Visual Tract Integrity before and after gene therapy in congenital Achromatopsia

Abstract CNGA3-achromatopsia is a rare hereditary syndrome caused by dysfunction of cone photoreceptors, resulting in low acuity, photoaversion and complete color blindness. Trials utilizing gene therapy have recently been initiated, but only limited clinical improvement has been observed. To explain this suboptimal outcome, we used diffusion tensor image (DTI) to assess visual pathway integrity in three CNGA3-achromatopsia patients before and after gene therapy, and compared them to 16 normally sighted adults. No significant differences from normal subjects in optic tract and radiation integrity were detected. Fiber integrity reduction was observed in the occipito-callosal fibers. These differences showed some normalization after treatment, but inter-subject variability was evident. Specifically, the observed changes were related to radial diffusivities, reflecting fiber myelination or glial cell alterations. Despite the fundamental role of cone photoreceptors in human sight, primary visual pathways in CNGA3-achromatopsia patients are comparable to those of healthy individuals. Nevertheless, splenial fibers, which are involved in a later phase of visual processing, appear to be affected by the altered cortical activity, being less cohesive in naïve patients. Following treatment, these fibers regain some integrity, suggesting that novel information is processed within the visual cortex and that integrity may be restored to better transmit this information.