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Pharmacological clearance of misfolded rhodopsin for the treatment of RHO ‐associated retinitis pigmentosa
Author(s) -
Liu Xujie,
Feng Bing,
Vats Abhishek,
Tang Hong,
Seibel William,
Swaroop Manju,
Tawa Gregory,
Zheng Wei,
Byrne Leah,
Schurdak Mark,
Chen Yuanyuan
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.202000282r
Subject(s) - rhodopsin , retinitis pigmentosa , chemistry , microbiology and biotechnology , biology , biochemistry , retinal
Rhodopsin mutation and misfolding is a common cause of autosomal dominant retinitis pigmentosa (RP). Using a luciferase reporter assay, we undertook a small‐molecule high‐throughput screening (HTS) of 68, 979 compounds and identified nine compounds that selectively reduced the misfolded P23H rhodopsin without an effect on the wild type (WT) rhodopsin protein. Further, we found five of these compounds, including methotrexate (MTX), promoted P23H rhodopsin degradation that also cleared out other misfolded rhodopsin mutant proteins. We showed MTX increased P23H rhodopsin degradation via the lysosomal but not the proteasomal pathway. Importantly, one intravitreal injection (IVI) of 25 pmol MTX increased electroretinogram (ERG) response and rhodopsin level in the retinae of Rho P23H/+ knock‐in mice at 1 month of age. Additionally, four weekly IVIs increased the photoreceptor cell number in the retinae of Rho P23H/+ mice compared to vehicle control. Our study indicates a therapeutic potential of repurposing MTX for the treatment of rhodopsin‐associated RP.