Reduction of retinal ganglion cell death in mouse models of familial dysautonomia using AAV-mediated gene therapy and splicing modulators
Schultz, Anastasia Cheng, Shun-Yun Kirchner, Emily Costello, Stephanann Miettinen, Heini Chaverra, Marta King, Colin George, Lynn Zhao, Xin Narasimhan, Jana
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Abstract
Familial dysautonomia (FD) is a rare neurodevelopmental and neurodegenerative disease caused by a splicing mutation in the Elongator Acetyltransferase Complex Subunit 1 (ELP1) gene. The reduction in ELP1 mRNA and protein leads to the death of retinal ganglion cells (RGCs) and visual impairment in all FD patients. Currently patient symptoms are managed, but there is no treatment for the disease. We sought to test the hypothesis that restoring levels of Elp1 would thwart the death of RGCs in FD. To this end, we tested the effectiveness of two therapeutic strategies for rescuing RGCs. Here we provide proof-of-concept data that gene replacement therapy and small molecule splicing modifiers effectively reduce the death of RGCs in mouse models for FD and provide pre-clinical foundational data for translation to FD patients.
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Schultz A, Cheng SY, Kirchner E, Costello S, Miettinen H, Chaverra M, King C, George L, Zhao X, Narasimhan J, Weetall M, Slaugenhaupt S, Morini E, Punzo C, Lefcort F. Reduction of retinal ganglion cell death in mouse models of familial dysautonomia using AAV-mediated gene therapy and splicing modulators. Sci Rep. 2023 Oct 30;13(1):18600. doi: 10.1038/s41598-023-45376-w. PMID: 37903840; PMCID: PMC10616160.