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Preclinical Evaluation of Pitavastatin Nanoparticles for Preserving Cone Photoreceptors in Mouse Models of RP
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DOI：10.1167/iovs.66.13.15.png)
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Abstract
En 中文
PURPOSE. We previously demonstrated that intravenous pitavastatin Poly (lactic-co-glycolic acid) nanoparticles (PVS-NPs) reduced monocyte/macrophage activation and mitigated cone-cell death in a mouse model of RP. Here, we sought to optimize the PVS-NP administration regimen and investigated underlying molecular mechanisms by single-cell analyses. METHODS. In our previous study, twice-weekly administration of 0.3 mg/kg PVS-NPs reduced cone-cell degeneration in rd10 mice with Pde6b mutations. Here, we conducted a dose escalation study with weekly injections of 0.1, 0.3, and 1.0 mg/kg PVS-NPs in rd10 mice, followed by interval optimization with monthly and twice-monthly regimens from postnatal day 21 (P21) to P49. The cone-cell density (primary outcome) and photopic b-wave amplitude (secondary outcome) were assessed at P50. Finally, PVS-NP efficacy was validated in RhoP23H mice with Rhodopsin mutations. RESULTS. Cone densities and photopic b-wave amplitudes were approximately doubled in rd10 mice treated weekly with 0.3 or 1.0 mg/kg PVS-NPs compared with PBS-treated controls. Based on the efficacy of a 1.5 mg/kg cumulative dose in the weekly 0.3 mg/kg group, we evaluated lower dose, reduced frequency regimens: twice monthly 0.5 mg/kg (1.0 mg total) and monthly 0.75 mg/kg (0.75 mg total). The monthly 0.75 mg/kg regimen significantly preserved cone-cell density and function in rd10 mice and RhoP23H mice. Single-cell analyses of rd10 retinas and peripheral blood revealed that PVS-NPs shifted monocytes from a proinflammatory to an anti-inflammatory state and reduced their infiltration into the retina. CONCLUSIONS. Monthly intravenous administration of PVS-NPs may be an effective treatment regimen to delay cone-cell degeneration in RP. The therapeutic effect of PVS-NPs likely involves the modulation of circulating inflammatory monocytes and their engraftment.
Keywords:
pitavastatin
nano particle
inflammatory monocyte
retinitis pigmentosa
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