June 2017
Volume 58, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2017
Modeling Pharmacological Treatment of Retinitis Pigmentosa with Heterozygous Tvrm4 Rhodopsin Mutant Mice
Author Affiliations & Notes
  • Robin H Schmidt
    Ophthalmology, Emory University, Atlanta, Georgia, United States
  • Preston E Girardot
    Ophthalmology, Emory University, Atlanta, Georgia, United States
  • Jana Terrell Sellers
    Ophthalmology, Emory University, Atlanta, Georgia, United States
  • Micah A Chrenek
    Ophthalmology, Emory University, Atlanta, Georgia, United States
  • Jeffrey H Boatright
    Ophthalmology, Emory University, Atlanta, Georgia, United States
    Atlanta VA Center of Excellence in Vision and Neurocognitive Rehabilitation, Atlanta, Georgia, United States
  • Footnotes
    Commercial Relationships   Robin Schmidt, None; Preston Girardot, None; Jana Sellers, None; Micah Chrenek, None; Jeffrey Boatright, None
  • Footnotes
    Support  NIH R01EY014026; VA RR&D C1924P; VA RR&D C9246C (Atlanta VA Center of Excellence in Vision and Neurocognitive Rehabilitation); Abraham and Phyllis J. Katz Foundation, Research to Prevent Blindness
Investigative Ophthalmology & Visual Science June 2017, Vol.58, 3595. doi:
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      Robin H Schmidt, Preston E Girardot, Jana Terrell Sellers, Micah A Chrenek, Jeffrey H Boatright; Modeling Pharmacological Treatment of Retinitis Pigmentosa with Heterozygous Tvrm4 Rhodopsin Mutant Mice. Invest. Ophthalmol. Vis. Sci. 2017;58(8):3595.

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

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Abstract

Purpose : Pharmacological treatments for retinitis pigmentosa (RP), a disease characterized by progressive loss of vision, can be challenging to develop and test. The mostly widely-used mouse models of RP are transgenic strains. The Rho(Tvrm4/+) mouse, a model of Class B phenotype RP, carries a single point mutation in the gene that encodes rhodopsin, causing retinal degeneration after brief exposure to bright light. In contrast to transgenic models, the degeneration process that occurs in the Rho(Tvrm4/+) mouse model is inducible, allowing for more precise coordination of drug administration with particular stages in disease progression. We tested the ability of the neuroprotectant tauroursodeoxycholic acid (TUDCA) to prevent retinal degeneration in the Rho(Tvrm4/+) mouse.

Methods : TUDCA (500 mg/kg) was injected i.p. in Rho(Tvrm4/+) mice (N=5 for each group) prior to light exposure. Pupils were dilated by applying a 0.2% atropine solution. After 30 minutes, mice were exposed to 12,000 lux LED white light for 5 minutes. Mice were then returned to maintenance housing and TUDCA administered every 3 days thereafter. Retinal function was assessed by electroretinography (ERG) and visual function assessed by optokinetic tracking (OKT). Eyes were removed at sacrifice for histology and gene transcription analysis by ddPCR. Photoreceptor nuclei were counted in histological sections stained with toluidine blue.

Results : ERG analysis showed that TUDCA treatment completely prevented changes in a- and b-wave amplitude (p<0.0001). TUDCA preserved the number of photoreceptors in light-exposed mice (p=0.0002). Protection against degeneration coincided with decreased mRNA transcripts of genes regulating the complement system. TUDCA treatment had no effect on retinal structure or visual function in mice that were not exposed to bright light.

Conclusions : TUDCA-treated Rho(Tvrm4/+) mice were protected against loss of visual function caused by brief bright light exposure. TUDCA treatment also showed near-complete preservation of retinal morphology and photoreceptor cell numbers. Our data support the use of TUDCA in RP, and potentially in other retinal degenerative diseases. Additionally, the predictable triggering of retinal degeneration in the Rho(Tvrm4/+) mouse means that this genetic model may be useful for testing other candidate drugs.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.

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