Optic neuropathy in familial dysautonomia: determination of disease mechanisms and functional rescue.

Schepens Eye Research Institute, Boston MA

Investigators

Abstract

SUMMARY/ABSTRACT Familial dysautonomia (FD) is a severe neurodegenerative disorder caused by a splice site mutation in intron 20 of the elongator acetyltransferase complex subunit 1 (ELP1). Despite its complex neurological phenotype, FD patients suffer from progressive blindness that severely affects their quality of life. Patients with FD show a significant reduction in the thickness of the retinal nerve fiber layer (RNFL) due to progressive and selective loss of retinal ganglion cells (RGCs). Here, we aim to develop a retina-specific treatment for FD by comprehensive evaluation of systemic (SMC PTC680) and local (AAV2-U1a-ELP) therapeutic approaches to rescue visual function in FD. Our previous studies show that genetic or pharmacological modulation of ELP1 splicing or genetic supplementation of human ELP1 in the retina can rescue RGC loss in FD. However, the efficacy of these treatment options to rescue visual function in FD has not been investigated. Through a detailed interrogation of the cellular and visual function of the FD retina, we will not only compare the efficacy of systemic and local therapeutic approaches to rescue visual function but also better understand the disease pathology. We propose to evaluate the impact on the visual function of two different therapeutic approaches through comprehensive visual function testing using electrophysiological and optokinetic methods in novel retina-specific conditional Elp1 knock-out with human ELP1 transgene containing FD mutation (transgenic cKO) mice (Aim 1). To understand the molecular mechanism of selective RGC loss in FD through the identification of key regulatory pathways involved in RGC survival which are dysregulated by the reduction of ELP1. We will use single-cell RNA seq (scRNAseq) to computationally link RGC survival to transcriptomic alterations in the FD mouse RGCs (Aim 2). Finally, by using patient-derived induced pluripotent stem cell (iPSC) RGCs, we will investigate the RGC degeneration and test the efficacy of the therapeutic approaches in a human model system (Aim 3). The proposed work will investigate the efficacy of therapeutic options for FD and uncover the underlying molecular mechanism behind RGC loss. The proposed work will directly translate to designing the best therapeutic strategies to treat optic neuropathy in FD.