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Pharmacological clearance of misfolded rhodopsin for the treatment of RHO ‐associated retinitis pigmentosa

Year: 2020
Type: article
Abstract: 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.
DOI: 10.1096/fj.202000282r
Authors: Xujie Liu, Bing Feng, Abhishek Vats, Hong Tang, William Seibel, Manju Swaroop, Gregory Tawa, Wei Zheng, Leah Byrne, Mark Schurdak, Yuanyuan Chen
Institutions: University of Pittsburgh, McGowan Institute for Regenerative Medicine, University of Cincinnati, Cincinnati Children's Hospital Medical Center, National Institutes of Health, National Center for Advancing Translational Sciences, National Institutes of Health Clinical Center
Language: English
Open Access status: hybrid
Estimated APC paid: $2,500
Funders: Eye and Ear Foundation of Pittsburgh, Research to Prevent Blindness, Center for Outcomes Research and Evaluation, Yale School of Medicine, University of Cincinnati, National Institutes of Health, National Eye Institute
Awards: G119702646, G1551733795, G2169015523, G2660728670, G3304228026, Drug discovery and mechanistic study of P23H rhodopsin associated retinitis pigmentosa, G7409076016, G9000061582, Core Grant for Vision Research
OpenAlex ID: W3035215263
FWCI: 0.761
Cites: 69
Cited by: 20
Related to: 10