[HTML][HTML] Pharmacological clearance of misfolded rhodopsin for the treatment of RHO-associated retinitis pigmentosa.

X Liu, B Feng, A Vats, H Tang, W Seibel… - … : official publication of …, 2020 - ncbi.nlm.nih.gov
X Liu, B Feng, A Vats, H Tang, W Seibel, M Swaroop, G Tawa, W Zheng, L Byrne…
FASEB journal: official publication of the Federation of American …, 2020ncbi.nlm.nih.gov
Rhodopsin mutation and misfolding is a common cause of autosomal dominant retinitis
pigmentosa. Using a luciferase reporter assay, we undertook a small-molecule high-
throughput screening of 68,979 compounds and identified nine compounds that selectively
reduced the misfolded P23H rhodopsin without an effect on the wild type 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 …
Abstract
Rhodopsin mutation and misfolding is a common cause of autosomal dominant retinitis pigmentosa. Using a luciferase reporter assay, we undertook a small-molecule high-throughput screening of 68,979 compounds and identified nine compounds that selectively reduced the misfolded P23H rhodopsin without an effect on the wild type 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 of 25 pmol MTX increased electroretinogram response and rhodopsin level in the retinae of Rho P23H/+ mice at one month of age. Additionally, four weekly intravitreal injections 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 retinitis pigmentosa.
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