{Reference Type}: Journal Article
{Title}: A combination treatment based on drug repurposing demonstrates mutation-agnostic efficacy in pre-clinical retinopathy models.
{Author}: Leinonen H;Zhang J;Occelli LM;Seemab U;Choi EH;L P Marinho LF;Querubin J;Kolesnikov AV;Galinska A;Kordecka K;Hoang T;Lewandowski D;Lee TT;Einstein EE;Einstein DE;Dong Z;Kiser PD;Blackshaw S;Kefalov VJ;Tabaka M;Foik A;Petersen-Jones SM;Palczewski K;
{Journal}: Nat Commun
{Volume}: 15
{Issue}: 1
{Year}: 2024 Jul 15
{Factor}: 17.694
{DOI}: 10.1038/s41467-024-50033-5
{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.