Drug Screening with Zebrafish Visual Behavior Identifies Carvedilol as a Potential Treatment for Retinitis Pigmentosa

Ganzen, L.; Ko, M. J.; Zhang, M.; Xie, R.; Chen, Y.; Zhang, L.; James, R.; Mumm, J.; van Rijn, R.; Zhong, W.; Pang, C. P.; Tsujikawa, M.; Leung, Y. F.

doi:10.1101/2020.07.28.225789

bioRxiv · 10.1101/2020.07.28.225789

Drug Screening with Zebrafish Visual Behavior Identifies Carvedilol as a Potential Treatment for Retinitis Pigmentosa

Ganzen, L.·Ko, M. J.·Zhang, M.·Xie, R.·Chen, Y.·Zhang, L.·James, R.·Mumm, J.·van Rijn, R.·Zhong, W.·Pang, C. P.·Tsujikawa, M.·Leung, Y. F.

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Abstract

Retinitis Pigmentosa (RP) is an incurable inherited retinal degeneration affecting approximately 1 in 4,000 individuals globally. The goal of this work was to identify drugs that can help patients suffering from the disease. To accomplish this, we screened drugs on a zebrafish RP model. This model expresses a truncated human rhodopsin transgene (Tg(rho:Hsa.RH1_Q344X)) causing significant rod degeneration by 7 days post-fertilization (dpf). Consequently, the larvae displayed a deficit in visual motor response (VMR) under scotopic condition. The diminished VMR was leveraged to screen an ENZO SCREEN-WELL(R) REDOX library since oxidative stress is postulated to play a role in RP progression. Our screening identified a beta-blocker, carvedilol, that ameliorated the deficient VMR of the RP larvae and increased their rod number. Carvedilol can act directly on rods as it affected the adrenergic pathway in a rod-like human Y79 cell line. Since carvedilol is an FDA-approved drug, our findings suggest that carvedilol can potentially be repurposed to treat RP patients. Summary StatementThis paper presents the utilization of zebrafish visual behavior, a novel paradigm to screen and identify drugs to treat retinitis pigmentosa, an incurable retinal-degenerative disease.

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Ganzen, L., Ko, M. J., Zhang, M., Xie, R., Chen, Y., Zhang, L., James, R., Mumm, J., van Rijn, R., Zhong, W., Pang, C. P., Tsujikawa, M., Leung, Y. F.. 2020-07-29. Drug Screening with Zebrafish Visual Behavior Identifies Carvedilol as a Potential Treatment for Retinitis Pigmentosa. https://doi.org/10.1101/2020.07.28.225789

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