Exosome-Mediated Delivery of the Neuroprotective Peptide PACAP38 Promotes Retinal Ganglion Cell Survival and Axon Regeneration in Rats With Traumatic Optic Neuropathy.

Tian Wang,Miao Guo,Xiaohong Wang,Haifang Yin,Yiming Li,Hua Yan,Mengyu Liao,Mei Du,Xue Dong

doi:10.3389/fcell.2021.659783

Abstract

Traumatic optic neuropathy (TON) refers to optic nerve damage caused by trauma, leading to partial or complete loss of vision. The primary treatment options, such as hormonal therapy and surgery, have limited efficacy. Pituitary adenylate cyclase-activating polypeptide 38 (PACAP38), a functional endogenous neuroprotective peptide, has emerged as a promising therapeutic agent. In this study, we used rat retinal ganglion cell (RGC) exosomes as nanosized vesicles for the delivery of PACAP38 loaded via the exosomal anchor peptide CP05 (EXOPACAP38). EXOPACAP38 showed greater uptake efficiency in vitro and in vivo than PACAP38. The results showed that EXOPACAP38 significantly enhanced the RGC survival rate and retinal nerve fiber layer thickness in a rat TON model. Moreover, EXOPACAP38 significantly promoted axon regeneration and optic nerve function after injury. These findings indicate that EXOPACAP38 can be used as a treatment option and may have therapeutic implications for patients with TON.

Highlights

Traumatic optic neuropathy (TON) refers to optic nerve damage secondary to trauma, and leads to partial and complete loss of vision
Significantly increased fluorescence intensity was found in retinal ganglion cell (RGC) incubated with EXOPACAP38, in which exosomes derived from rat RGCs (EXOs) were labeled with DiR and Pituitary adenylate cyclaseactivating polypeptide 38 (PACAP38) was labeled with FITC, compared with RGCs treated with the mixture of EXOs and PACAP38 without CP05 (Figure 1C)
The FACS results showed up to 86.9% uptake in RGCs treated with EXOPACAP38 (Figure 1D), indicating that EXOs mediate the efficient delivery of PACAP38 to RGCs

Summary

Introduction

Traumatic optic neuropathy (TON) refers to optic nerve damage secondary to trauma, and leads to partial and complete loss of vision. TON is one of the most severe eye traumas, accounting for 0.5–5% of all craniocerebral traumas (Pirouzmand, 2012). Intraductal optic nerve injury is the most common cause of TON owing to the anatomical structure and physiological characteristics of the region (Ganguly and Barik, 2015). TON can result in axonal damage, leading to the gradual irreversible loss of retinal ganglion cells (RGCs) and, to permanent visual deficiency. No effective treatment is available for TON (Chaon and Lee, 2015; Singman et al, 2016; Yan et al, 2016). The clinical treatment options for TON include observation (conservative management), high-dose corticosteroid treatment, or surgery (optic canal decompression), which

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