A combination treatment based on drug repurposing demonstrates mutation-agnostic efficacy in pre-clinical retinopathy models

Henri Leinonen (), Jianye Zhang, Laurence M. Occelli, Umair Seemab, Elliot H. Choi, Luis Felipe L.P. Marinho, Janice Querubin, Alexander V. Kolesnikov, Anna Galinska, Katarzyna Kordecka, Thanh Hoang, Dominik Lewandowski, Timothy T. Lee, Elliott E. Einstein, David E. Einstein, Zhiqian Dong, Philip D. Kiser, Seth Blackshaw, Vladimir J. Kefalov, Marcin Tabaka, Andrzej Foik, Simon M. Petersen-Jones and Krzysztof Palczewski ()
Additional contact information
Henri Leinonen: University of Eastern Finland
Jianye Zhang: University of California
Laurence M. Occelli: Michigan State University
Umair Seemab: University of Eastern Finland
Elliot H. Choi: University of California
Luis Felipe L.P. Marinho: Michigan State University
Janice Querubin: Michigan State University
Alexander V. Kolesnikov: University of California
Anna Galinska: International Centre for Translational Eye Research
Katarzyna Kordecka: International Centre for Translational Eye Research
Thanh Hoang: Department of Cell & Developmental Biology
Dominik Lewandowski: University of California
Timothy T. Lee: University of California
Elliott E. Einstein: University of California
David E. Einstein: University of California
Zhiqian Dong: University of California
Philip D. Kiser: University of California
Seth Blackshaw: Johns Hopkins University School of Medicine
Vladimir J. Kefalov: University of California
Marcin Tabaka: International Centre for Translational Eye Research
Andrzej Foik: International Centre for Translational Eye Research
Simon M. Petersen-Jones: Michigan State University
Krzysztof Palczewski: University of California

Nature Communications, 2024, vol. 15, issue 1, 1-22

Abstract: Abstract Inherited retinopathies are devastating diseases that in most cases lack treatment options. Disease-modifying therapies that mitigate pathophysiology regardless of the underlying genetic lesion are desirable due to the diversity of mutations found in such diseases. We tested a systems pharmacology-based strategy that suppresses intracellular cAMP and Ca2+ activity via G protein-coupled receptor (GPCR) modulation using tamsulosin, metoprolol, and bromocriptine coadministration. The treatment improves cone photoreceptor function and slows degeneration in Pde6βrd10 and RhoP23H/WT retinitis pigmentosa mice. Cone degeneration is modestly mitigated after a 7-month-long drug infusion in PDE6A-/- dogs. The treatment also improves rod pathway function in an Rpe65-/- mouse model of Leber congenital amaurosis but does not protect from cone degeneration. RNA-sequencing analyses indicate improved metabolic function in drug-treated Rpe65-/- and rd10 mice. Our data show that catecholaminergic GPCR drug combinations that modify second messenger levels via multiple receptor actions provide a potential disease-modifying therapy against retinal degeneration.

Date: 2024
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DOI: 10.1038/s41467-024-50033-5

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