- Tytuł:
- A combination treatment based on drug repurposing demonstrates mutation-agnostic efficacy in pre-clinical retinopathy models
- Autorzy:
-
Kolesnikov, Alexander V.
Petersen-Jones, Simon M.
Leinonen, Henri
Palczewski, Krzysztof
Lewandowski, Dominik
Kiser, Philip D.
Tabaka, Marcin
Querubin, Janice
Marinho, Luis Felipe L.P.
Einstein, David E.
Dong, Zhiqian
Kordecka, Katarzyna
Seemab, Umair
Choi, Elliot H.
Occelli, Laurence M.
Kefalov, Vladimir J.
Blackshaw, Seth
Zhang, Jianye
Galinska, Anna
Hoang, Thanh
Zhao Yuan
Lee, Timothy
Foik, Andrzej T.
Einstein, Elliott E. - Współwytwórcy:
- Zhao Yuan
- Wydawca:
- Nature Portfolio
- Cytata wydawnicza:
- Leinonen, H., Zhang, J., Occelli, L.M. et al. A combination treatment based on drug repurposing demonstrates mutation-agnostic efficacy in pre-clinical retinopathy models. Nat Commun 15, 5943 (2024). https://doi.org/10.1038/s41467-024-50033-5
- Opis:
- 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.
- Dostawca treści:
- Repozytorium Centrum Otwartej Nauki
Artykuł