June 2020
Volume 61, Issue 7
Open Access
ARVO Annual Meeting Abstract  |   June 2020
Characterization of the retinal phenotype in a humanized FD mouse model with defective ELP1 splicing.
Author Affiliations & Notes
  • Anil Kumar Chekuri
    Center for Genomic Medicine, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, Massachusetts, United States
    Department of Neurology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, Massachusetts, United States
  • Elisabetta Morini
    Center for Genomic Medicine, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, Massachusetts, United States
    Department of Neurology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, Massachusetts, United States
  • Xia Wang
    Grousbeck Gene Therapy Center, Schepens Eye Research Institute and Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, United States
  • Emily Logan
    Center for Genomic Medicine, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, Massachusetts, United States
    Department of Neurology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, Massachusetts, United States
  • Aram Krauson
    Center for Genomic Medicine, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, Massachusetts, United States
    Department of Neurology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, Massachusetts, United States
  • Monica Salani
    Center for Genomic Medicine, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, Massachusetts, United States
    Department of Neurology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, Massachusetts, United States
  • Paula Dietrich
    Department of Physiology, the University of Tennessee, Health Science Center, Memphis, Tennessee, United States
  • Ioannis Dragatsis
    Department of Physiology, the University of Tennessee, Health Science Center, Memphis, Tennessee, United States
  • Luk H Vandenberghe
    Grousbeck Gene Therapy Center, Schepens Eye Research Institute and Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, United States
  • Susan Slaugenhaupt
    Center for Genomic Medicine, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, Massachusetts, United States
    Department of Neurology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, Massachusetts, United States
  • Footnotes
    Commercial Relationships   Anil Chekuri, None; Elisabetta Morini, None; Xia Wang, None; Emily Logan, None; Aram Krauson, None; Monica Salani, None; Paula Dietrich, None; Ioannis Dragatsis, None; Luk Vandenberghe, None; Susan Slaugenhaupt, None
  • Footnotes
    Support  NIH
Investigative Ophthalmology & Visual Science June 2020, Vol.61, 191. doi:
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      Anil Kumar Chekuri, Elisabetta Morini, Xia Wang, Emily Logan, Aram Krauson, Monica Salani, Paula Dietrich, Ioannis Dragatsis, Luk H Vandenberghe, Susan Slaugenhaupt; Characterization of the retinal phenotype in a humanized FD mouse model with defective ELP1 splicing.. Invest. Ophthalmol. Vis. Sci. 2020;61(7):191.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Familial dysautonomia (FD) is an autosomal recessive neurodegenerative disorder caused by a splice mutation in the gene encoding Elongator complex protein 1 (ELP1, also known as IKBKAP). This mutation results in skipping of exon 20 and tissue specific reduction of ELP1 protein levels, predominantly in the central and peripheral nervous system. Although FD patients exhibit a complex neurological phenotype due to the degeneration of sensory and autonomic neurons, progressive retinal degeneration severely impacts quality of life. Two different mouse models have been previously generated to study the retinal phenotype that results from complete loss of ELP1. However, neither of these models accurately recapitulates the tissue specific defective splicing observed in FD patients. Therefore, we developed a novel FD phenotypic mouse model by introducing a transgene carrying the human ELP1 gene with the FD splice mutation (TgFD9) into a hypomorphic mouse that expresses low levels of endogenous Elp1 (Elp1△20/flox). This mouse model displays both the clinical features of the disease and the tissue specific mis-splicing observed in FD patients.

Methods : Detailed characterization of the retinal phenotype in the FD mouse model was performed to investigate the pathology associated with the splice mutation in ELP1. Optical Coherence Tomography (OCT) was performed to investigate retinal thickness and retinal morphology was studied using H and E staining. Retinal ganglion cell (RGC) cell counting was performed using retinal whole mounts.

Results : Optical Coherence Tomography (OCT) analysis to investigate retinal thickness revealed significant reduction in the thickness of the retinal nerve fiber layer (RFNL) and Ganglion cell layer (GCL) when compared to control littermates. Analysis of retinal morphology revealed progressive loss of RGC's. Results from whole mount analysis also indicated the loss RGC's in the FD mouse model.

Conclusions : Our findings suggest that our novel FD mouse model recapitulates optic neuropathy observed in FD patients and will provide a platform to test the in vivo efficacy of ELP1 splicing modulation to increase functional ELP1 in the retina.

This is a 2020 ARVO Annual Meeting abstract.

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