Mutations in rhodopsin lead to its misfolding resulting in autosomal dominant retinitis pigmentosa (adRP). Pharmacological inhibition of the ATP-driven chaperone valosin-containing protein (VCP), a molecular checkpoint for protein quality control, slows down retinal degeneration in animal models. However, poor water-solubility of VCP inhibitors poses a challenge to their clinical translation as intravitreal injections for retinal treatment. In order to enable the delivery of VCP inhibitors, we have developed and investigated two formulations for the VCP inhibitor ML240. Nanoformulations of ML240 were obtained by using amphiphilic polymers methoxy-poly (ethylene glycol)_5kDa–cholane (mPEG_5kDa-cholane) and methoxy-poly (ethylene glycol)_5kDa–cholesterol (mPEG_5kDa-cholesterol). Both formulations increased the water-solubility of ML240 by two orders of magnitude and prolonged the drug released over ten days. In addition, encapsulation of ML240 in mPEG_5kDa-cholane showed superior photoreceptor protection at lower drug concentrations, normalized rhodopsin localization, and alleviated inflammatory microglial responses in an ex vivo rat model of retinal degeneration. The study demonstrates the potential of VCP inhibitor nanoformulations to treat adRP, a pharmacologically orphan disease.

视紫红质的突变导致其错误折叠，导致常染色体显性视网膜色素变性（adRP）。ATP 驱动的伴侣 valosin 蛋白 (VCP) 的药理抑制作用是蛋白质质量控​​制的分子检查点，可减缓动物模型中的视网膜变性。然而，VCP 抑制剂的水溶性差对其作为玻璃体内注射用于视网膜治疗的临床转化提出了挑战。为了能够递送 VCP 抑制剂，我们开发并研究了 VCP 抑制剂 ML240 的两种配方。ML240 的纳米制剂是通过使用两亲聚合物甲氧基聚（乙二醇）_5kDa -胆烷（mPEG _5kDa -cholane）和甲氧基聚（乙二醇）_5kDa -胆固醇（mPEG_5kDa-胆固醇）。两种配方都将 ML240 的水溶性提高了两个数量级，并将药物释放时间延长了十天。此外，在离体大鼠视网膜变性模型中，将 ML240 封装在 mPEG _5kDa -胆烷中显示出在较低药物浓度下对光感受器的出色保护、使视紫红质定位正常化和减轻炎症性小胶质细胞反应。该研究证明了 VCP 抑制剂纳米制剂治疗 adRP（一种药理学孤儿病）的潜力。