Glaucoma remains a major cause of vision loss globally. Advancing age, genetics, and high IOP are all considerable risk factors. With an increasingly aged population, the number of patients with glaucoma is set to increase, and thus glaucoma will continue to be a significant health and economic burden.
AT A GLANCE
- Metabolic and mitochondrial dysfunction is present in human glaucoma patients and animal models of glaucoma.
- Declining systemic levels of nicotinamide adenine dinucleotide or nicotinamide (NAM) may be risk factors and biomarkers for glaucoma.
- NAM treatment is robustly protective in animal models of glaucoma.
- Ongoing NAM clinical trials show promise.
- New paradigms for clinical trial execution will allow the identification of potential neuroprotective treatments for glaucoma in the short to medium term.
CRUCIAL NEXT STEPS
- Establish meaningful parameters for neuroprotective clinical trials.
- Continue to identify systemic and retinal ganglion cell–specific risk factors.
- Focus on protecting the vulnerable retinal ganglion cell rather than regenerating the dead retinal ganglion cell.
Current treatment strategies for glaucoma target only IOP, the principal treatable risk factor. Patient adherence is variable, and many individuals are subject to surgical interventions due to progressive damage. In addition, many patients do not respond to pressure-lowering treatments or progress to blindness despite low IOP.
To date, the search for a treatment that targets retinal ganglion cells (RGCs) and arrests disease progression has been unsuccessful. Neuroprotective treatments for glaucoma are of great therapeutic need, as are new clinical trial paradigms that facilitate translation of candidate treatments from bench to bedside in an expedited fashion.
THE KEY TO Rgc DEGENERATION: METABOLISM?
The progressive dysfunction and loss of RGCs (and their axons that make up the optic nerve) are the hallmark features of glaucoma. RGCs are highly sensitive to metabolic fluctuations and sit on a metabolic knife-edge during times of stress that may be exacerbated by aging, genetic impairment, or increased IOP (Figure). During these periods of metabolic stress, the viability of RGCs is reliant on mitochondria and supportive glial cells to maintain cellular homeostasis and bioenergetic needs.
Figure. There is potential for functional vision recovery with neuroprotective treatments at multiple stages during glaucomatous progression. It is becoming increasingly important to understand the early factors that influence retinal ganglion cell health during normal aging and following insults from elevated IOP. Many systemic risk factors predispose retinal ganglion cells to bioenergetic failure, such as advancing age, genetics, and loss of metabolic substrates (Table 1), whereas elevated IOP, neuroinflammation, and hypoxic damage necessitate the initiation of energy-expensive repair processes. A consequence of this process is an induction of compensatory mechanisms that divert energy use from retinal ganglion cell axon potential propagation to repair, initiating retinal ganglion cell degeneration and remodeling. The following degenerative processes, synapse and dendrite pruning, protect injured retinal ganglion cells from excitatory bipolar cell inputs facilitating repair. If compensatory processes permit repair function, then dendrites and synaptic inputs can be restored. If not, then potentially irreversible apoptotic processes are induced. Preventing retinal ganglion cell decline prior to the initiation of apoptosis should be a key factor in designing the next generation of glaucoma neuroprotective treatments. (Figure adapted in part from Caprioli J.1)
Disease-causing mutations in mitochondrial protein-coding genes are prevalent in the human population and are present throughout the majority of cell types in the body. Yet, interestingly, abnormalities in these genes predominantly affect RGCs and present in the form of blinding disorders that, in most cases, have little or no overt extra-ophthalmic pathology (eg, autosomal dominant optic atrophy or Leber hereditary optic neuropathy).
Emerging research suggests that a systemic vulnerability to mitochondrial abnormalities exists in glaucoma patients. Genomic analysis has demonstrated altered mitochondrial DNA content and a spectrum of mitochondrial DNA mutations in individuals with glaucoma. These abnormalities are also present systemically in leukocytes, suggesting a systemic susceptibility to metabolic defects. Such systemic susceptibility conspires with elevated IOP to increase glaucoma susceptibility with age, this research suggests (Table 1). Metabolic decline may thus be a critical, and targetable, pathogenic component of glaucoma.
