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  3. Preventing and treating neurotrophic keratopathy by a single intrastromal injection of AAV-mediated gene therapy

Preventing and treating neurotrophic keratopathy by a single intrastromal injection of AAV-mediated gene therapy

  • Ocul Surf. 2024 Oct 1:34:406-414. doi: 10.1016/j.jtos.2024.09.010.
Lin Cong 1,  Benxiang Qi 2,  Wenhui Ma 2,  Zhongmei Ren 2,  Qian Liang 3,  Qingjun Zhou 2,  Bi Ning Zhang 4,  Lixin Xie 5
Affiliations

Affiliations

  • 1 Eye Institute of Shandong First Medical University, Qingdao Eye Hospital of Shandong First Medical University, Qingdao, China; School of Ophthalmology, Shandong First Medical University, Qingdao, China.
  • 2 Eye Institute of Shandong First Medical University, Qingdao Eye Hospital of Shandong First Medical University, Qingdao, China; School of Ophthalmology, Shandong First Medical University, Qingdao, China; State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Qingdao, China.
  • 3 Eye Institute of Shandong First Medical University, Qingdao Eye Hospital of Shandong First Medical University, Qingdao, China.
  • 4 Eye Institute of Shandong First Medical University, Qingdao Eye Hospital of Shandong First Medical University, Qingdao, China; School of Ophthalmology, Shandong First Medical University, Qingdao, China; State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Qingdao, China. Electronic address: zbnxtt@gmail.com.
  • 5 Eye Institute of Shandong First Medical University, Qingdao Eye Hospital of Shandong First Medical University, Qingdao, China; School of Ophthalmology, Shandong First Medical University, Qingdao, China; State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Qingdao, China. Electronic address: lixin_xie@hotmail.com.
PMID: 39362525 DOI: 10.1016/j.jtos.2024.09.010
Abstract

Purpose: Neurotrophic keratopathy (NK) is a degenerative corneal condition resulting from corneal nerve injury. Current therapies, including the recombinant human nerve growth factor (rhNGF) therapy, requires continuous administration. This study aims to develop a novel and highly effective gene therapy strategy for the prevention and treatment of NK.

Methods: Adeno-associated virus (AAV) was transduced into corneal stromal cells by intrastromal injection. Three dimensional corneal wholemount imaging with co-immunostaining of ZO-1 and tubulin was utilized to assess the transduction of AAV.rh10. The efficacy of prevention and treatment of NK by a single intrastromal injection of AAV-Ngf was tested using capsaicin mouse model, herpes simplex keratitis (HSK) model, type Ⅱ diabetes model and alkali burn model. rhNGF eye drops served as the positive control.

Results: Intrastromal injection of AAV.rh10 efficiently transduced the subepithelial nerve plexus and retrogradely transported to the trigeminal ganglion (TG). A single injection of AAV.rh10-Ngf can significantly promote corneal nerve repair, accelerate corneal epithelial repair, reduce corneal stromal edema, and improve corneal sensitivity across the four NK models. The therapeutic effects were consistent with those achieved by continuous administration of rhNGF drops by 6 times daily.

Conclusions: This proof-of-concept study demonstrates that AAV.rh10-Ngf gene therapy is a promising method for preventing and treating of NK. Our results underline the potential for developing clinical trials to further explore the safety and efficacy of such gene therapy.

Keywords

AAV.rh10; Gene therapy; Neurotrophic keratopathy; Retrograde transport; rhNGF.

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