Related Experiment Video
Updated: Jun 21, 2025
Implementation of In Vitro Drug Resistance Assays: Maximizing the Potential for Uncovering Clinically Relevant Resistance Mechanisms
Published on: December 9, 2015
A combination treatment based on drug repurposing demonstrates mutation-agnostic efficacy in pre-clinical retinopathy
Henri Leinonen1, Jianye Zhang2, Laurence M Occelli3
1School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Yliopistonranta 1C, 70211, Kuopio, Finland. henri.leinonen@uef.fi.
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.
Insights
A novel drug combination targeting G protein-coupled receptors (GPCRs) shows promise for treating inherited retinopathies. This approach improves photoreceptor function and slows degeneration in animal models, offering a potential disease-modifying therapy.
Area of Science:
- Ophthalmology
- Pharmacology
- Genetics
Background:
- Inherited retinopathies represent a significant unmet medical need, often lacking effective treatment options.
- The genetic heterogeneity of these conditions necessitates therapies that target common pathological pathways.
- Developing disease-modifying treatments that are independent of specific genetic mutations is a key goal.
Purpose of the Study:
- To investigate a systems pharmacology strategy for treating inherited retinopathies.
- To evaluate the efficacy of coadministering tamsulosin, metoprolol, and bromocriptine in preclinical models.
- To assess the impact of this combination therapy on photoreceptor function and degeneration.
Main Methods:
- Utilized a combination of tamsulosin, metoprolol, and bromocriptine to modulate G protein-coupled receptor (GPCR) activity and suppress intracellular cAMP and Ca2+.
- Tested the therapeutic strategy in mouse models of retinitis pigmentosa (Pde6βrd10 and RhoP23H/WT) and Leber congenital amaurosis (Rpe65-/-).
- Assessed treatment effects on cone and rod photoreceptor function and degeneration, including RNA-sequencing for metabolic analysis.
Main Results:
- The drug combination improved cone photoreceptor function and slowed degeneration in Pde6βrd10 and RhoP23H/WT retinitis pigmentosa mice.
- Modest mitigation of cone degeneration was observed in PDE6A-/- dogs after 7 months of drug infusion.
- Rod pathway function improved in Rpe65-/- mice, with RNA-sequencing revealing enhanced metabolic function in treated Rpe65-/- and rd10 mice.
Conclusions:
- Catecholaminergic GPCR drug combinations can modify second messenger levels through multiple receptor actions.
- This approach represents a potential disease-modifying therapy for retinal degeneration.
- The findings support the development of GPCR-targeted therapies for a range of inherited retinopathies.
