Wu Jie, Huang Yulei, Yu Hanrui, Li Kaixiu, Zhang Shifeng, Qiao Guoqing, Liu Xiao, Duan Hongmei, Huang Yifei, So Kwok-Fai, Yang Zhaoyang, Li Xiaoguang, Wang Liqiang
Department of Ophthalmology, the Third Medical Center, Chinese PLA General Hospital; The PLA Medical College, Department of Nephrology, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing; Department of Ophthalmology, Hainan Hospital of Chinese PLA General Hospital, Sanya, Hainan Province, China.
Medical School of Chinese PLA, Beijing, China.
Neural Regen Res. 2024 Mar;19(3):680-686. doi: 10.4103/1673-5374.380908.
Neurotrophic keratopathy is a persistent defect of the corneal epithelium, with or without stromal ulceration, due to corneal nerve deficiency caused by a variety of etiologies. The treatment options for neurotrophic keratopathy are limited. In this study, an ophthalmic solution was constructed from a chitosan-based thermosensitive hydrogel with long-term release of murine nerve growth factor (CTH-mNGF). Its effectiveness was evaluated in corneal denervation (CD) mice and patients with neurotrophic keratopathy. In the preclinical setting, CTH-mNGF was assessed in a murine corneal denervation model. CTH-mNGF was transparent, thermosensitive, and ensured sustained release of mNGF for over 20 hours on the ocular surface, maintaining the local mNGF concentration around 1300 pg/mL in vivo. Corneal denervation mice treated with CTH-mNGF for 10 days showed a significant increase in corneal nerve area and total corneal nerve length compared with non-treated and CTH treated mice. A subsequent clinical trial of CTH-mNGF was conducted in patients with stage 2 or 3 neurotrophic keratopathy. Patients received topical CTH-mNGF twice daily for 8 weeks. Fluorescein sodium images, Schirmer's test, intraocular pressure, Cochet-Bonnet corneal perception test, and best corrected visual acuity were evaluated. In total, six patients (total of seven eyes) diagnosed with neurotrophic keratopathy were enrolled. After 8 weeks of CTH-mNGF treatment, all participants showed a decreased area of corneal epithelial defect, as stained by fluorescence. Overall, six out of seven eyes had fluorescence staining scores < 5. Moreover, best corrected visual acuity, intraocular pressure, Schirmer's test and Cochet-Bonnet corneal perception test results showed no significant improvement. An increase in corneal nerve density was observed by in vivo confocal microscopy after 8 weeks of CTH-mNGF treatment in three out of seven eyes. This study demonstrates that CTH-mNGF is transparent, thermosensitive, and has sustained-release properties. Its effectiveness in healing corneal epithelial defects in all eyes with neurotrophic keratopathy suggests CTH-mNGF has promising application prospects in the treatment of neurotrophic keratopathy, being convenient and cost effective.
神经营养性角膜病变是一种角膜上皮的持续性缺损，伴有或不伴有基质溃疡，由多种病因导致的角膜神经缺乏引起。神经营养性角膜病变的治疗选择有限。在本研究中，构建了一种基于壳聚糖的热敏水凝胶眼科溶液，其可长期释放小鼠神经生长因子（CTH-mNGF）。在角膜去神经支配（CD）小鼠和神经营养性角膜病变患者中评估了其有效性。在临床前研究中，在小鼠角膜去神经支配模型中评估了CTH-mNGF。CTH-mNGF是透明的、热敏的，可确保mNGF在眼表持续释放超过20小时，在体内维持局部mNGF浓度在1300 pg/mL左右。用CTH-mNGF治疗10天的角膜去神经支配小鼠与未治疗和CTH治疗的小鼠相比，角膜神经面积和角膜总神经长度显著增加。随后在2期或3期神经营养性角膜病变患者中进行了CTH-mNGF的临床试验。患者每天两次局部应用CTH-mNGF，持续8周。评估了荧光素钠图像、泪液分泌试验、眼压、Cochet-Bonnet角膜知觉试验和最佳矫正视力。总共纳入了6例（共7只眼）诊断为神经营养性角膜病变的患者。CTH-mNGF治疗8周后，所有参与者的角膜上皮缺损面积均减小，经荧光染色显示。总体而言，7只眼中有6只眼的荧光染色评分<5。此外，最佳矫正视力、眼压、泪液分泌试验和Cochet-Bonnet角膜知觉试验结果均无显著改善。7只眼中有3只眼在CTH-mNGF治疗8周后通过体内共聚焦显微镜观察到角膜神经密度增加。本研究表明，CTH-mNGF是透明的、热敏的，具有缓释特性。其在所有神经营养性角膜病变眼中愈合角膜上皮缺损的有效性表明CTH-mNGF在神经营养性角膜病变治疗中具有广阔的应用前景，既方便又经济有效。
