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Glaucoma: neuroprotection with NAD-based therapeutic interventions
1Section of Clinical Pharmacology and Oncology, Department of Health Sciences, University of Florence, Florence, Italy; Headache Center and Clinical Pharmacology Unit, Careggi University Hospital, Florence, Italy.
Abstract:
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.
Insights
Glaucoma treatment is shifting focus from intraocular pressure to neuroprotection. Targeting programmed axonal degeneration via NAD+ homeostasis offers a promising therapeutic strategy for retinal ganglion cell survival.
Area of Science:
- Ophthalmology
- Neuroscience
- Pharmacology
Background:
- Glaucoma's primary pathology is retinal ganglion cell (RGC) neurodegeneration, not intraocular hypertension.
- Previous neuroprotective strategies, like memantine, have faced clinical trial failures, leading to skepticism.
- The programmed axonal degeneration (PAD) pathway, influenced by nicotinamide mononucleotide (NMN)/NAD+ ratio, presents a new therapeutic target.
Purpose of the Study:
- To re-evaluate the context of neurodegeneration in glaucoma.
- To appraise the pharmacological rationale for NAD+-supporting therapies in glaucoma treatment.
Main Methods:
- Review of clinical evidence on glaucoma pathogenesis.
- Analysis of neuroprotective agent trial outcomes.
- Evaluation of the programmed axonal degeneration (PAD) pathway and NAD+ homeostasis.
Main Results:
- Early RGC neurodegeneration is a critical therapeutic target in glaucoma.
- Skepticism exists regarding neuroprotection due to past trial failures.
- Sustaining axonal NAD+ homeostasis shows promise, with positive proof-of-concept studies.
Conclusions:
- NAD+-supporting therapies offer a novel neuroprotective approach for glaucoma.
- Further clinical trials (Phase 2/3) are underway based on promising preliminary results.
- Contextualizing neurodegeneration and leveraging NAD+ pathways are key for future glaucoma treatments.
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