%0 Journal Article
%T A combination treatment based on drug repurposing demonstrates mutation-agnostic efficacy in pre-clinical retinopathy models.
%A Leinonen H
%A Zhang J
%A Occelli LM
%A Seemab U
%A Choi EH
%A L P Marinho LF
%A Querubin J
%A Kolesnikov AV
%A Galinska A
%A Kordecka K
%A Hoang T
%A Lewandowski D
%A Lee TT
%A Einstein EE
%A Einstein DE
%A Dong Z
%A Kiser PD
%A Blackshaw S
%A Kefalov VJ
%A Tabaka M
%A Foik A
%A Petersen-Jones SM
%A Palczewski K
%J Nat Commun
%V 15
%N 1
%D 2024 Jul 15
%M 39009597
%F 17.694
%R 10.1038/s41467-024-50033-5
%X 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.