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Applying precision medication to glaucoma and genomics

Optometry Times JournalVol. 10 No. 10
Volume 10
Issue 10

Technology is rapidly changing the way optometrists manage patients. For the profession to progress as an integral part of interprofessional healthcare teams, it must embrace important key advancements in eye care. 

Precision medicine is an innovative approach that uses individual differences in genomics, the environment, and patient lifestyles.1 It tailors treatment or management strategies to individuals based on their genome and susceptibility to conditions and disease states.

Advances in precision medicine are creating new insights and enhancing our knowledge of cancer and other complex disease processes.

Therapies for disease have varied greatly in their success rate. In most cases, ODs and other healthcare providers follow the same treatment protocol for all patients.

Tailoring health care to patients
In 2015 during President Barack Obama’s State of the Union address, he announced the launch of the Precision Medicine Initiative: an innovative and novel research effort to reinvent how ODs improve health and treat disease. 

The White House, working with the Department of Health and Human Services, collaborated with patient groups, biotechnologists, privacy and civil liberties advocates, and bioethicists to identify and address privacy and data security, as well as legal and technical concerns related to precision medicine.

The White House initiative gave $130 million to the National Institutes of Health (NIH) for development of a voluntary national research cohort.

• $70 million to the National Cancer Institute (NCI) to scale up efforts to identify genomic drivers in cancer
• $10 million to the Food and Drug Administration (FDA) to develop high quality, curated databases advancing innovation in precision medicine
• $5 million to the Office of the National Coordinator for Health Information Technology (ONC) to support the development of interoperability standards addressing privacy concerns arising from patient data exchange.   

What is the future of precision medicine and patient health?

Is it time for precision optometry?
In 2016, Columbia University delivered its Inaugural Precision Ophthalmology Conference.2 With the incidence of preventable blindness due to an aging worldwide population predicted to double by the year 2020, it is important for optometrists to understand and apply clinical applications of precision medicine.

An understanding of the disease’s epidemiology and pathophysiology could influence the future of glaucoma treatment and management

Precision medicine and genomics
In eye care, precision medicine is already applied in age-related macular degeneration (AMD). Genetic screening kits are readily available to assess patients’ risk of developing AMD and what types of supplements may be beneficial at slowing progression.

Research is underway, however, to apply precision medicine to the management and treatment of glaucoma.

The National Eye Institute recently published research identifying 133 genetic variants that predict, with 75 percent accuracy, individuals’ risk for developing glaucoma relative to their intraocular pressures (IOP).3

IOP readings and genotype data from 139,555 subjects of European ancestry were analyzed for correlation. These loci were then further researched into their link to primary open-angle glaucoma (POAG); 62 of them were associated with glaucoma specifically-and not just elevated IOP.

While many of the genetic loci identified to have an association with elevated IOP were already known, 68 were novel.

Genomic studies help decipher the complex processes involved in elevated IOP at the cellular physiological level, allowing for the development of novel treatments.

For example, two genetic loci uncovered by this study were genes coding for proteins and enzymes associated with angiopoietin and tyrosine kinase, suggesting that biochemical pathways involving these proteins could be regulating IOP. This pathway could present a new therapeutic target for IOP regulation.

Such research also helps ODs tailor management strategies with existing therapies based on patients’ genetic profiles and susceptibility to increased IOP and glaucoma.

Much like the example of a buccal cheek swab sent to a lab that produces a printout on AMD risk, perhaps similar tests may be developed-using data from genomic studies-to show a patient’s risk for elevated IOP and/or glaucoma.

Gene editing today
Gene editing currently focuses on IOP lowering and neuroprotection. Gene delivery methods include viral and non-viral vectors and, most recently, CRISPR-Cas9.4,5

Gene editing allows ODs to target mutated genes and correct the mutations in vivo. Current animal studies focusing on the trabecular meshwork involve editing the mutant myocilin (MYOC) gene, which leads to endoplasmic reticulum (ER) stress within the trabecular meshwork. 

Gene sequencing is also used to understand the patient’s metabolism profile to know which medications would have a better response and longer half-life in the eye.3

Development of targeted approaches
In recent years, doctors have been gene sequencing tumor cells to determine what types of cancer therapy would be most effective.

