Stem cell therapy for treatment of ischemic optic neuropathy

Abstract

Purpose : Ischemic insult to the central nervous system (CNS) is clinically devastating. Ischemic optic neuropathy typically affects the anterior optic nerve and is the most common cause of sudden vision loss in those older than 50. Although neurons are a target in treatment design, they are difficult to salvage due to lack of plasticity. In contrast, glial cells are greater in number and regenerative potential. Oligodendrocytes are the most abundant CNS glia and are progressively lost after optic nerve ischemia. While most preclinical transplantation studies rely on intravitreal injections, facing barriers for integration into the retina or optic nerve, injections into the optic nerve are difficult in small animals, especially in mice. We investigated whether intravitreally delivered oligodendrocyte progenitor cells (OPCs) could target the ischemic optic nerve and propose different routes for transplantation in mice.

Methods : We injected mouse OPCs intravitreally after optic nerve ischemia induction by photochemical thrombosis in adult mice and performed in vivo optical coherence tomography (OCT) and histology. We delivered dyes or GFP⁺/luciferase⁺ fibroblasts a) intranasally, b) by direct injection after exposure of the optic nerve or c) by blind injection through the superior orbital fissure. Fibroblasts were tracked in vivo by bioluminescence imaging (BLI) after intraperitoneal injection of luciferase substrate (D-luciferin) and by histology.

Results : OPCs accumulated in the vitreous body (OCT), with rare integration into the retina (histology). Intranasal injection of fibroblasts led to a discrete BLI signal after 24h, which disappeared within 5 days. Direct optic nerve injection led to increased signal, seen in the orbital area, whereas blind injection led to faint signal in the orbital area. Histologic analyses showed the presence of dyes or cells mostly in the sclera and optic nerve sheath, with few cells across the dura. Direct injection targeted the vicinity of the optic nerve head, while blind injection targeted the mid portion of the nerve.

Conclusions : Intravitreal cell injection has poor chance to target the optic nerve. Direct optic nerve injection has a higher integration potential when compared to the less invasive, blind injection through the orbital fissure. Studies aiming for cell injection at the optic nerve are needed to design cell therapies for optic neuropathies.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.