Three-year follow-up after unilateral subretinal delivery of adeno-associated virus in patients with Leber congenital Amaurosis type 2

Abstract

Objective: The aim of this study was to show the clinical data of long-term (3-year) follow-up of 5 patients affected by Leber congenital amaurosis type 2 (LCA2) treated with a single unilateral injection of adeno-associated virus AAV2-hRPE65v2.

Design: Clinical trial.

Participants: Five LCA2 patients with RPE65 gene mutations.

Methods: After informed consent and confirmation of trial eligibility criteria, the eye with worse visual function was selected for subretinal delivery of adeno-associated virus (AAV2-hRPE65v2). Subjects were evaluated before and after surgery at designated follow-up visits (1, 2, 3, 14, 30, 60, 90, 180, 270, and 365 days, 1.5 years, and 3 years) by complete ophthalmic examination. Efficacy for each subject was monitored with best-corrected visual acuity, kinetic visual field, nystagmus testing, and pupillary light reflex.

Main outcome measures: Best-corrected visual acuity, kinetic visual field, nystagmus testing, and pupillary light reflex.

Results: The data showed a statistically significant improvement of best-corrected visual acuity between baseline and 3 years after treatment in the treated eye (P<0.001). In all patients, an enlargement of the area of visual field was observed that remained stable until 3 years after injection (average values: baseline, 1058 deg(2) vs. 3 years after treatment, 4630 deg(2)) and a reduction of the nystagmus frequency compared with baseline at the 3-year time point. Furthermore, a statistically significant difference was observed in the pupillary constriction of the treated eye (P<0.05) compared with the untreated eye in 3 patients at 1- and 3-year time points. No patients experienced serious adverse events related to the vector in the 3-year postinjection period.

Conclusions: The long-term follow-up data (3 years) on the 5-patient Italian cohort involved in the LCA2 gene therapy clinical trial clearly showed a stability of improvement in visual and retinal function that had been achieved a few months after treatment. Longitudinal data analysis showed that the maximum improvement was achieved within 6 months after treatment, and the visual improvement was stable up to the last observed time point.

Financial disclosure(s): Proprietary or commercial disclosure may be found after the references.

Conflict of interest statement

Conflict of interest: J.B. and A.M.M. are co-inventors on a patent (2797-11-US) for a method to treat or slow the development of blindness, but both waived any financial interest in this technology in 2002. K.A.H. and J.F.W. are co-inventors on a patent regarding methods of making AAV vectors for clinical studies (U.S. patent 61/299,184, 2010). J.B. and J.F.W. serve on the scientific advisory board for Avalanche Technologies. J.F.W. has consulted for Tacere Therapeutics, Genzyme, Novartis, and Genetix Inc. The other authors declare that they have no competing interests

Copyright © 2013 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1. Longitudinal data analysis of Best Corrected Visual Acuity (BCVA) in all the patients

The longitudinal data analysis showed an improvement of BCVA in treated eyes of all patients. LogMAR: logarithm of Minimum angle of resolution

Figure 2. Goldmann Visual Field (VF) at selected time-points and comparison with the injection site

Area of retina exposed to adeno-associated virus-mediated delivery of wild-type retinal pigment epithelium (AAV2-hRPE65v2) are shown on the left; overlapped VF isopters at baseline and post-treatment time-points are shown on the right. Average values of VF areas were the following: baseline: 1058 deg2 - day 60: 6387 deg2- day 180: 6402 deg2- 1,5 years: 4565 deg2- 3 years: 4630 deg2.. Age of the patient4s at baseline are reported in brackets.

Figure 5. Fundus Autofluorescence (AF) of NP01 and NP04

An increase of AF is shown in the treated eye compared to baseline and to the untreated eye for NP01 and NP04. The macula of NP01 showed moderately decreased AF of a mottled appearance. The AF signal from the center of the macula in NP04 is surrounded by a ring of moderately increased AF more evident in the left eye after treatment.