A disease-modifying therapy for retinal degenerations by drug repurposing

Abstract

Purpose : To test the hypothesis that dampening intracellular second-messenger signaling by a combination of approved G protein-coupled receptor-targeting drugs provides an effective therapeutic approach against retinal degenerative diseases.

Methods : We investigated a drug combination (TMB) consisting of tamsulosin and metoprolol (alpha- and beta-adrenergic antagonists, G_q- and G_s-coupled, respectively); and bromocriptine (a D2-like dopamine-receptor agonist, G_i-coupled). Longitudinal drug efficacy was tested in four distinct translationally relevant disease models: Pde6β^Rd10, Rho^P23H, and Rpe65^-/- mice; and Pde6a^-/- dogs. The duration of the drug trials ranged from 1-week to 7-months. Drug serum levels were measured by liquid chromatography-mass spectrometry (LC-MS). We primarily used photopic and scotopic electroretinography (ERG) and optical coherence tomography (OCT) to assess drug efficacy during the chronic trials. Immunohistochemistry, Western blotting, bulk and single-cell RNA-sequencing, and proteomics were used to document therapeutic mechanisms, as well as to confirm therapeutic effects at trial termination.

Results : Dietary TMB improved rod and cone function and slowed cone degeneration in Rho^P23H and Pde6β^Rd10 mouse models of Retinitis Pigmentosa (RP). Drug efficacy was associated with decreased lipid peroxidation preceding the onset of cone degeneration in dark-reared Pde6β^Rd10 mice. Dietary TMB improved retinal function and optomotor tracking behavior in Rpe65^-/- mouse model of Leber Congenital Amaurosis type 2, but did not halt rod or cone degeneration. Seven-month-long subcutaneous sustained infusion of TMB in Pde6a^-/- dog model of RP led to higher cone counts at the end of the trial, and was associated with improved ERG response kinetics during the trial. LC-MS analysis showed that efficacious drug serum levels in the context of blinding diseases were generally at or below the clinically relevant concentration ranges for the drugs’ original clinical indications, extrapolated from published literature. Remarkably, monotherapies with the same drugs and dosages did not alleviate disease phenotypes in Pde6β^Rd10 or Rpe65^-/- mice.

Conclusions : Our results suggest that simultaneous inhibition of G_s- and G_q-coupled receptors and activation of G_i-coupled receptors by a combination of existing drugs is a versatile option to mitigate progressive retinal degeneration caused by distinct etiologies.

This is a 2021 ARVO Annual Meeting abstract.