Research Article: Canine and Human Visual Cortex Intact and Responsive Despite Early Retinal Blindness from RPE65 Mutation

Date Published: June 26, 2007

Publisher: Public Library of Science

Author(s): Geoffrey K Aguirre, András M Komáromy, Artur V Cideciyan, David H Brainard, Tomas S Aleman, Alejandro J Roman, Brian B Avants, James C Gee, Marc Korczykowski, William W Hauswirth, Gregory M Acland, Gustavo D Aguirre, Geoffrey K Aguirre, Alvaro Pascual-Leone

Abstract: BackgroundRPE65 is an essential molecule in the retinoid-visual cycle, and RPE65 gene mutations cause the congenital human blindness known as Leber congenital amaurosis (LCA). Somatic gene therapy delivered to the retina of blind dogs with an RPE65 mutation dramatically restores retinal physiology and has sparked international interest in human treatment trials for this incurable disease. An unanswered question is how the visual cortex responds after prolonged sensory deprivation from retinal dysfunction. We therefore studied the cortex of RPE65-mutant dogs before and after retinal gene therapy. Then, we inquired whether there is visual pathway integrity and responsivity in adult humans with LCA due to RPE65 mutations (RPE65-LCA).Methods and FindingsRPE65-mutant dogs were studied with fMRI. Prior to therapy, retinal and subcortical responses to light were markedly diminished, and there were minimal cortical responses within the primary visual areas of the lateral gyrus (activation amplitude mean ± standard deviation [SD] = 0.07% ± 0.06% and volume = 1.3 ± 0.6 cm3). Following therapy, retinal and subcortical response restoration was accompanied by increased amplitude (0.18% ± 0.06%) and volume (8.2 ± 0.8 cm3) of activation within the lateral gyrus (p < 0.005 for both). Cortical recovery occurred rapidly (within a month of treatment) and was persistent (as long as 2.5 y after treatment). Recovery was present even when treatment was provided as late as 1–4 y of age. Human RPE65-LCA patients (ages 18–23 y) were studied with structural magnetic resonance imaging. Optic nerve diameter (3.2 ± 0.5 mm) was within the normal range (3.2 ± 0.3 mm), and occipital cortical white matter density as judged by voxel-based morphometry was slightly but significantly altered (1.3 SD below control average, p = 0.005). Functional magnetic resonance imaging in human RPE65-LCA patients revealed cortical responses with a markedly diminished activation volume (8.8 ± 1.2 cm3) compared to controls (29.7 ± 8.3 cm3, p < 0.001) when stimulated with lower intensity light. Unexpectedly, cortical response volume (41.2 ± 11.1 cm3) was comparable to normal (48.8 ± 3.1 cm3, p = 0.2) with higher intensity light stimulation.ConclusionsVisual cortical responses dramatically improve after retinal gene therapy in the canine model of RPE65-LCA. Human RPE65-LCA patients have preserved visual pathway anatomy and detectable cortical activation despite limited visual experience. Taken together, the results support the potential for human visual benefit from retinal therapies currently being aimed at restoring vision to the congenitally blind with genetic retinal disease.

Partial Text: The childhood-onset incurable human retinal blindness termed Leber congenital amaurosis (LCA) has become a target for in vivo gene transfer because of remarkable success in animal models of several molecular forms [1–5]. The most studied form of LCA is that due to mutations in RPE65 (RPE65-LCA), the critical retinoid (visual) cycle gene that encodes the isomerohydrolase in retinal pigment epithelium (RPE) cells [6,7]. Physiological and biochemical recovery at the level of the retina of RPE65-deficient dogs and mice is dramatic after a single viral-mediated transfer of the RPE65 gene (for example, [1,2,8,9]). Far less information is available on the details of recovery in postretinal visual pathways [10], and especially cortical visual function [1,11].

Congenitally blind RPE65-mutant dogs recovered responses within cortical visual areas after retinal gene therapy. Recovery was present even in a dog treated at 4 y of age. These results are concordant with demonstrations of recovery at retinal and subcortical levels [1,2,39,40] and relate well to the findings of improved visual evoked potentials and simple visual behavioral tasks in dogs and mice [1,11,39–41]. RPE65 deficiency essentially causes severe binocular light attenuation to the visual system, and a comparison to the extensive literature on cortical effects of early visual deprivation is of interest (reviewed in [42,43]). Visual deprivation in animals shortly after birth leads to a dramatic reduction of visually responsive neurons within cortical visual areas. The timing and type of deprivation affects the character and severity of alteration of cortical function [42–44]. Binocular eyelid suture, which produces modest light attenuation but severe form deprivation, produces greater abnormalities in cortical physiology than an equivalent period of dark rearing [45]. The standard model is that early visual experience during a critical period of neuronal plasticity defines the response properties of cortical visual neurons, and that after this period these properties become relatively immutable [43]. The 4-log-unit reduction in light sensitivity from retinoid cycle blockade in RPE65 deficiency likely falls between dark-rearing and lid-suture experimental paradigms. The recovery we observed after retinal gene therapy suggests that the visual cortex of the RPE65-mutant dog remained receptive to increased visual input for over 4 y.



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