TARGETING MITOCHONDRIA AND METABOLISM
The mechanisms by which mitochondrial defects influence neuronal metabolism and lead to neurodegeneration are a topic of active research and interest. Current research has discovered metabolic dysfunction and mitochondrial abnormalities occurring prior to neurodegeneration in multiple experimental models of glaucoma. Targeting mitochondria and metabolism has shown promise in animal models of glaucoma (Table 2). Importantly, many of the changes discovered in animal models sensitize RGCs, leaving them vulnerable to the insults of elevated IOP.
One such molecule is the essential redox cofactor and metabolite nicotinamide adenine dinucleotide (NAD), which declines in the retina in an age-dependent manner. NAD is well established to be a potent mediator of axonal and neuronal survival following damaging disease-related insults. A key pathway to NAD synthesis in neurons is through the salvage pathway whose input is nicotinamide (NAM), the amide form of vitamin B3.
Recently, NAM has been demonstrated to be low in the sera of patients with primary open-angle glaucoma. In mouse models of glaucoma, dietary supplementation with NAM or intravitreal introduction of gene therapy (Nmnat1, a terminal enzyme for NAD biosynthesis) robustly protects against neuronal metabolic decline and prevents glaucoma. NAM has a long clinical history and a robust safety profile, even at megadoses (up to 12 g/day long-term); therefore, it is an ideal target for neuroprotection in glaucoma, and clinical trials of NAM in glaucoma are under way.
THE PROMISE OF NAM FOR NEUROPROTECTION IN GLAUCOMA
NAM’s widespread availability in health food stores, excellent safety profile, good tolerability, and affordability will all facilitate its rapid translation into clinical trials. At least two such trials are currently registered. The first, a crossover study (ACTRN12617000809336) based in Melbourne, Australia, is completed, and the manuscript is under review. The second, a New York–based NAM-pyruvate combination study (NCT03797469) has started recruitment and is underway, with a planned completion date of December 2019. A third Sweden-based study of NAM is planned for 2019 to 2020.
DESIGNING EFFICIENT AND EXPEDITED CLINICAL TRIALS
An ongoing challenge is the time required to conduct clinical trials for neuroprotection in glaucoma. The United Kingdom Glaucoma Treatment Study (UKGTS) demonstrated that, with intensive visual field testing, a change in glaucomatous progression rate could be determined as early as 11 months (when a prostaglandin was compared with placebo).
In a neuroprotective clinical trial, the test agent is assessed with placebo but in the presence of concomitant IOP lowering, a requirement on ethical grounds. Subsequently, longer follow-up periods are required, reducing feasibility and increasing cost. Thus, there is a clear need to develop surrogate clinical markers that provide information on RGC health and accurately predict longer-term progression rates.
We have been exploring whether short-term improvement in inner retinal function as determined by electroretinography or contrast sensitivity is seen after IOP lowering or in the presence of candidate neuroprotective treatment (ie, NAM). One of the aims of our collective research programs is to more accurately match clinical biomarkers with markers of glaucomatous neurodegeneration between human samples and donor tissue and animal models of glaucoma. This is essential to understanding the pathogenesis of RGC degeneration in glaucoma and will therefore aid in the search for relevant markers of RGC health.
THE FUTURE OF NEUROPROTECTION IN GLAUCOMA
With improvement in clinical trial testing and available resources for exploring early degenerative events in glaucoma, in addition to a better understanding of the utility of animal models, we are stepping into the future of neuroprotection in glaucoma. Over the coming year, we will see the first results from the NAM clinical trials, which will inform clinicians whether targeting neuronal metabolism is a viable strategy for protecting the vulnerable RGC in glaucoma patients.
