A demonstration of cone function plasticity after gene therapy in achromatopsia

Recent advances in regenerative therapy have placed the treatment of many previously incurable eye diseases within arms-reach (Ciulla et al., 2020). Achromatopsia (ACHM) is a severe monogenic heritable retinal disease that disrupts cone function from gestation, leaving patients with complete colour blindness, low acuity, photosensitivity, and nystagmus (Hirji, Aboshiha, et al., 2018). In non-primate animal models of ACHM, retinal gene-replacement therapy has successfully induced cone function in the young (Alexander et al., 2007; Carvalho et al., 2011), but it was yet to be determined if and when these therapies could effectively impact cone-mediated pathways in the human brain. Here we demonstrate in children with ACHM that gene therapy can yield substantial improvement in cone-mediated vision, via cascading effects on signal transmission from retina to cortex. To measure the effects of treatment in children with ACHM (CNGA3- and CNGB3-associated, all aged 10+ years), we developed novel visual stimuli, calibrated to selectively activate cone photoreceptors. We used these in behavioural psychophysics and functional MRI with population receptive field mapping, pre- and post-treatment. The results of treatment, contextualized against data from 12 untreated ACHM patients and 25 normal-sighted, revealed that six months post-therapy, two patients displayed novel responses to our cone-selective stimuli in the visual cortex, with a retinotopic organisation characteristic of normal-sighted individuals, not present in untreated ACHM. This was paired with significant improvement in cone-mediated perception specific to the treated eye, and self-reports of improved vision. Two other patients did not show a post-treatment effect, potentially reflecting individual differences in therapeutic outcome. Together, these data show that gene replacement therapy in humans with ACHM can activate dormant cone pathways despite long-term deprivation. This offers great promise for regenerative therapies, and their ability to trigger the neural plasticity needed to cure congenital vision loss in human patients.