Novel oral drug treatment rescues progressive optic neuropathy in a phenotypic mouse model of familial dysautonomia

Abstract

Purpose : Familial Dysautonomia (FD) is a progressive neurodegenerative disease caused by a splice site mutation in the Elongator complex Protein 1 (ELP1). This mutation leads to the skipping of exon 20 and a tissue-specific reduction of ELP1 protein, mainly in the nervous system. Despite its complex neurological phenotype, FD patients also suffer from progressive retinal degeneration due to significant reduction of the retinal nerve fiber layer (RNFL) resulted by death of retinal ganglion cells (RGCs). We generated a novel class of compounds with improved potency that can specifically correct the ELP1 splicing defect. We optimized the potency, efficacy, and biodistribution of these compounds to develop an oral treatment for FD that could efficiently pass the blood-brain barrier and correct the ELP1 splicing defect in the central nervous system, including the retina. In this study, we demonstrated that the novel compound PTC258 efficiently restores ELP1 splicing defect in the retina and significantly rescues optic neuropathy in a phenotypic mouse model of FD.

Methods : To assess the therapeutic efficacy of PTC258, we treated the phenotypic FD mouse model TgFD9; Elp1^Δ20/flox through specially formulated chow. Further evaluation of the effect of PTC258 on optic neuropathy observed in FD mice was performed using high-definition spectral-domain optical coherence tomography (SD-OCT). RGC number in the treated and control mice was evaluated using retinal flat-mount analysis.

Results : Our results indicate that PTC258 significantly corrects ELP1 splicing defect in the retina and rescues optic neuropathy in FD mice. SD-OCT analysis of the treated and control retinas showed a significant dose-dependent improvement in the thickness of the RNFL in the treated FD mice compared to control mice. Furthermore, analysis of RGC number indicated significant rescue of RGC loss in the retinas of PTC258 treated mice compared to the control.

Conclusions : We show for the first time the therapeutic efficacy of an oral drug to treat progressive optic neuropathy in FD. Our data indicate that the phenotypic improvement in FD mice correlates with the correction of the underlying FD splicing defect, which leads to an increase in full-length ELP1 transcript. Our findings highlight the therapeutic potential of this novel class of small molecules as an oral treatment for FD.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.