1. Caprioli J. The importance of rates in glaucoma. Am J Ophthalmol. 2008;145(2):191-192.
2. Abu-Amero KK, Morales J, Bosley TM. Mitochondrial abnormalities in patients with primary open-angle glaucoma. Invest Ophthalmol Vis Sci. 2006;47(6):2533-2541.
3. Banerjee D, Banerjee A, Mookherjee S, et al. Mitochondrial genome analysis of primary open angle glaucoma patients. PLoS One. 2013;8(8):e70760.
4. Tanwar M, Dada T, Sihota R, Dada R. Mitochondrial DNA analysis in primary congenital glaucoma. Mol Vis. 2010;16:518-533.
5. Lee S, Van Bergen NJ, Kong GY, et al. Mitochondrial dysfunction in glaucoma and emerging bioenergetic therapies. Exp Eye Res. 2011;93(2):204-212.
6. Sundaresan P, Simpson DA, Sambare C, et al. Whole-mitochondrial genome sequencing in primary open-angle glaucoma using massively parallel sequencing identifies novel and known pathogenic variants. Genet Med. 2015;17(4):279-284.
7. Opial D, Boehnke M, Tadesse S, et al. Leber’s hereditary optic neuropathy mitochondrial DNA mutations in normal-tension glaucoma. Graefes Arch Clin Exp Ophthalmol. 2001;239(6):437-440.
8. Kumar M, Tanwar M, Faiq MA, et al. Mitochondrial DNA nucleotide changes in primary congenital glaucoma patients. Mol Vis. 2013;19:220-230.
9. Abu-Amero KK, González AM, Osman EA, Larruga JM, Cabrera VM, Al-Obeidan SA. Susceptibility to primary angle closure glaucoma in Saudi Arabia: the possible role of mitochondrial DNA ancestry informative haplogroups. Mol Vis. 2011;17:2171-2176.
10. Abu-Amero KK, Hauser MA, Mohamed G, et al. Mitochondrial genetic background in Ghanaian patients with primary open-angle glaucoma. Mol Vis. 2012;18:1955-1959.
11. Izzotti A, Longobardi M, Cartiglia C, Saccà SC. Mitochondrial damage in the trabecular meshwork occurs only in primary open-angle glaucoma and in pseudoexfoliative glaucoma. PLoS One. 2011;6(1):e14567.
12. Collins DW, Gudiseva HV, Trachtman BT, et al. Mitochondrial sequence variation in African-American primary open-angle glaucoma patients. PLoS One. 2013;8(10):e76627.
13. Collins DW, Gudiseva HV, Trachtman B, et al. Association of primary open-angle glaucoma with mitochondrial variants and haplogroups common in African Americans. Mol Vis. 2016;22:454-471.
14. Kouassi Nzoughet J, Chao de la Barca JM, Guehlouz K, et al. Nicotinamide deficiency in primary open-angle glaucoma. Invest Ophthalmol Vis Sci. 2019;60(7):2509-2514.
15. Fraenkl SA, Muser J, Groell R, et al. Plasma citrate levels as a potential biomarker for glaucoma. J Ocul Pharmacol Ther. 2011;27(6):577-580.
16. Aung T, Ocaka L, Ebenezer ND, et al. A major marker for normal tension glaucoma: association with polymorphisms in the OPA1 gene. Hum Genet. 2002;110(1):52-56.
17. Aung T, Ocaka L, Ebenezer ND, et al. Investigating the association between OPA1 polymorphisms and glaucoma: comparison between normal tension and high tension primary open angle glaucoma. Hum Genet. 2002;110(5):513-514.
18. Bosley TM, Hellani A, Spaeth GL, et al. Down-regulation of OPA1 in patients with primary open angle glaucoma. Mol Vis. 2011;17:1074-1079.
19. Yu-Wai-Man P, Stewart JD, Hudson G, et al. OPA1 increases the risk of normal but not high tension glaucoma. J Med Genet. 2010;47(2):120-125.
20. Bailey JN, Loomis SJ, Kang JH, et al. Genome-wide association analysis identifies TXNRD2, ATXN2 and FOXC1 as susceptibility loci for primary open-angle glaucoma. Nat Genet. 2016;48(2):189-194.
