About 5 years ago, results were made public from three independent early phase clinical gene therapy trials for an inherited and early onset form of retinal blindness called Leber congenital amaurosis due to RPE65 deficiency (LCA2)(Bainbridge et al., 2008; Cideciyan et al., 2008; Hauswirth et al., 2008; Maguire et al., 2008). These studies were arguably a first for an in vivo gene therapy approach to convincingly deliver both on safety and efficacy. Indeed, subjects suffering from a progressive loss of vision due to this retinal dystrophy regained moderate yet significant improvements in light perception and more complex vision. The binary hallmark of the pathology of LCA2, as well as of most other hereditary retinal blindness, is a combined dysfunction and degeneration of photoreceptor cells (Bramall et al., 2010; Hartong et al., 2006). For these retinal dystrophies with autosomal recessive inheritance, the hope and anticipation was that supplementation of the wild-type cDNA of the disease gene would ameliorate both the dysfunction, resulting in improved vision, and the degeneration, leading to preservation of photoreceptors. In the first reports from the LCA2 trials, vision tests were primarily used to evaluate efficacy. However, a recently published follow-up study by Cideciyan et al.(2013) studied both aspects of the disease in subjects enrolled in one of the three clinical trials. Remarkably, the authors found that while gene therapy indeed leads to a long-term improvement of vision, the photoreceptor cell layer continued to decline and gene augmentation effectively leaves the degenerative processes undisturbed.

Cideciyan and others (2013) first performed a thorough study of the natural history of the disease, which provided essential data for interpreting the findings from the treated patients. They used a key measure of retinal degeneration, the thickness of the photoreceptor layer, referred to as the outer nuclear layer (ONL). Improvements in imaging technology over the last decade now make it possible to noninvasively monitor ONL thickness by optical coherence tomography (OCT), which can provide retinal cross-section images at high resolution. OCT has allowed for longitudinal evaluations of retinal degenerative disease processes, as well as the impact of experimental therapies. Once the natural