Topical administration of MP-004 improves retinal function and structure in a mouse model of retinitis pigmentosa.

Abstract

Purpose : To develop an innovative therapy for hereditary retinal dystrophies (IRDs), based on a new small molecule, termed MP-004. Oxidative stress, and calcium dysregulation are common pathogenic mechanisms in IRDs. Ryanodine receptor type 2 (RyR2) isa large calcium release channel at the endoplasmic reticulum that has been recently implicated in photoreceptor degeneration in animal models of achromatopsia. In the present work, we tested the hypothesis that MP-004, a novel ligand of FKBP12 (FK506 binding protein of 12kD), is able to preserve retinal function and structure by modulating RyR2 activity, in a mouse model of retinitis pigmentosa (RP).

Methods : We used rd10 mice, a well-established model of recessive RP based on a spontaneous mutation on pde6b gene. Mice were treated by ocular instillation with MP-004 (n=14) for 11 days (17μg/eye) or with vehicle (PBS, n=12) from P14 to P24. Retinal activity: rd10 mice were dark adapted 8 hours at P25, and full-field flash ERG responses were recorded using a standard stimulation protocol. Visual acuity: a modified water maze was used to assess a visual discrimination task. Morphometric analysis: Eyes were processed for confocal microscopy. Two-tailed Student's t-test was used for statistical analysis.

Results : Ocular instillation of MP-004 in rd10 mice, preserved photoreceptor function and structure compared to rd10 non-treated group, as measured by electroretinography (ERG), visual acuity (water maze) and morphometric analysis of the retina. ERG analysis revealed improved rod, cone and amacrine function by increasing b-wave amplitude by 42 ± 4% (p<0.05); 66 ± 7% (p<0.001) and 81 ± 6% (p=0.001), respectively. Furthermore, we observed an improved visual acuity, with significant differences in spatial frequency values at 0.01 and 0.35 cycles/degree (both p<0.05). Finally, the morphometric analysis revealed an increased number or rods and cones by 62 ± 5% (p<0.01) and 38 ± 6% (p<0.01), respectively, increased thickness of the ONL by 26 ± 3% (p<0.01), and length of the photoreceptor outer and inner segments by 49 ± 7% (p<0.05).

Conclusions : Our results support the hypothesis that ocular instillation of MP-004 can improve the function and the structure of the retina of rd10 mice.

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

 

Flat mount of a WT mouse retina stained with antibodies against rhodopsin (green) and cone arrestin (red).