Long-term nerve regeneration in diabetic keratopathy mediated by a novel NGF delivery system

IF 6.2 1区医学 Q1 ENDOCRINOLOGY & METABOLISM

Diabetes Pub Date : 2024-10-24 DOI:10.2337/db24-0393

Lin Cong, Benxiang Qi, Shijiu Chen, Ruiling Liu, Suxia Li, Qingjun Zhou, Yihai Cao, Bi Ning Zhang, Lixin Xie

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Abstract

Diabetic keratopathy (DK) is a common chronic metabolic disorder that causes ocular surface complications. Among various therapeutic approaches, local delivery of nerve growth factor (NGF) remains the most effective treatment for DK. However, achieving a sustained therapeutic effect with NGF and the frequent drug delivery burden remain challenging during clinical practice. Here, we developed a novel adeno-associated virus (AAV)-based NGF delivery system that achieved one-year-long-lasting effects by a single injection. We refined the corneal stromal injection technique, resulting in reduced corneal edema and improved AAV distribution homogeneity. AAV serotype AAV.rh10 exhibited high tropism and specificity to corneal nerves. A dose of 2×109 vector genomes (vg) was determined to achieve efficient Ngf gene expression without inducing corneal immune responses. Moreover, NGF protein was highly expressed in trigeminal ganglion (TG) through a retrograde transport mechanism, indicating the capacity for repairing corneal nerve damage both at the root and corneal nerve endings. In a mouse DK model, a single injection of AAV-Ngf into the corneal stroma led to marked corneal nerve regeneration for over 5 months. Together, we provide a novel therapeutic paradigm for long-term effective treatment of DK and this therapeutic approach is superior to current DK therapies.

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新型 NGF 递送系统介导糖尿病角膜病变中的长期神经再生

糖尿病性角膜病（DK）是一种常见的慢性代谢性疾病，会引起眼表并发症。在各种治疗方法中，局部给药神经生长因子（NGF）仍然是治疗 DK 的最有效方法。然而，在临床实践中，实现 NGF 的持续治疗效果以及频繁给药带来的负担仍是一项挑战。在此，我们开发了一种基于腺相关病毒（AAV）的新型 NGF 给药系统，只需注射一次，就能获得长达一年的持久疗效。我们改进了角膜基质注射技术，从而减轻了角膜水肿，提高了 AAV 分布的均匀性。AAV血清型AAV.rh10表现出对角膜神经的高度滋养性和特异性。2×109载体基因组（vg）的剂量可实现Ngf基因的高效表达，且不会诱发角膜免疫反应。此外，NGF蛋白通过逆行运输机制在三叉神经节（TG）中高表达，表明其有能力修复角膜神经根和角膜神经末梢的损伤。在小鼠 DK 模型中，将 AAV-Ngf 单次注射到角膜基质可使角膜神经再生超过 5 个月。总之，我们为长期有效治疗 DK 提供了一种新的治疗模式，这种治疗方法优于目前的 DK 治疗方法。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Diabetes 医学-内分泌学与代谢

CiteScore

12.50

自引率

2.60%

发文量

1968

审稿时长

1 months

期刊介绍： Diabetes is a scientific journal that publishes original research exploring the physiological and pathophysiological aspects of diabetes mellitus. We encourage submissions of manuscripts pertaining to laboratory, animal, or human research, covering a wide range of topics. Our primary focus is on investigative reports investigating various aspects such as the development and progression of diabetes, along with its associated complications. We also welcome studies delving into normal and pathological pancreatic islet function and intermediary metabolism, as well as exploring the mechanisms of drug and hormone action from a pharmacological perspective. Additionally, we encourage submissions that delve into the biochemical and molecular aspects of both normal and abnormal biological processes. However, it is important to note that we do not publish studies relating to diabetes education or the application of accepted therapeutic and diagnostic approaches to patients with diabetes mellitus. Our aim is to provide a platform for research that contributes to advancing our understanding of the underlying mechanisms and processes of diabetes.