Wang Wenjing, Yu Xiang, Yang Zheng, Zhang Yu, Yang Wen, Xu Yingjie, Xu Wei
Department of Neurology and Institute of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Diabetes. 2025 Aug 1;74(8):1427-1440. doi: 10.2337/db24-0989.
Diabetic peripheral neuropathy (DPN) poses significant clinical challenges due to progressive nerve degeneration and vascular insufficiency. To address both neural and vascular complications simultaneously, we employed an mRNA-based protein replacement therapy. In this study, leveraging mRNA template design, structure-based screening identified NGFR100W as a variant dissociating neuroprotective and nociceptive functions, demonstrating enhanced neuritogenic activity without pain sensitization. Additionally, transcriptome analysis of NGF mutants versus wild type further reveals the potential mechanism by which NGFR100W uncouples neuroprotective and nociceptive pathways. We cotransfected chemically modified NGFR100W mRNA and vascular endothelial growth factor A (VEGFA) mRNA, and the conditioned media collected from this transfection promoted endothelial cell migration, tubulogenesis, and neurite outgrowth. In a diabetic mouse model, combination therapy with lipid nanoparticle codelivery of NGFR100W and VEGFA mRNA significantly improved blood flow in the plantar region and mitigated nerve function decline compared with monotherapy. Histological analysis showed increased microvessel formation and higher intraepidermal nerve fiber density in treated mice. Our findings highlight the therapeutic potential of NGFR100W and VEGFA mRNA coadministration for DPN, suggesting that protein supplementation via mRNA could offer a novel strategy for clinical intervention in some chronic medical conditions.
We aimed to develop a dual-targeted mRNA-based therapy to address both neural degeneration and vascular insufficiency in diabetic peripheral neuropathy. We identified NGFR100W as a mutation that enhances neuritogenic activity without pain sensitization and investigated its transcriptome to explore its ability to uncouple neuroprotective and nociceptive pathways. Combination therapy using lipid nanoparticles for codelivery of NGFR100W and VEGFA mRNA improved blood flow, increased microvessel formation, and preserved nerve function in a diabetic mouse model. This approach, which combines structure-based design and mRNA therapy, offers a novel strategy for decoupling protein functions and developing therapeutic molecules with specific functionalities.
糖尿病性周围神经病变（DPN）由于进行性神经退变和血管功能不全而带来了重大的临床挑战。为了同时解决神经和血管并发症，我们采用了基于信使核糖核酸（mRNA）的蛋白质替代疗法。在本研究中，利用mRNA模板设计，基于结构的筛选确定神经生长因子受体100W（NGFR100W）为一种可分离神经保护和伤害感受功能的变体，显示出增强的神经突生长活性且无疼痛敏化现象。此外，对神经生长因子（NGF）突变体与野生型的转录组分析进一步揭示了NGFR100W分离神经保护和伤害感受途径的潜在机制。我们共转染了化学修饰的NGFR100W mRNA和血管内皮生长因子A（VEGFA）mRNA，并且从该转染收集的条件培养基促进了内皮细胞迁移、管状结构形成和神经突生长。在糖尿病小鼠模型中，与单一疗法相比，用脂质纳米颗粒共递送NGFR100W和VEGFA mRNA的联合疗法显著改善了足底区域的血流并减轻了神经功能衰退。组织学分析显示，治疗小鼠的微血管形成增加且表皮内神经纤维密度更高。我们的研究结果突出了NGFR100W和VEGFA mRNA联合给药对DPN的治疗潜力，表明通过mRNA进行蛋白质补充可为某些慢性疾病的临床干预提供一种新策略。
我们旨在开发一种基于mRNA的双靶点疗法，以解决糖尿病性周围神经病变中的神经退变和血管功能不全问题。我们确定NGFR100W为一种在无疼痛敏化情况下增强神经突生长活性的突变，并研究了其转录组以探索其分离神经保护和伤害感受途径的能力。在糖尿病小鼠模型中，使用脂质纳米颗粒共递送NGFR100W和VEGFA mRNA的联合疗法改善了血流、增加了微血管形成并保留了神经功能。这种结合基于结构的设计和mRNA疗法的方法为分离蛋白质功能和开发具有特定功能的治疗分子提供了一种新策略。
