Abstract
Purpose :
The optic nerve, like other pathways in the mature CNS, cannot regenerate after traumatic injury or degenerative diseases, leading to permanent vision loss. Altering the intrinsic growth ability of retinal ganglion cells (RGCs) by manipulating transcription factors or by activating growth factor-induced signaling pathways has resulted in appreciable levels of axon growth, but we are still far from achieving substantial visual recovery, underlining the need for therapies with higher efficacy. Oncomodulin (Ocm), an 11 kDa protein expressed by neutrophils and macrophages, is a critical mediator of optic nerve regeneration induced by intraocular inflammation. Intraocular inflammation combined with a cAMP analog and deletion of Phosphatase and tensin homolog (Pten) is one of the few treatments reported to promote optic nerve regeneration back to central brain target areas. This study's purpose is to obviate the need for intraocular inflammation and to apply treatments in a clinically relevant manner.
Methods :
We incorporated the Ocm gene into the glial-specific shH10 virus, and injected this virus intraocularly together with AAV2 viruses expressing constitutively-activated adenylyl cyclase (AAV2-c/a-AC to elevate cAMP, a co-factor of Ocm) and shPten (AAV2-shPten) after optic nerve injury. Regenerating axons were labeled by an antereograde tracer cholera toxin subunit B (CTB) and quatified at different distances distal to the nerve injury site.
Results :
After survival periods of up to 8 weeks, this combined treatment stimulated axon growth through the full length of the optic nerve, with 500-800 axons at the end of optic nerve and many axons crossing the optic chiasm and entering the brain.
Conclusions :
Gene therapy directed at manipulating defined molecules and delivered after injury has occurred can promote substantial optic nerve regeneration and provides a model for future studies of brain target reinnervation.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.