DEVELOPMENT OF A NOVEL ORAL COMPOUND THAT RESTORES ELP1 SPLICING AND RESCUES GAIT ATAXIA AND RETINAL DEGENERATION IN A MOUSE MODEL OF FAMILIAL DYSAUTONOMIA

Abstract

Familial dysautonomia (FD) is a neurodegenerative disorder that affects the development and survival of sensory and autonomic neurons. FD is caused by a splicing mutation in the Elongator complex protein 1 (ELP1) gene that leads to a tissue-specific skipping of exon 20 and a corresponding reduction of ELP1 protein. Patients with FD have a complex neurological phenotype with diminished pain and temperature perception, decreased or absent myotatic reflexes, proprioceptive gait ataxia, and progressive retinal degeneration. There is still no effective treatment available to restore ELP1 protein expression in individuals with FD, and the disease is ultimately fatal. We developed a novel splicing modulator compound, BPN-36964, that selectively increases the inclusion of ELP1 exon 20, and we tested in vivo efficacy in a phenotypic mouse model of FD. This mouse recapitulates the tissue-specific ELP1 mis-splicing observed in FD patients as well as key disease phenotypes including gait ataxia. Mice were treated via specially formulated chow at doses of 4.5 mg/kg/day. Treatment resulted in a dose-dependent increase in full-length ELP1 transcript. Functional assessments at six months of age showed that FD mice treated with 4.5 mg/kg/day exhibited significantly improved stride length compared to vehicle-treated controls, indicating improved motor coordination. Immunohistochemical analysis was used to find the volume of dorsal root ganglion (DRG) and number of proprioceptive neurons. BPN-36964 also rescued retinal degeneration in FD mice. High-definition spectral-domain optical coherence tomography (OCT) revealed a significant rescue at 4.5 mg/kg/day. Immunohistochemical analysis of retinal flat-mounts showed partial rescue of RGCs at the low dose and complete rescue at the high dose. Our findings demonstrate the therapeutic potential of BPN-36964 as an oral splicing modulator to restore ELP1 expression and ameliorate key clinical features of FD.

For more information: amiura@eckerd.edu