Topical administration of novel FKBP12 ligand MP-004 improves retinal function and structure in retinitis pigmentosa models

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Abstract Purpose This study evaluates the therapeutic potential of MP-004, a novel FKBP12 ligand, in the treatment of inherited retinal dystrophies (IRDs). MP-004 targets FKBP12/RyR interaction, which is disrupted in several neurological disorders with underlying oxidative stress. Methods The toxicity and efficacy of MP-004 were examined in vitro in 661W cells. Efficacy was evaluated in phototoxic and H 2 O 2 -induced damage using impedance assays, calcium igaing and in situ PLA. In vivo, MP-004 efficacy was evaluated in the rd10 mouse model of retinitis pigmenetosa (RP) by topical ocular instillation. Retinal function was assessed by electroretinography (ERG), visual acuity was measured using a water maze test, and retinal structure was analyzed morphometrically. Results MP-004 exhibited low toxicity (LD 50 : 1.22 mM) and effectively protected 661W cells from phototoxicity (EC 50 : 30.6 nM). Under oxidative stress conditions, MP-004 preserved FKBP12.6/RyR2 interaction, partially restored endoplasmic reticulum calcium stores and prevented cell death. In vivo, MP-004 significantly preserved retinal function in rd10 mice, with ERG wave amplitude increases of up to 50% in scotopic and 71% in photopic conditions, corresponding to rod and cone functions, respectively. Additionally, MP-004 improved visual acuity for low spatial frequency patterns, and preserved retinal structure with a 23% increase in outer nuclear layer thickness, and preservation in the number of rods and cones and their segment length. Conclusions MP-004 shows promise as a therapeutic agent for RP, preserving retinal structure and function, likely through modulation of FKBP12.6/RyR2 interaction. Further studies are needed to explore its pharmacokinetics and efficacy in other IRD models.

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