were observed in younger patients with better baseline visual acuity. Evaluation of more patients and a longer duration of follow-up will be needed to determine the rate of uncommon or rare side effects or safety concerns.
Casey Eye Institute, Department of Ophthalmology, Oregon Health & Science University, Portland, Oregon. Electronic address: weleberr@ohsu.edu.
Richard G
RG
Weleber
Casey Eye Institute, Department of Ophthalmology, Oregon Health & Science University, Portland, Oregon.
Mark E
ME
Pennesi
Casey Eye Institute, Department of Ophthalmology, Oregon Health & Science University, Portland, Oregon.
David J
DJ
Wilson
Department of Ophthalmology, University of Massachusetts Medical Center, Worcester, Massachusetts.
Shalesh
S
Kaushal
Casey Eye Institute, Department of Ophthalmology, Oregon Health & Science University, Portland, Oregon.
Laura R
LR
Erker
Casey Eye Institute, Department of Ophthalmology, Oregon Health & Science University, Portland, Oregon.
Lauren
L
Jensen
Casey Eye Institute, Department of Ophthalmology, Oregon Health & Science University, Portland, Oregon.
Maureen T
MT
McBride
Office of the Dean, University of Massachusetts, Medical Center, Worcester, Massachusetts.
Terence R
TR
Flotte
Department of Ophthalmology, University of Massachusetts Medical Center, Worcester, Massachusetts.
Margaret
M
Humphries
Gene Therapy Program, University of Pennsylvania, Philadelphia, Pennsylvania.
Roberto
R
Calcedo
Department of Ophthalmology, University of Florida School of Medicine, Gainesville, Florida.
William W
WW
Hauswirth
Applied Genetic Technologies Corporation, Alachua, Florida.
Jeffrey D
JD
Chulay
Casey Eye Institute, Department of Ophthalmology, Oregon Health & Science University, Portland, Oregon.
J Timothy
JT
Stout
D000328:Adult; D002648:Child; D000229:Dependovirus / Q000235:genetics*; D004596:Electroretinography; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D056965:Injections, Intraocular; D057130:Leber Congenital Amaurosis / Q000235:genetics / Q000503:physiopathology / Q000628:therapy*; D008297:Male; D011788:Quality of Life; D012162:Retinal Degeneration / Q000209:etiology / Q000628:therapy*; D014792:Visual Acuity / Q000502:physiology; D014794:Visual Fields / Q000502:physiology; D055815:Young Adult; D019745:cis-trans-Isomerases / Q000235:genetics; D000099178:Retinoid Isomerohydrolase
D019745:cis-trans-Isomerases; D000099178:Retinoid Isomerohydrolase