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

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-b...

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Published in:	Nature communications Vol. 15; no. 1; pp. 5943 - 22
Main Authors:	Leinonen, Henri, Zhang, Jianye, Occelli, Laurence M., Seemab, Umair, Choi, Elliot H., L.P. Marinho, Luis Felipe, Querubin, Janice, Kolesnikov, Alexander V., Galinska, Anna, Kordecka, Katarzyna, Hoang, Thanh, Lewandowski, Dominik, Lee, Timothy T., Einstein, Elliott E., Einstein, David E., Dong, Zhiqian, Kiser, Philip D., Blackshaw, Seth, Kefalov, Vladimir J., Tabaka, Marcin, Foik, Andrzej, Petersen-Jones, Simon M., Palczewski, Krzysztof
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 15-07-2024 Nature Publishing Group Nature Portfolio
Subjects:	13/1 13/51 14/34 14/63 38 38/91 631/154/436/2388 631/378/2613/1786 64/110 64/60 692/308/2778 692/4017 9/30 9/97 Animal models Animals Bromocriptine Bromocriptine - pharmacology Bromocriptine - therapeutic use Calcium (intracellular) Calcium - metabolism Calcium ions cis-trans-Isomerases - genetics cis-trans-Isomerases - metabolism Cyclic AMP - metabolism Cyclic Nucleotide Phosphodiesterases, Type 6 - genetics Cyclic Nucleotide Phosphodiesterases, Type 6 - metabolism Degeneration Disease control Disease Models, Animal Dogs Drug Repositioning Drug Therapy, Combination Female G protein-coupled receptors Gene sequencing Genetic diversity Health services Humanities and Social Sciences Humans Leber congenital amaurosis Leber Congenital Amaurosis - drug therapy Leber Congenital Amaurosis - genetics Male Metoprolol Mice Mice, Inbred C57BL Mice, Knockout multidisciplinary Mutation Pharmacology Receptors Receptors, G-Protein-Coupled - genetics Receptors, G-Protein-Coupled - metabolism Retina Retinal Cone Photoreceptor Cells - drug effects Retinal Cone Photoreceptor Cells - metabolism Retinal Cone Photoreceptor Cells - pathology Retinal degeneration Retinal Degeneration - drug therapy Retinal Degeneration - genetics Retinitis pigmentosa Retinitis Pigmentosa - drug therapy Retinitis Pigmentosa - genetics Retinopathy Science Science (multidisciplinary)
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Summary:	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. This preclinical study demonstrates the potential of a drug repurposing strategy using the coadministration of tamsulosin, metoprolol, and bromocriptine to provide a mutation-agnostic therapy for inherited retinal degeneration.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2041-1723 2041-1723
DOI:	10.1038/s41467-024-50033-5