To learn more about this potential new therapeutic avenue for glaucoma, The Ophthalmologist spoke with study authors Simon John, Dan Stamer, Jiang Qian, Nicholas Tolman, and Taibo Li.
What did your recent eLife study find?
Nicholas Tolman: Using high-resolution single-cell transcriptomic and chromatin analyses, we mapped the cellular composition of the trabecular meshwork (TM) in mice. We identified three molecularly distinct TM cell subtypes, each with characteristic gene expression profiles and preferential localization within the TM. One subtype, termed TM3, showed strong enrichment for mitochondrial and metabolic pathways, and demonstrated particular vulnerability to mitochondrial dysfunction in a mouse glaucoma model. Significantly, supplementation with vitamin B3 (nicotinamide), which supports mitochondrial function, prevented intraocular pressure (IOP) elevation and glaucoma.
Were you surprised by how much cellular diversity you found in the TM?
Dan Stamer: Not necessarily surprised, but the degree of specialization was greater than expected. We found that although all TM cells are largely alike in overall gene expression patterns, there are distinct subpopulations with specialized roles. For example, enriched roles in specific subtypes range from regulation of metabolic processes and contractility (TM3) to paracrine signaling and phagocytic functions (TM2), and extracellular matrix production and remodeling (TM1). While the human TM has long been appreciated as a heterogeneous tissue, particularly the structural and functional differences between cells that reside in different locations (inner versus outer TM), the extent of molecular specialization was greater than anticipated.
Why might TM3 especially be considered a critical cell type in glaucoma progression?
Dan Stamer: Based on gene expression, TM3 are highly metabolically active. Additionally, TM3 has enriched expression of metabolism related genes that are associated with human IOP elevation and glaucoma in GWAS studies, as well as high expression of LMX1B – an important glaucoma gene. Given their high metabolic needs, TM3 cells may be especially vulnerable to metabolic stress.
Can you explain the role of vitamin B3 (nicotinamide) in potential glaucoma protection?
Nicholas Tolman: Nicotinamide increases intracellular levels of nicotinamide adenine dinucleotide (NAD⁺), a critical cofactor for enzymes that are essential in mitochondrial function and in cellular energy metabolism. In other published work, we showed that nicotinamide improves cellular health and function in retinal ganglion cells by improving their metabolism and inducing a resilient state that better withstands stresses resulting from elevated IOP; thus lessening potential for glaucoma.
In the current paper, we extend this resilience and protection effect to TM cells. Our data suggest that nicotinamide protects against disrupted mitochondrial metabolism in the TM cells (likely TM3 cells but not yet directly proven) in our glaucoma model, which lessens IOP elevation and glaucoma. Together, the direct neuroprotective effects of nicotinamide and the protection from IOP elevation suggest a dual benefit, which is promising when considering patients. Related to this we have found similar protective effects of another metabolism supporting molecule, pyruvate against IOP elevation and glaucoma, while a collaboration with Drs Keva Li, Louis Pasquale and others demonstrated that pyruvate protects from high genetic risk of glaucoma in humans.
What could be the implications for glaucoma?
Simon John: If metabolic susceptibilities are present in an analogous TM3-like cell subpopulation in humans, therapies aimed at improving cellular metabolism, such as nicotinamide or related agents, could serve as IOP-preserving/lowering treatments. These treatments will likely complement other treatment strategies because their mechanism of action is distinct from all current therapies.
Importantly, there is also relevance to childhood glaucoma. Although not part of this paper, our ongoing unpublished findings are increasingly showing that these resilience inducing, metabolism supporting molecules may protect from developmental anomalies of the TM and Schlemm’s canal. This is an exciting area that we are continuing to investigate.
What would be the main takeaway of this study for glaucoma specialists?
Simon John: Our findings suggest that nicotinamide enhances the resilience of TM cells to mitochondrial metabolic stress. Similar mitochondrial dysfunction has been observed in the optic nerve in response to elevated IOP. Nicotinamide is already being evaluated in clinical trials for neuroprotection of the optic nerve, with encouraging early results from three published independent short-term studies. Together, this indicates that nicotinamide is a strong candidate for prophylactic or adjunctive therapy in glaucoma, with the potential to support both TM and optic nerve health.
What are the next steps in translating this type of therapy to humans?
Nicholas Tolman: A critical next step is in-depth comparison of the TM cell subtypes identified in mice with those present in human TM tissue. This will help identify the human counterpart(s) to the TM3 population and clarify its metabolic vulnerabilities and potential causative genes and pathways, including LMX1B. In parallel, well-designed clinical studies will be required to define the safety, optimal dosing, and therapeutic efficacy of nicotinamide or other metabolism-targeted treatments in patients to lessen IOP elevation (prevention).
Is there anything else you would like to add?
Jiang Qian: This study provides a comprehensive atlas of TM cell subtypes that will be a useful resource for understanding TM biology and IOP regulation. Outflow dysfunction in glaucoma may reflect selective vulnerability of specific TM cell populations. Understanding these cell-type-specific metabolic profiles opens the door to targeted, disease-modifying therapies that may increase efficacy.
