Glaucoma: neuroprotection with NAD-based therapeutic interventions

• Published in: Trends in pharmacological sciences (Regular ed.) 2023-12, Vol.44 (12), p.869-879
• Main Author: Chiarugi, Alberto
• Format: Article
• Language: English
• Subjects: axonopathy; glaucoma; Glaucoma - drug therapy; Glaucoma - pathology; Humans; NAD; Neuroprotection; Neuroprotective Agents - pharmacology; Neuroprotective Agents - therapeutic use; Retinal Ganglion Cells - pathology; SARM1
• ISSN: 0165-6147; 1873-3735
• DOI: 10.1016/j.tips.2023.09.010

Glaucoma is a leading cause of blindness; despite efficacious lowering of intraocular pressure, the disease progresses because neurodegeneration of retinal ganglion cells (RGCs)represents the primary neurodegenerative event.Recently, the identification of a programmed axonal degeneration program triggered by NAD shortage opened new vistas on the possibility of developing efficacious neuroprotective strategies to counteract glaucoma progression, and proof-of-concept clinical trials with NAD supplements have already provided positive results in patients with glaucoma.Here, I provide a critical reappraisal on how the pathogenesis of RGC death should instruct drug development programs for neuroprotection in glaucoma. Clinical evidence shows that intraocular hypertension is not the primary pathogenetic event of glaucoma, whereas early neurodegeneration of retinal ganglion cells (RGCs) represents a key therapeutic target. Unfortunately, failure of clinical trials with neuroprotective agents, in particular those testing the anti-excitotoxic drug memantine, generated widespread skepticism regarding the possibility of counteracting neurodegeneration during glaucoma. New avenues for neuroprotective approaches to counteract glaucoma evolution have been opened by the identification of a programmed axonal degeneration (PAD) program triggered by increased nicotinamide mononucleotide (NMN)/NAD concentration ratio. Positive results of proof-of-concept clinical studies based on sustaining axonal NAD homeostasis facilitated the design of Phase 2/3 trials. Here, I share my opinion on how neurodegeneration in glaucoma should be put into context, together with an appraisal of the pharmacological rationale of NAD-supporting therapies for use during glaucoma progression. Clinical evidence shows that intraocular hypertension is not the primary pathogenetic event of glaucoma, whereas early neurodegeneration of retinal ganglion cells (RGCs) represents a key therapeutic target. Unfortunately, failure of clinical trials with neuroprotective agents, in particular those testing the anti-excitotoxic drug memantine, generated widespread skepticism regarding the possibility of counteracting neurodegeneration during glaucoma. New avenues for neuroprotective approaches to counteract glaucoma evolution have been opened by the identification of a programmed axonal degeneration (PAD) program triggered by increased nicotinamide mononucleotide (NMN)/NAD concentration ratio. Positive results of p