Small molecules restore bestrophin 1 expression and function of both dominant and recessive bestrophinopathies in patient-derived retinal pigment epithelium

Jingshu Liu, Rachel L. Taylor, Richard A. Baines, Lisa Swanton, Sally Freeman, Barbara Corneo, Achchhe Patel, Alan Marmorstein, Travis Knudsen, Graeme C. Black, Forbes Manson

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

PURPOSE. Bestrophinopathies are a group of untreatable inherited retinal dystrophies caused by mutations in the retinal pigment epithelium (RPE) Cl− channel bestrophin 1. We tested whether sodium phenylbutyrate (4PBA) could rescue the function of mutant bestrophin 1 associated with autosomal dominant and recessive disease. We then sought analogues of 4PBA with increased potency and determined the mode of action for 4PBA and a lead compound 2-naphthoxyacetic acid (2-NOAA). Lastly, we tested if 4PBA and 2-NOAA could functionally rescue bestrophin 1 function in RPE generated from induced pluripotent stem cells (iPSC-RPEs) derived from patients with a dominant or recessive bestrophinopathy. METHODS. Global and plasma membrane expression was determined by Western blot and immunofluorescent microscopy, respectively. The effect of 4PBA and 2-NOAA on transcription was measured by quantitative RT-PCR and the rate of protein turnover by cycloheximide chase and Western blot. Channel function was measured by whole-cell patch clamp. RESULTS. 4PBA and 2-NOAA can rescue the global and membrane expression of mutant bestrophin 1 associated with autosomal dominant disease (Best vitelliform macular dystrophy [BVMD]) and autosome recessive bestrophinopathy (ARB), and these small molecules have different modes of action. Both 4PBA and 2-NOAA significantly increased the channel function of mutant BVMD and ARB bestrophin 1 in HEK293T and iPSC-RPE cells derived from patients with BVMD and ARB. For 4PBA, the increased mutant channel function in BVMD and ARB iPSC-RPE was equal to that of wild-type iPSC-RPE bestrophin 1. CONCLUSIONS. The restoration of bestrophin 1 function in patient-derived RPE confirms the US Food and Drug Administration–approved drug 4PBA as a promising therapeutic treatment for bestrophinopathies.

Original languageEnglish (US)
Article number28
JournalInvestigative Ophthalmology and Visual Science
Volume61
Issue number5
DOIs
StatePublished - May 2020

Keywords

  • Bestrophin 1
  • Bestrophinopathies
  • Functional rescue
  • Small molecule
  • Sodium phenylbutyrate (4PBA)

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

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