MP-004, a novel FKBP12 ligand as a candidate for treating IRDs

Abstract

Purpose : Calcium dysregulation and oxidative stress have been described as pathogenic mechanisms contributing to photoreceptor death in inherited retinal dystrophies (IRDs). Recently, rianodine receptor type 2 (RyR2) calcium channels have been shown to play a central role in photoreceptor calcium homeostasis in achromatopsia. We have developed a novel FKBP12 ligand, namely MP-004, which normalizes intracellular calcium by stabilizing FKBP12/RyR2 interaction. Our goal is to evaluate the suitability of MP-004 as a novel treatment for IRDs.

Methods : In the present work we evaluated in vitro toxicity and efficacy of MP-004 in a cellular model of phototoxicity, using the impedance assay in the Maestro Edge platform. We also evaluated in vivo toxicity and bioavailability of MP-004 in the retina of several animal models, after topical ocular instillation, by histopathology and HPLC analyses. Target engagement of FKBP12 was verified in the rd10 mouse model of retinitis pigmentosa by in situ proximity ligation assay, immunohistochemistry, and qPCR.

Results : MP-004 protects 661W cells against induced phototoxicity in a dose-response manner with high potency (EC50= 30.5 nM) and low toxicity (LD50= 1.22mM). In mouse, rabbit and pig species, MP-004 is able to reach the retina in therapeutic concentration 4 hours after topical ocular instillation, with a half-life in the retina of more than 12 hours in mice and 6.34 hours in rabbit. In rd10 mice, retinas show reduced FKBP12-RyR2 interaction by postnatal day 16. This deficient interaction, as well as subsequent photoreceptor death are partially rescued by daily MP-004 treatment.

Conclusions : MP-004 is a promising candidate for treating retinitis pigmentosa and other IRDs, since it shows reduced toxicity, high efficacy, good bioavailability and target engagement after ocular instillation. To our knowledge, this is the first therapeutic candidate targeting IRDs that qualifies for topical administration.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.