Abstract
Familial dysautonomia (FD) is an autosomal recessive neurodegenerative disease caused by a splicing mutation in the gene encoding Elongator complex protein 1 (ELP1, also known as IKBKAP). This mutation results in tissue-specific skipping of exon 20 with a corresponding reduction of ELP1 protein, predominantly in the central and peripheral nervous system. Although FD patients have a complex neurological phenotype caused by continuous depletion of sensory and autonomic neurons, progressive visual decline leading to blindness is one of the most problematic aspect of the disease, as it severely affects their quality of life. To better understand the disease mechanism as well as to test the in vivo efficacy of targeted therapies for FD, we have recently generated a novel phenotypic mouse model, TgFD9; Elp1∆20/flox. This mouse exhibits most of the clinical features of the disease and accurately recapitulates the tissue-specific splicing defect observed in FD patients. Driven by the dire need to develop therapies targeting retinal degeneration in FD, herein, we comprehensively characterized the progression of the retinal phenotype in this mouse, and we demonstrated that it is possible to correct ELP1 splicing defect in the retina using the splicing modulator compound (SMC) BPN-15477.
Competing Interest Statement
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 entitled RNA Splicing Modulation related to use of BPN-15477 in modulating splicing. Luk H. Vandenberghe (LHV) holds equity in Affinia Therapeutics and Akouos and serves on the Board of Directors of Affinia Therapeutics, Addgene and Odylia. LHV is compensated for his scientific advisory position with Affinia and Akouos. LHV is an SAB member to Akouos, consultant to Affinia and Novartis and receives research support from Novartis. LHV's interests were reviewed and are managed by Mass Eye and Ear and Mass General Brigham in accordance with their conflict-of-interest policies.
Abbreviations
- FBS
- Fetal bovine serum
- DAPI
- 4′,6-diamidino-2-phenylindole
- HCL
- Hydrochloric acid
- EDTA
- Ethylenediaminetetraacetic acid
- mRNA
- messenger Ribonucleic acid
- Tg
- Transgenic
