ELP1 Gene Augmentation Restores Visual Function in a Mouse Model of Familial Dysautonomia

Familial dysautonomia (FD) is an autosomal recessive sensory and autonomic neurodevelopmental and degenerative disorder characterized by complex neurological phenotypes. One of its most debilitating features is progressive optic neuropathy, which leads to severe visual impairment in FD patients by the third decade of life. Although several preclinical approaches have shown partial rescue of retinal ganglion cell (RGC) degeneration through increasing Elongator acetyltransferase complex subunit 1 (ELP1) expression in the retina, currently no treatments exist to prevent vision loss in FD. In this study, 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 protein levels in the retina. Longitudinal retinal assessments indicated that FD mice exhibit significant retinal nerve fiber layer (RNFL) thinning, as observed in FD patients. FD mice also showed reduced flash visual evoked potentials (VEPs), pattern electroretinography (pERGs), and photopic negative responses (phNRs) amplitudes, along with impaired visual acuity and contrast sensitivity, as assessed using optomotor response assay (OMR). Full-field electroretinography (ffERG) revealed reduced amplitude of dark-adapted a-waves, dark and light-adapted b-waves, indicating combined RGC and bipolar cell dysfunction. Intravitreal delivery of an adeno associated vector (AAV) vector (AAV2.U1a.hELP1) effectively restored physiological ELP1 protein expression, which resulted in a significant rescue of retinal structure and function. Gene supplementation with AAV2.U1a.hELP1 resulted in broad functional and structural improvement compared with untreated FD mice. In summary, our findings provide the first demonstration that ELP1 gene supplementation can effectively rescue RGC function in an FD mouse model and support AAV2.hELP1 at an optimized dose (5.4x108 vg) as a promising therapeutic approach for FD-associated optic neuropathy.