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Researchers are zeroing in on genes that play a role in many forms of glaucoma, according to Janey L. Wiggs, MD, PhD.
The studies could lead the way to cures for some forms of the disease, said Dr. Wiggs, who presented the Drs. Henry and Frederick Sutro Memorial Lecture at this year's Glaucoma 360 New Horizons Forum of the Glaucoma Research Foundation.
"Genetic studies have identified glaucoma genes and biological pathways that are defining disease mechanisms and could be targets of new therapies," Dr. Wiggs, professor of ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary.
The genetic studies fall into two broad categories, she said.
"Early onset glaucomas are caused by rare mutations that have a large biological effect," she said. "They disrupt proteins and are identified early in life. In contrast the adult onset glaucomas are common in the population and the genetic risk factors are relatively common, but they have relatively small effects."
The small effects makes identifying late onset genes particularly challenging, said Dr. Wiggs.
This task requires a large sample size. To meet that challenge, Dr. Wiggs and other researchers have formed the Neighborhood Consortium for glaucoma genetics. The consortium has collected over 5,000 samples from primary open-angle glaucoma patients, as well as 30,000 control samples.
Studying this population has helped identify multiple biological processes implicated in glaucoma. Contributing biological processes include mitochondria, extracellular matrix, vasculature and lymph, membranes and lipid metabolism, transforming growth factor (TGF) beta, cell death, cell division, and ocular development.
"The diversity of biological pathways underscores something we clinicians know," she said. "This is a very diverse disease."
As one promising line of research, she cited the MYOC gene which codes for myocilin. Mutations in this gene cause familial juvenile open angle glaucoma and early onset adult open angle glaucoma. Mutant proteins accumulate in the endoplasmic reticulum and kill cells.
In mice, researchers have used CRISPR/cas9 gene editing to remove the MYOC mutation and lower IOP.
"These preclinical studies pave the way for developing treatments for human glaucoma patients," said Dr. Wiggs. "This would be curative therapies for these patients."
Likewise the TEK gene codes for TEK receptor tyrosine kinase, which is involved in vasculature endothelial cell proliferation and survival and in lymphanogenesis. Rare mutations can interfere with Schlemm's canal formation and are associated with elevated intraocular pressure, congenital glaucoma and even adult onset glaucoma.
Meanwhile mutations in CAV1, ABCA1, and ARHGEF12 affect cholesterol efflux. The cholesterol pathway is associated with primary open angle glaucoma as part of the Acetyl-CoA pathway. It is inhibited by statins, which may reduce primary open-angle glaucoma (POAG) risk, said Dr. Wiggs.
DKGK which codes for diacylglycerol kinase gamma may impact cell growth, neuronal transmission and cytoskeleton remodeling.
Genes affecting mitochondria are important in glaucoma because mitochondria densely populate the metabolically active unmyelinated prelaminar optic nerve and may leak electrons, causing formation of free radicals and damaging reactive species.
The gene TXNRD2 codes for thioredoxin reductase 2, which is important in maintaining a reactive oxygen scavenging system in mitochondria. TXNRD2 DNA variants are associated with the risk of POAG.
In a study using data from the UK Biobank, researchers identified four additional loci associated with mitochondrial function and intraocular pressure: ME3, VPS13C, GCAT and PTCD2.
Despite this promising work, researchers believe there are more genes to identify in glaucoma, said Dr. Wiggs.
They want to conduct functional studies in animal models, study the relevant cell biology and add genetic components to clinical trials, said Dr. Wiggs.