Glaukom
Glaucoma is a complex, multifactorial disease affecting an estimated 80 million people worldwide and is the leading cause of irreversible blindness. It is a significant health and economic burden. Age, genetics, and high intraocular pressure (IOP) are all considerable risk factors.
Research description
The Pete Williams Lab uses the eye as a model of the central nervous system to elucidate early mechanisms of neurodegeneration. We utilize modern transcriptomic and molecular tools to delicately dissect pathways pertaining to early aging and neurodegenerative disease mechanisms and to identify potential therapeutic targets which we then test and verify in animal and cell models of neurodegeneration. We work with clinicians to develop novel protective strategies that will benefit human health, aging, and disease.
Glaucoma is a complex, multifactorial disease affecting an estimated 80 million people worldwide and is the leading cause of irreversible blindness. It is a significant health and economic burden at both individual and societal level. Age, genetics, and high intraocular pressure (IOP) are all considerable risk factors. Despite strategies to manage IOP, >40% of treated glaucoma patients will progress to blindness. Neuroprotective treatments for glaucoma are of great therapeutic need. The Pete Williams Lab is developing new neuroprotective treatments for glaucoma, from bench-to-bedside.
The overarching theme of the Pete Williams Lab is to explore how bioenergetic insufficiency drives neurodegeneration and to identify novel neuroprotective therapies based on these data
Glaucoma is characterized by the progressive dysfunction and loss of retinal ganglion cells (RGCs). RGCs are the output neurons of the retina, the axons of which become the optic nerve before integrating with key visual centers in the brain. Axon and dendritic degeneration are core components of glaucomatous neurodegeneration. RGCs sit on a metabolic knife-edge during times of stress that may be exacerbated by aging, genetic risk, and elevated IOP. During these periods, the viability of RGCs is reliant on mitochondria and supportive glia to maintain homeostasis and bioenergetic needs. Emerging research suggests that a systemic vulnerability to mitochondrial and metabolic abnormalities exists in glaucoma patients. Genomic analysis has demonstrated increased mitochondrial DNA content and a spectrum of mitochondrial DNA mutations in glaucoma patients. These abnormalities are also present in leukocytes, suggesting a systemic susceptibility to metabolic defects. Such systemic susceptibility is expected to increase glaucoma susceptibility with age.
Only strategies to lower IOP have been translated to the clinic and these therapeutics do not treat the neurodegenerative component of glaucoma. Patient adherence is variable and too many patients are subject to surgical interventions because of progressive damage. In addition, many patients are refractory to pressure lowering treatments and progress to blindness despite low pressures. So far, search for a treatment that targets RGCs and arrests progression, has a low side effect profile, and is cost-effective has been unsuccessful. Neuroprotective treatments for glaucoma are of great therapeutic need. Our research explores how this bioenergetic insufficiency drives neurodegeneration and identifies novel neuroprotective therapies based on these findings.
Major Current Research Theme: Neuronal NAD+ metabolism
NAD supplementation protects from bioenergetic insufficiency in glaucoma. We have previously discovered metabolic dysfunction and mitochondrial abnormalities occurring prior to neurodegeneration in glaucoma (in glaucoma patients and animal models). A key finding of these studies identified that NAD (an essential REDOX cofactor and metabolite) declines in the retina in an age-dependent manner and renders RGCs susceptible to glaucoma-related stresses, driving neurodegeneration. Preventing NAD depletion via administration of nicotinamide (NAM; the amide of vitamin B₃; an NAD precursor) or through gene therapy (Nmnat1 or Nmnat2; terminal enzymes for NAD production) robustly protects from age-related neuronal metabolic decline and prevents glaucoma in chronic animal models. Supporting a hypothesis in which pathogenically low NAD leads to glaucoma susceptibility, glaucoma patients have been demonstrated to have systemically low levels of nicotinamide (in sera), and we, as part of a multi-national collaborative clinical trial, have demonstrated that nicotinamide administration can restore visual function in existing glaucoma patients. Our continued work with nicotinamide exemplifies the lab’s commitment to developing translational neuroprotective strategies, from bench-to-bedside.
Ongoing Research Themes
Mitochondria
We use a variety of novel reporter mice, mitochondrial markers, and live/vital dyes to image and analyze mitochondria at ultra-high resolution in healthy, disease, and treated states.
Neuronal Metabolism
We use targeted assays, targeted and enriched mass. spec. protocols, and high resolution untargeted metabolomics to identify novel disease pathways and candidate biomarkers in glaucoma.
Gene Therapies
Viral gene therapy has been successful in a handful of rare, monogenic ophthalmic diseases. We are expanding this work to develop gene therapies targeting common neurodegenerative pathways.
Neuroinflammation
Neuroinflammation within the retina and optic nerve may be a critical pathogenic event in early glaucoma. Our research explores microglia activation throughout the visual system in glaucoma.
Selected Publications
NAD salvage pathway machinery expression in normal and glaucomatous retina and optic nerve
James R Tribble, Anna Hagström, Kenza Jusseaume, Emma Lardner, Raymond Ching-Bong Wong, Gustav Stålhammar, Pete A Williams
Acta Neuropathol Commun. 2023 Jan 22;11(1):18.doi: 10.1186/s40478-023-01513-0.
De Moraes Cg, John Swm, Williams Pa, Blumberg Dm, Cioffi Ga, Liebmann Jm
JAMA ophthalmology 2021;():-
Tribble Jr, Otmani A, Sun S, Ellis Sa, Cimaglia G, Vohra R, Jöe M, Lardner E, Venkataraman Ap, Domínguez-vicent A, Kokkali E, Rho S, Jóhannesson G, Burgess Rw, Fuerst Pg, Brautaset R, Kolko M, Morgan Je, Crowston Jg, Votruba M, Williams Pa
Redox biology 2021;43():101988-
Disturbed glucose and pyruvate metabolism in glaucoma with neuroprotection by pyruvate or rapamycin
Harder Jm, Guymer C, Wood Jpm, Daskalaki E, Chidlow G, Zhang C, Balasubramanian R, Cardozo Bh, Foxworth Ne, Deering Ke, Ouellette Tb, Montgomery C, Wheelock Ce, Casson Rj, Williams Pa, John Swm
Proceedings of the National Academy of Sciences of the United States of America 2020;117(52):33619-33627
Hui F, Tang J, Williams Pa, Mcguinness Mb, Hadoux X, Casson Rj, Coote M, Trounce Ia, Martin Kr, Van Wijngaarden P, Crowston Jg
Clinical & experimental ophthalmology 2020;48(7):903-914
Tribble Jr, Vasalauskaite A, Redmond T, Young Rd, Hassan S, Fautsch Mp, Sengpiel F, Williams Pa, Morgan Je
Brain communications 2019;1(1):fcz035-
Vitamin B3 modulates mitochondrial vulnerability and prevents glaucoma in aged mice
Williams Pa, Harder Jm, Foxworth Ne, Cochran Ke, Philip Vm, Porciatti V, Smithies O, John Sw
Science (New York, N.Y.) 2017;355(6326):756-760
Group leader
Pete Williams
Lektor