Targeting NMNAT2 for neuroprotection in glaucoma

Abstract

Purpose : Glaucoma is the leading cause of irreversible blindness. Despite treatments to lower intraocular pressure many patients will continue to go blind. Neuroprotective therapies that target the retina and optic nerve in glaucoma are of great therapeutic need. Repleting NAD robustly protect from glaucoma-related insults in a variety of animal models and improves visual function in existing glaucoma patients.

Methods : The aim of this study is to assess the role of NMNAT2 in glaucomatous neurodegeneration and neuroprotection. NAD production in retinal ganglion cells is controlled through two terminal enzymes; NMNAT1 (localized to the nucleus) and NMNAT2 (localized in the cytoplasm). NMNAT2 is expressed exclusively in neurons and shows high expression in retinal ganglion cells. We used rodent and cellular systems to assess the role of high and low NMNAT2 in retinal ganglion cell susceptibility to neurodegeneration (genetic, viral gene therapy, and pharmacology).

Results : We demonstrate that there is down-regulation of NMNAT2 in models of glaucoma and retinal ganglion cell axon degeneration and confirm this in post-mortem human glaucoma tissue. Gene therapy restoring NMNAT2 levels to retinal ganglion cells robustly protects from glaucoma and axon injury (in vivo and ex vivo models). Supporting this, mice with genetically depleted NMNAT2 show increased susceptibility to glaucoma related injury. To further target NMNAT2 function, we have identified novel NMNAT2 activators that work in an NAD/NMN- and NMNAT2- dependent mechanism (this specificity was confirmed by using pharmacological and genetic inhibition of enzymes in the NAD-salvage pathway in vitro and in vivo). We are now developing novel pharmacology based on this.

Conclusions : NMNAT2 is an important generator of NAD in retinal ganglion cells and low NMNAT2 critically drives retinal ganglion cell susceptibility to glaucoma-related stresses. Targeting NMNAT2 via viral gene therapy or novel small molecule pharmacology generates NAD and protects from neurodegeneration.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.