Leber Congenital Amaurosis gene therapy clinical trial

Abstract

The preclinical efficacy and safety basis for a recently initiated AAV vector clinical trial for LCA2 (Leber Congenital Amaurosis due to recessive RPE65 mutations) will be outlined and followed by a summary of our 12-month safety and visual function studies of the initial three clinical trial patients. LCA2 causes childhood blindness and has been considered incurable. Each LCA2 patient received 150ul (5.9 exp10 vector genomes) of GMP grade AAV2-CBA-hRPE65 vector subretinally at a single site and their visual function then followed periodically over the next year. No adverse events were noted for any patient and all patients tolerated the procedure without incident. All three patients also exhibited substantial and significant improvement in light sensitivity, but only in the area of retina that received vector, as documented by high density threshold perimetry. Surprisingly, within the treated area of retina, each patient also demonstrated very slow dark adaptation kinetics. When re-examined after full dark adaption, each patient now exhibited even more recovered sensitivity to light, up to 63,000 times better that their pretreatment baselines. After correcting for the fraction of photoreceptors lost in each patient before treatment, we conclude that two of the three patients experienced full recovery of retinal function within the vector treated area.

At one year post-treatment, but not before, one patient reported new visual perceptions that mapped to the treatment area. When the patient was asked to detect a very bright colored target that she could see before treatment she continued to use her fovea, her only area of useable, although poor, vision at baseline. If, however, she was asked to detect a dimmer target that she could not detect at pretreatment baseline, she could not see it at any time up to 9 months post-treatment. However, at 12 months the patient reported seeing the dim object for the first time. When detecting this target the patient now shifted her center of visual perception away from her fovea to the treated retinal area. In effect, the patient had developed a second fovea or “pseudo-fovea” that was used only when the target was too dim to be perceived by her anatomical fovea. Determination of the 3-dimensional retinal topography of cone sensitivity confirmed that the patient had not lost her area of foveal sensitivity but had gained an extra-foveal area of chromatic sensitivity corresponding to the vector treated area. This slow emergence of a pseudo-fovea suggests that cortical “learning” is possible but slow in a young adult.