Nature Communications (Jul 2024)

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,
  • Krzysztof Palczewski

DOI
https://doi.org/10.1038/s41467-024-50033-5
Journal volume & issue
Vol. 15, no. 1
pp. 1 – 22

Abstract

Read online

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.