Results at 2 Years after Gene Therapy for RPE65-Deficient Leber Congenital Amaurosis and Severe Early-Childhood-Onset Retinal Dystrophy

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• 作者：Richard G. Weleber ; MD¹ ; ^{weleberr@ohsu.edu" class="auth_mail" title="E-mail the corresponding author} ; Mark E. Pennesi ; MD ; PhD¹ ; David J. Wilson ; MD¹ ; Shalesh Kaushal ; MD ; PhD² ; Laura R. Erker ; PhD¹ ; Lauren Jensen ; MS ; RN¹ ; Maureen T. McBride ; BS¹ ; Terence R. Flotte ; MD³ ; Margaret Humphries ; RN² ; Roberto Calcedo ; PhD⁵ ; William W. Hauswirth ; PhD⁴ ; Jeffrey D. Chulay ; MD⁶ ; J. Timothy Stout ; MD ; PhD¹
• 关键词：AAV ; adeno-associated virus ; BCVA ; best-corrected visual acuity ; dB-sr ; decibel-steradian ; ETDRS ; Early Treatment Diabetic Retinopathy Study ; ERG ; electroretinogram ; LCA ; Leber congenital amaurosis ; logMAR ; logarithm of the minimum angle of resolution ; OCT ; optical coherence tomography ; rAAV2-CB-hRPE65 ; recombinant adeno-associated virus vector expressing RPE65 ; SECORD ; severe early childhood&ndash ; onset retinal degeneration ; NEI-VFQ-25 ; National Eye Institute 25-Item Visual Function Questionnai
• 刊名：Ophthalmology
• 出版年：2016
• 出版时间：July 2016
• 年：2016
• 卷：123
• 期：7
• 页码：1606-1620
• 全文大小：4171 K

文摘

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.

Design

Nonrandomized, multicenter clinical trial.

Participants

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

Methods

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.

Main Outcome Measures

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 (V_TOT), kinetic perimetry visual field area, and responses to a quality-of-life questionnaire.

Results

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, V_TOT 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.

Conclusions

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.