fMRI of Recovered Cortical Visual Responses Following Gene Therapy in Dogs

Abstract

Abstract: : Purpose:To determine if recovery of cortical function accompanies recovery of retinal function following gene therapy in RPE65 mutant dogs. Methods:Eight dogs participated in a total of 14 sessions: two normal animals, three pre–treatment and four post–treatment. Affected animals were congenitally blind from an RPE65 null mutation; an animal model of human Leber's congenital amaurosis. Treatment consisted of subretinal injection of an adeno–virus vector carrying the wild–type RPE65 gene. Animals were ventilated during scanning following administration of ketamine/valium and pancuronium. Visual stimulation during functional magnetic resonance imaging (fMRI) was produced with a full–field, flashing (5 Hz) checkerboard, with on–off periods of 21s. Evoked BOLD (blood oxygen level dependent) cortical responses were detected with a basis set analysis that did not rely upon specification of the hemodynamic response. Results:Robust fMRI responses were observed in striate and extra–striate cortical areas in normal animals, but were absent in affected dogs pre–treatment. Gene therapy produced robust cortical responses in the treated, affected animals as soon as 1 month post treatment, and were present over 2 years after treatment. fMRI responses were also observed in the retina in normal and treated animals only. Gene therapy at a later age (>340 days vs. <170 days) appeared to produce greater recovery in extra–striate cortex and less in primary visual cortex, although insufficient power was present to formally test this impression across the population. Conclusions:Recovered visual function in congenitally blind dogs following gene therapy is accompanied by recovered cortical and retinal responses readily detected using fMRI. Differential recovery in striate and extra–striate cortical areas would be consonant with lesion and physiology studies that have found different "critical periods" for visual development in feline striate and lateral suprasylvian areas.

Keywords: gene transfer/gene therapy • retinal degenerations: hereditary • imaging methods (CT, FA, ICG, MRI, OCT, RTA, SLO, ultrasound)