Affordable Access

deepdyve-link
Publisher Website

Selective retinal ganglion cell loss and optic neuropathy in a humanized mouse model of familial dysautonomia.

Authors
  • Chekuri, Anil1, 2, 3
  • Logan, Emily M1
  • Krauson, Aram J1
  • Salani, Monica1
  • Ackerman, Sophie1
  • Kirchner, Emily G1
  • Bolduc, Jessica M1
  • Wang, Xia3
  • Dietrich, Paula4
  • Dragatsis, Ioannis4
  • Vandenberghe, Luk H3
  • Slaugenhaupt, Susan A1, 2
  • Morini, Elisabetta1, 2
  • 1 Center for Genomic Medicine, Massachusetts General Hospital Research Institute, Boston, MA, USA.
  • 2 Department of Neurology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, MA, USA.
  • 3 Grousbeck Gene Therapy Center, Schepens Eye Research Institute and Massachusetts Eye and Ear Infirmary, Boston, MA, USA.
  • 4 Department of Physiology, The University of Tennessee, Health Science Center, Memphis, TN, USA.
Type
Published Article
Journal
Human Molecular Genetics
Publisher
Oxford University Press
Publication Date
Jun 04, 2022
Volume
31
Issue
11
Pages
1776–1787
Identifiers
DOI: 10.1093/hmg/ddab359
PMID: 34908112
Source
Medline
Language
English
License
Unknown

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 aspects 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; IkbkapΔ20/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. © The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected]

Report this publication

Statistics

Seen <100 times