An example of this is the Epidermal Growth Factor Receptor (EGFR) genes that show mutation in some forms of lung cancer. By sequencing the tumor’s DNA, physicians can see if there is an EGFR mutation present and recommend EGFR inhibitors like cetuximab or gefitinib.6

Animal studies are also being conducted on conjunctival tissue sequencing to determine wound healing characteristics and prevention of fibro proliferation in filtering procedures-increasing success in these surgeries.7

Knockout mice whose MYOC was downregulated showed reduced ER stress and lower IOP.4 The downregulation of metalloproteinase 1 (MMP1) expression in the trabecular meshwork and ciliary body is also being studied with stimulating results.7  

Another approach is neuroprotection. Injected intravitreal neurotrophins have reduced retinal ganglion cell (RGC) damage after axonal injury. By upregulating neurotrophins such as brain-derived neurotrophic factor (BDNF) and ciliary neurotrophic factor (CNTF), a reduction of apoptotic cell death in rat models was observed.5

Lastly, with the recent clinical trials of RPE65 gene replacement in Leber’s congenital amaurosis, regenerating RGCs might be a possibility soon.5

Future of glaucoma patient care
New technologies have altered the way glaucoma is monitored. Optical coherence tomography (OCT) has entirely changed the landscape of glaucoma management, often allowing for early detection of structural changes, before functional change occurs.8

Genomic advancements may promise similar changes in glaucoma management, as each patient’s genetic risk for glaucoma is unique, allowing for tailor-made treatment and management strategies. 

Companies offering genetic testing received approval from regulators in 2017 to sell genetic reports on an individual’s risk for 10 diseases, most prominently Alzheimer’s disease and Parkinson’s disease.

Will companies like 23andMe or Family Tree DNA become integral to the optometric care of patients??


1. White House. Fact Sheet: President Obama’s Precision Medicine Initiative. Available at: https://obamawhitehouse.archives.gov/the-press-office/2015/01/30/fact-sheet-president-obama-s-precision-medicine-initiative. Accessed 10/1/18.
2. Columbia University Department of Ophthalmology. Precision Ophthalmology. Available at: https://www.columbiaeye.org/about-us/precision-ophthalmology. Accessed 10/1/18.
3. Khawaja AP, Cooke Bailey JN, Wareham NJ, Scott RA, Simcoe M, Igo RP Jr., Song YE, Wojciechowski R, Cheng, CY, Khaw PT, Pasquale LR, Haines JL, Foster PJ, Wiggs JL, Hammond CJ, Hysi PG. UK Biobank Eye and Vision Consortium, NEIGHBORHOOD Consortium. Genome-wide analyses identify 68 new loci associated with intraocular pressure and improve risk prediction for primary open-angle glaucoma. Nat Genet 2018;50:778-82. Accessed 10/1/18.
4. Jain A, Zode G, Kasetti RB, Ran FA, Yan W, Sharma TP, Bugge K, Searby CC, Fingert JH, Zhang F, Clark AF, Sheffield VC. CRISPER-Ca9-based treatment of myocilin-associated glaucoma. Proc Natl Acad SciUSA. 2017 Oct 17;114(42):11199-11204.
5. Demetriades AM. Gene therapy for glaucoma. Cur Opinion Ophthal. 2011 Mar;(22):73-77. Accessed 10/1/18.
6. National Cancer Institute. Tumor DNA Sequencing in Cancer Treatment. Available at: https://www.cancer.gov/about-cancer/treatment/types/precision-medicine/tumor-dna-sequencing. Accessed 10/15/18.
7. Lui, X, Rasmussen CA, Gabelt BA, Brandt CR, Kaufman PL. Gene Therapy Targeting Glaucoma: Where Are We? Surv Ophth. 2009 Jul-Aug 54(4):472-486.
8. Medeiros FA, Zangwill LM, Bowd C, Mansouri K, Weinreb RN. The structure and function relationship in glaucoma: implications for detection of progression and measurement of rates of change. InvestOphthalmol Vis Sci. 2012 Oct 5;53(11):6939-46. 
9. Seife, Charles. 23andMe Is Terrifying; but Not for the Reasons the FDA Thinks. Available at: https://www.scientificamerican.com/article/23andme-is-terrifying-but-not-for-the-reasons-the-fda-thinks/. Accessed 10/9/18.

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