ELP1 gene augmentation restores visual function in a mouse model of familial dysautonomia.

Familial dysautonomia (FD) is a neurodevelopmental and neurodegenerative disorder characterized by complex neurological phenotypes. In FD patients, progressive optic neuropathy leads to severe visual impairment by the third decade of life, substantially impacting their quality of life. Although several preclinical approaches have demonstrated partial rescue of retinal ganglion cell (RGC) degeneration by increasing Elongator acetyltransferase complex subunit 1 (ELP1) expression, it has not been demonstrated that this translates into prevention of vision loss in FD, and there are currently no approved treatments. Here, we performed a comprehensive analysis of visual function in a retina-specific FD mouse model (Pax6-Cre+;Elp1loxp/loxp) and evaluated a gene-supplementation strategy to restore human ELP1 expression. Longitudinal retinal assessments revealed significant retinal nerve fiber layer thinning, consistent with findings in FD patients. FD mice exhibited broad visual dysfunction, including reduced electrophysiological responses and impaired visual acuity, indicative of combined RGC and bipolar cell deficits. Intravitreal delivery of AAV2.U1a.hELP1 significantly rescued retinal structure and function compared with untreated FD mice. Together, these findings provide the first demonstration that ELP1 gene supplementation restores RGC function in an FD model and support AAV2.hELP1 (5.4 × 108 vg) as a promising therapeutic approach for FD-associated optic neuropathy.