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A Combination of G Protein-Coupled Receptor Modulators Protects Photoreceptors from Degeneration

Tivadar Orban1, Henri Leinonen1, Tamar Getter1

  • 1Department of Pharmacology, Cleveland Center for Membrane and Structural Biology, School of Medicine, Case Western Reserve University, Cleveland, Ohio (T.O., H.L., T.G., S.G., A.V., H.H.-T., T.S.K., P.D.K., K.P.); Research Service, Louis Stokes Cleveland Veterans Affairs Medical Center, Cleveland, Ohio (T.S.K., P.D.K.); and Polgenix Inc., Cleveland, Ohio (Z.D., W.S.).

The Journal of Pharmacology and Experimental Therapeutics
|November 23, 2017
PubMed

Insights

This study shows a combination therapy using metoprolol, tamsulosin, and bromocriptine can protect cone cells, crucial for vision, from retinal degeneration. This approach offers potential for treating genetic and age-related eye diseases.

Area of Science:

  • Ophthalmology
  • Pharmacology
  • Genetics

Background:

  • Retinal degenerative diseases affect photoreceptor cells, retinal pigment epithelium (RPE), neurons, and glial cells.
  • Cone cells, vital for daily activity, are often impacted in retinal degeneration.
  • Existing treatments for retinal degeneration are limited, necessitating novel therapeutic strategies.

Purpose of the Study:

  • To investigate the protective effects of a combination therapy involving metoprolol, tamsulosin, and bromocriptine on cone cells.
  • To evaluate the safety and efficacy of this drug combination in a preclinical model of retinal degeneration.
  • To determine the ocular penetration and target engagement of the therapeutic agents.

Main Methods:

  • Testing a combination therapy of metoprolol, tamsulosin, and bromocriptine in *Abca4* mice, a model for retinal degeneration.
  • Assessing drug specificity against a comprehensive panel of human G protein-coupled receptors.
  • Evaluating electroretinographic responses in wild-type mice to determine safety.
  • Utilizing RNA sequencing and quantitative PCR to confirm target gene expression in ocular tissues.
  • Employing liquid chromatography-mass spectrometry to quantify drug levels in the eye following administration.

Main Results:

  • The combination therapy demonstrated protective effects on cone cells in the *Abca4* mouse model.
  • The drugs showed specificity for their G protein-coupled receptor targets.
  • No adverse effects on electroretinographic responses were observed in wild-type mice.
  • Metoprolol, tamsulosin, and bromocriptine were confirmed to penetrate ocular tissues after systemic administration.
  • Target receptors were found to be expressed in both human and mouse eyes.

Conclusions:

  • The combination of metoprolol, tamsulosin, and bromocriptine shows promise for protecting cone cells against retinal degeneration.
  • This therapy is a potential candidate for human clinical trials to treat genetic retinal diseases like Stargardt disease.
  • The low-dose combination may also offer protection against age-related macular degeneration and other complex retinal conditions.

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