Abstract
Purpose :
Glaucoma is one of the most prevalent neurodegenerative diseases and the leading cause of irreversible blindness. The first line of treatment for glaucoma patients is intraocular pressure-lowering medication. Despite intraocular pressure-lowering treatment, many patients lose vision in at least one eye. Preventing NAD depletion has been shown to protect from glaucoma-related insults and is a promising neuroprotective mechanism to pharmacologically target. NMNAT2 is a neuron-specific terminal enzyme that synthesizes NAD, is highly expressed in retinal ganglion cells, and can be positively modulated for increased NAD levels.
Methods :
We have identified a polyphenol that positively modulates NMNAT2. We demonstrate that this polyphenol increases NAD levels in primary cortical cells and prevents retinal ganglion cell degeneration. We are actively pursuing novel pharmacology based on the structure-activity relationship between the polyphenol and the NMNAT2 protein.
Results :
To date, we have synthesized and tested over 70 compounds for their NAD-boosting capacity in primary cortical neurons using a semi-high throughput assay screen. We have identified multiple compounds that drive efficient NAD production in an NMNAT2-dependent context.
Conclusions :
These novel small molecules, that increase NAD through NMNAT2 activity, show a genuine promise for targeted treatments of glaucoma and other neurodegenerative diseases and give novel insights into the role of NAD in axon degeneration.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.