Reduction of retinal ganglion cell death in mouse models of familial dysautonomia using AAV-mediated gene therapy and splicing modulators

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 data foundation for translation to FD patients. ### Competing Interest Statement The authors declare competing financial interests. Xin Zhao, Jana Narasimhan, and Marla Weetall are employees of PTC Therapeutics, Inc., a biotechnology company. In connection with such employment, the authors receive salary, benefits, and stock-based compensation, including stock options, restricted stock, other stock-related grants, and the right to purchase discounted stock through PTC's employee stock purchase plan. Susan A. Slaugenhaupt is a paid consultant to PTC Therapeutics and is an inventor on several U.S. and foreign patents and patent applications assigned to the Massachusetts General Hospital, including U.S Patents 8,729,025 and 9,265,766, both entitled Methods for altering mRNA splicing and treating familial dysautonomia by administering benzyladenine, filed on August 31, 2012 and May 19, 2014 and related to use of kinetin; and U.S. Patent 10,675,475 entitled, Compounds for improving mRNA splicing filed on July 14, 2017 and related to use of BPN-15477. Elisabetta Morini and Susan A. Slaugenhaupt are inventors on an International Patent Application Number PCT/US2021/012103, assigned to Massachusetts General Hospital and PTC Therapeutics entitled RNA Splicing Modulation related to use of BPN-15477 in modulating splicing. All other authors declare no competing interests.