The optic nerve cannot regenerate if injured, leaving victims of traumatic or ischemic nerve damage or degen- erative diseases such as glaucoma with permanent visual losses. We have recently identified ways to partially reverse this situation by activating the intrinsic growth state of retinal ganglion cells (RGCs), the projection neu- rons of the eye. When exposed to oncomodulin (Ocm), a growth factors produced by inflammatory cells, RGCs lacking the pten gene and having elevated levels of cAMP are able to regenerate injured axons through the en- tire optic nerve, across the optic chiasm, and into appropriate target areas, where they form synapses and par- tially restore visual responses. We now propose to develop ways to translate these findings into methods that are suitable for clinical application. We will develop and test adeno-associated viruses to express Ocm, elevate intracellular levels of cAMP, and counteract cell-intrinsic and cell-extrinsic inhibitors of axon growth. These studies will increase our ability to augment regeneration in the optic nerve, potentially helping many victims of traumatic or degenerative visual disorders. The methods and reagents developed here may also be useful for restoring neural circuits in other parts of the CNS. !! ! !

Public Health Relevance

The optic nerve, like most pathways in the mature central nervous system, cannot regenerate when injured, leaving victims of optic nerve damage or degenerative diseases such as glaucoma with life-long losses in vision. We have recently developed ways to enable retinal ganglion cells, the projection neurons of the eye, to regrow damaged axons back to the correct brain areas and restore some visual responses. However, those studies utilized methods that cannot be used clinically in their present form. The proposed research will translate the successful regeneration obtained in those studies into methods that can be applied clinically.

National Institute of Health (NIH)
National Eye Institute (NEI)
Exploratory/Developmental Grants (R21)
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Chin, Hemin R
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Children's Hospital Boston
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Benowitz, Larry I; He, Zhigang; Goldberg, Jeffrey L (2017) Reaching the brain: Advances in optic nerve regeneration. Exp Neurol 287:365-373
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Xiong, Wenjun; MacColl Garfinkel, Alexandra E; Li, Yiqing et al. (2015) NRF2 promotes neuronal survival in neurodegeneration and acute nerve damage. J Clin Invest 125:1433-45
Koriyama, Yoshiki; Kurimoto, Takuji; de Lima, Silmara et al. (2014) [Reinnervation of central visual areas and recovery of visual functions following optic nerve regeneration in adult mice]. Brain Nerve 66:265-72
de Lima, Silmara; Habboub, Ghaith; Benowitz, Larry I (2012) Combinatorial therapy stimulates long-distance regeneration, target reinnervation, and partial recovery of vision after optic nerve injury in mice. Int Rev Neurobiol 106:153-72