Week in Review: Number 7

International Team Identifies 127 Glaucoma Genes in Large Genome-Wide Association Study
An international team of researchers recently identified 44 new gene loci and confirmed 83 previously known gene loci reported to be linked with glaucoma in a large genome-wide association study comparing the genes of 34,179 people with the disease to 349,321 control subjects. It is the largest study of its kind to date and the first cross-ancestry glaucoma genome-wide association study to include data of people from Europe, Africa, and Asia (in addition to data from people of European, African, and Asian ancestry). While glaucoma is an eye disease that predominantly affects people with African and Asian ancestry, previous studies have looked mostly at the genes of people of European ancestry. By gathering data from such a large and diverse pool of subjects, this cross-ancestry study improves upon the fine-mapping of causal variants linked with glaucoma as well as provides new avenues of research, via the newly identified genes, that could implicate previously unknown biological processes leading to the disease. In other words, the exceptionally large size and diversity provided by this study improves the precision of genetic associations of the disease.

RUNX1 Inhibition as Treatment for CNV
In this study, researchers affiliated with Harvard Medical School explored the use of a Runt-related transcription factor 1 (RUNX1) inhibitor, with and without the anti–vascular endothelial growth factor (VEGF) aflibercept (Eylea), for the treatment of choroidal neovascularization (CNV) in exudative age-related macular degeneration (wet AMD). RUNX1 has previously been linked with CNV pathogenesis, that is, it seems to be involved in not only angiogenesis but also in the inflammation and fibrosis leading to CNV. Inhibition of RUNX1 thus provides a novel and intriguing approach to address the problem of incomplete response in anti-VEGF therapy. The researchers used a mouse model of CNV to test intravitreal injection of saline, aflibercept, the RUNX1 inhibitor Ro5-3335, and a combination of Ro5-3335 and aflibercept. They found that a single intravitreal injection of Ro5-3335 alone significantly decreased the CNV lesion size seven days after induction of the CNV lesions, and that the combination of Ro5-3335 and aflibercept was more effective at reducing vascular leakage than aflibercept alone. One of the researchers states, “RUNX1 inhibitors hold significant promise to complement or replace anti-VEGF therapies for patients in which anti-VEGF therapy is no longer effective, and with the potential to be administered topically it could be transformative in the field.” Because many eye diseases involve neovascularization, RUNX1 inhibition has great potential to be applicable to diseases ranging from wet AMD and diabetic retinopathy to retinopathy of prematurity and retinal vein occlusion.

An Oxidized Ketocholesterol and Wet AMD
Researchers at the Moran Eye Center at the University of Utah Health are using a mouse model to investigate how an oxidized form of cholesterol, called oxysterol 7-ketocholesterol (7KC), contributes to the fibrosis of choroidal endothelial cells (CECs) that eventually lead to a neovascular age-related macular degeneration (wet AMD) that is poorly responsive to anti-VEGF therapy. The ketocholesterol accumulates in Bruch's membrane, cause changes in the CECs, which then invade the neural retina and lead to enlarged lesions and fibrosis. These lesions and fibrosis account for 40% of poor vision in neovascular AMD. What is particularly interesting about this study is that it suggests a link between 7KC, choroidal fibrosis in neovascular AMD, and poor response to anti-VEGF treatment. Up to 50% of patients who undergo anti-VEGF therapy stop responding to the therapy long-term. In addition to research into novel therapeutics, studies such as this point to a potential explanation for the failure of therapy and provide an avenue of research to interfere with the process and potentially improve treatment outcomes.

Investigations in Intravitreal AAV Gene Therapies
This is an interesting study as a follow up to the article about AAV gene therapies by researchers at the Wyss Institute at Harvard University, as this study also addresses the topic of AAV gene therapy, in this case with a focus on intravitreal injection. As with the Wyss Institute study, the researchers note the limitations of subretinal injection, which prompted further investigation of vector delivery intravitreally. The news article itself is short, and the only section that discusses methods states, "Further studies on three animal models [mice, dogs and non‐human primates] confirmed the efficacy of the procedure, and experiments on human retinal tissue grown in culture confirmed that the vectors can infect photoreceptors and other retinal cells. Finally, initial results of experiments on a mouse model of achromatopsia (complete lack of color vision) suggested that the procedure is capable of restoring some degree of daylight vision." With regard to intraocular inflammation, two of the five dogs used in the study developed inflammation events, which the researchers hypothesized was in response to the enhanced green fluorescent protein (eGFP) rather than the vector capsid, without detailed explanation. In either case, though a good addition to the archive of knowledge about intravitreal gene therapies, the study still shows that this method has not surmounted the obstacle of inflammation if vectors are delivered intravitreally. The approach would probably have been more novel had it been published prior to the study by the Wyss Institute.

Eye Care Beyond Blindness
This study brings up a valid point for consideration. Because sight is such a valued sense modality, its absolute loss is an understandable emphasis and justification for advancing research and treatments for eye diseases. Both news articles and journal articles focus on keywords associated with blindness. A research group in the U.K. wants to call attention to the much greater proportion of people who are afflicted by eye disease that comes short of robbing them of vision, but nonetheless presents difficulties both for the individual and for the health care system overall. For example, the paper notes that while 8 million people around the world have moderate to severe visual impairment or blindness from glaucoma, around 76 million people around the world have the condition. Similarly, diabetic retinopathy has caused 4.4 million to be blind or have moderate to severe vision impairment, but around 160 million people have the condition. In short, stages of eye disease that involve moderate or severe visual impairment and blindness represent merely the tip of the iceberg of the plethora of eye conditions that need attention. Said researcher is leading a call for a UK-wide sensory health survey to provide robust data to inform health services. Reports like these provide a glimpse into differences in health care systems in different countries and the mentalities and emphases resulting from those different systems. On the one hand, one might ask, "Are not conjunctivitis, sore eyes or dry eyes the topics of ubiquitous discussions already?" On the other hand, to see a call for a survey to inform health services is an interesting public health perspective.

Investigating Sound Waves for IOP Measurement
Glaucoma is indeed a very complex constellation of disease states, and accurate measurement of intraocular pressure (IOP) is equally complex. Many would argue that even methods of IOP measurement in clinical settings, including the gold standard of Goldmann applanation tonometry, have limitations. Alternatives to provide around-the-clock IOP monitoring, such as through contact lenses, have been proposed but so far lack translatability to patient care. The present study is another such project, in a very early stage of engineering, that seeks to approach the problem from the perspective of soundwaves. One of the researchers states, “We discovered a relationship between the internal pressure of an object and its acoustic reflection coefficient. With further investigation into eye geometry and how this affects the interaction with soundwaves, it is possible to use a smartphone to accurately measure IOP from the comfort of the user’s home.” IOP measurement is one of those problems that is easier to talk about than it is to solve, but projects like these, with further development, could contribute to methods to monitor eye pressures around the clock.

In Other News
(1) Attention modulated by projections between frontal and visual cortices
(2) Heterochromia and iris color changes (Related)
(3) Eye drops to correct presbyopia