21. Khawaja AP, Cooke Bailey JN, Kang JH, et al. Assessing the association of mitochondrial genetic variation with primary open-angle glaucoma using gene-set analyses. Invest Ophthalmol Vis Sci. 2016;57(11):5046-5052.
22. Khawaja AP, Cooke Bailey JN, Wareham NJ, et al. Genome-wide analyses identify 68 new loci associated with intraocular pressure and improve risk prediction for primary open-angle glaucoma. Nat Genet. 2018;50(6):778-782.
23. Williams P, Harder J, Foxworth N, Cardozo B, Cochran K, John S. Nicotinamide and WLDS act together to prevent neurodegeneration in glaucoma. Front Neurosci. 2017;11(232).
24. Williams PA, Harder JM, Foxworth NE, et al. Vitamin B3 modulates mitochondrial vulnerability and prevents glaucoma in aged mice. Science. 2017;355(6326):756-760.
25. Williams PA, Harder JM, Cardozo BH, Foxworth NE, John SWM. Nicotinamide treatment robustly protects from inherited mouse glaucoma. Commun Integr Biol. 2018;11(1):e1356956.
26. Harun-Or-Rashid M, Pappenhagen N, Palmer PG, et al. Structural and functional rescue of chronic metabolically stressed optic nerves through respiration. J Neurosci. 2018;38(22):5122-5139.
27. Lee D, Shim MS, Kim KY, et al. Coenzyme Q10 inhibits glutamate excitotoxicity and oxidative stress-mediated mitochondrial alteration in a mouse model of glaucoma. Invest Ophthalmol Vis Sci. 2014;55(2):993-1005.
28. Nucci C, Tartaglione R, Cerulli A, et al. Retinal damage caused by high intraocular pressure-induced transient ischemia is prevented by coenzyme Q10 in rat. Int Rev Neurobiol. 2007;82:397-406.
29. Davis BM, Tian K, Pahlitzsch M, et al. Topical coenzyme Q10 demonstrates mitochondrial-mediated neuroprotection in a rodent model of ocular hypertension. Mitochondrion. 2017;36:114-123.
30. Luna C, Li G, Liton PB, et al. Resveratrol prevents the expression of glaucoma markers induced by chronic oxidative stress in trabecular meshwork cells. Food Chem Toxicol. 2009;47(1):198-204.
31. Zuo L, Khan RS, Lee V, Dine K, Wu W, Shindler KS. SIRT1 promotes RGC survival and delays loss of function following optic nerve crush. Invest Ophthalmol Vis Sci. 2013;54(7):5097-5102.
32. Pirhan D, Yüksel N, Emre E, Cengiz A, Kürat Yıldız D. Riluzole- and resveratrol-induced delay of retinal ganglion cell death in an experimental model of glaucoma. Curr Eye Res. 2016;41(1):59-69.
33. Parisi V. Electrophysiological assessment of glaucomatous visual dysfunction during treatment with cytidine-5’-diphosphocholine (citicoline): a study of 8 years of follow-up. Doc Ophthalmol. 2005;110(1):91-102.
34. Parisi V, Coppola G, Centofanti M, et al. Evidence of the neuroprotective role of citicoline in glaucoma patients. Prog Brain Res. 2008;173:541-554.
35. Han YS, Chung IY, Park JM, Yu JM. Neuroprotective effect of citicoline on retinal cell damage induced by kainic acid in rats. Korean J Ophthalmol. 2005;19(3):219-226.
36. Oshitari T, Fujimoto N, Adachi-Usami E. Citicoline has a protective effect on damaged retinal ganglion cells in mouse culture retina. Neuroreport. 2002;13(16):2109-2111.
37. Schuettauf F, Rejdak R, Thaler S, et al. Citicoline and lithium rescue retinal ganglion cells following partial optic nerve crush in the rat. Exp Eye Res. 2006;83(5):1128-1134.