July 2019
Volume 60, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2019
Small molecules restore the expression and function of mutant alleles underpinning autosomal dominant and recessive inherited retinal dystrophies
Author Affiliations & Notes
  • Jingshu Liu
    The University of Manchester, Manchester, United Kingdom
  • Forbes Manson
    The University of Manchester, Manchester, United Kingdom
  • Graeme Black
    The University of Manchester, Manchester, United Kingdom
  • Footnotes
    Commercial Relationships   Jingshu Liu, None; Forbes Manson, None; Graeme Black, None
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science July 2019, Vol.60, 6056. doi:
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      Jingshu Liu, Forbes Manson, Graeme Black; Small molecules restore the expression and function of mutant alleles underpinning autosomal dominant and recessive inherited retinal dystrophies. Invest. Ophthalmol. Vis. Sci. 2019;60(9):6056.

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

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Abstract

Purpose : Mutations leading to protein misfolding are associated with many retinal dystrophies. The cellular response to this can result in reduced expression or mislocalisation of the mutant protein. Gene therapy is expensive and can time consuming to develop, and is restricted to autosomal recessive disease. We sought to identify small molecules that could rescue the function of multiple mutant alleles associated with different modes of inheritance as a faster and more economic approach to developing therapeutic agents using bestrophin-1 as an exemplar.

Methods : Expression and localization of wildtype and mutant bestrophin-1 was tested by western blot and immunofluorescence in stably-transfected MDCKII cell lines. Whole-cell patch-clamp was performed on transiently transfected HEK293T cells for functional analysis. Sodium phenylbutyrate (4PBA) and its analogue 2-Naphthoxyacetic acid sodium salt (2-NOAA) were tested for their ability to rescue the expression and function of mutant bestrophin-1.

Results : Western blot result showed that the expression level of mutant bestrophhin-1 was significantly increased by 4PBA (p<0.05) or 2-NOAA (p<0.001) compared to the untreated groups. Immunofluorescence showed that the membrane-localized mutant bestrophin-1 was remarkably increased by 4PBA (p<0.05) or 2-NOAA (p<0.01) treatment. The impaired Cl- channel function of the dominant mutants was partially rescued by the treatment (p<0.05 compared to the untreated group and p<0.05 compared to the wild-type) and that of the recessive mutant was fully restored to the wild-type level.

Conclusions : Our data demonstrates that small molecules can restore the expression, trafficking and channel function of autosomal dominant and recessive mutant bestrophin-1 in vitro, paving the way for using small molecules as a therapy for bestrophinopathies.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.

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