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Clinical Trial
. 2008 May 22;358(21):2240-8.
doi: 10.1056/NEJMoa0802315. Epub 2008 Apr 27.

Safety and Efficacy of Gene Transfer for Leber's Congenital Amaurosis

Free PMC article
Clinical Trial

Safety and Efficacy of Gene Transfer for Leber's Congenital Amaurosis

Albert M Maguire et al. N Engl J Med. .
Free PMC article


Leber's congenital amaurosis (LCA) is a group of inherited blinding diseases with onset during childhood. One form of the disease, LCA2, is caused by mutations in the retinal pigment epithelium-specific 65-kDa protein gene (RPE65). We investigated the safety of subretinal delivery of a recombinant adeno-associated virus (AAV) carrying RPE65 complementary DNA (cDNA) ( number, NCT00516477 []). Three patients with LCA2 had an acceptable local and systemic adverse-event profile after delivery of AAV2.hRPE65v2. Each patient had a modest improvement in measures of retinal function on subjective tests of visual acuity. In one patient, an asymptomatic macular hole developed, and although the occurrence was considered to be an adverse event, the patient had some return of retinal function. Although the follow-up was very short and normal vision was not achieved, this study provides the basis for further gene therapy studies in patients with LCA.


Figure 1
Figure 1. Retinal Appearance and Morphologic Features before and after Surgery in the Three Patients
In Panel A, 30-degree fundus photographs taken with a Topcon camera show the disk and macula of the right and left eyes of Patients 1, 2, and 3 before surgery. In the right eye of Patient 2, the preretinal membrane and retinal striae are visible (arrow), and in Patient 3, pigmentary changes in the foveal region are apparent. In Panel B, still photographs from video footage taken through the operating microscope show the right eye of each patient during subretinal injection of AAV2.hRPE65v2. The “before” photographs show the injection cannula just before delivery of the vector, and the “after” photographs show the appearance of the bleb. In Patient 1, the raised edge of the superonasal bleb is visible (arrows). In Patients 2 and 3, the margins of the macular blebs can be seen (arrows). In Panel C, fundus photographs taken during the early postoperative period show that blebs have resolved, leaving the retinas flat and without hemorrhage or retinal opacification. On day 5, a montage of fundus photographs of Patient’s 1 retina shows both the macula and the injected region, with the extent of the original detachment indicated (arrows); in Patient 2, the fovea is visibly intact. (Fundus photographs were not taken of Patient 3’s retina on day 5, but there was no evidence of hemorrhage or retinal opacification.) Panel D shows the retinal structure measured by optical coherence tomography before and after surgery in all three patients, with the respective fundus photographs. Optical coherence–tomographic images through the fovea are shown for all three patients at baseline and on day 30, for Patients 1 and 2 on day 5, and for Patient 2 on day 60. In Patient 2, the epiretinal membrane is visible at baseline (arrow) and can be seen in several subsequent scans; also visible is the normal foveal depression despite mild thinning. A full-thickness macular hole is apparent on day 30 and has not enlarged on day 60, and the surrounding retina has not detached. There was no cystic macular edema at any point.
Figure 2
Figure 2. Representative Results of Pupillometry in a Control Subject and before and after Subretinal Injection in the Right Eye of the Three Patients
Panels A and B show pupillary light reflexes in a control subject after dark adaptation and alternating stimulation with 0.04 lux, starting first in the right eye (red columns) and then in the left eye (blue columns), respectively. The red curves represent the diameter of the right pupil, and the blue curves represent the diameter of the left pupil. The pupillary light reflexes are shown after alternating stimulation with 10.0 lux, starting in the right and then in the left eye, respectively, for Patient 1 at baseline and 4.75 months after injection (Panels C and D) and for Patient 2 at baseline and 2.75 months after injection (Panels E and F). The pupillary light reflexes for Patient 3 at baseline and 1 month after injection are shown after alternating stimulation with 0.04 lux (Panels G and H) and with 10.0 lux (Panels I and J), first in the right eye and then in the left eye, respectively. To facilitate the comparison of overlapping curves in Panel C and Panels E through J, the baseline curves have been shifted up 2 mm with respect to the curves after treatment. The “before” curves were not captured in Panel D or for the left eye in Panel J because of interference from nystagmus.

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