Understanding the biological causes and cell types that lead to one of the leading causes of irreversible blindness worldwide could benefit treatment in patients

Ayellet Segrè, PhD, presented her work on trying to understand the biological causes and cell types that lead to one of the leading causes of irreversible blindness worldwide, which is primary open angle glaucoma during the 2022 ARVO annual meeting, held in Denver, Colorado.

This transcript has been lightly edited for clarity.

I presented work on trying to understand the biological causes and cell types that lead to one of the leading causes of irreversible blindness worldwide, which is primary open angle glaucoma.

It's characterized by gradual retinal ganglion cell death that leads eventually to the degeneration of the optic nerve head and visual field loss and can lead to blindness. And the underlying causes, the genes and processes that lead to the disease, are not very well understood.

So we use the approach that integrates both very large population-based genetic study that covered over 100 regions in the genome with common DNA changes associated with risk for developing primary open angle glaucoma and integrated that with additional functional genomic information that tells us about what the different DNA changes in the genome do to gene expression, and in which cell types in eye tissues both in the front and back of the eye in which cell types they're expressed.

By developing a method that integrates both genetic associations from these very large population-based studies, what we call genome wide association studies, together with gene expression in single cells both in tissues in the front of the eye, for example, the outflow pathway through which the aqueous humor flows and it's the blockage of its drainage has been thought to affect and lead to elevated intraocular pressure, which is one of the major risk factors of primary open angle glaucoma, as well as looking at expression in the back of the eye and in the optic nerve head and in the retina and the optic nerve head where the retinal ganglion cell death occurs, and by integrating both pieces of information we found we're able to uncover genes and biological processes we think may be affecting the risk for developing this form of glaucoma. And we found that a lot of the genes tend to be expressed both in the conventional and the unconventional outflow pathway, also genes associated with intraocular pressure, there's a major risk factor.

But also an interesting fact is that about 40% of patients with primary open angle glaucoma have an intraocular pressure in a normal range of pressure. And that suggests that there may also be intraocular pressure independent mechanisms that lead to the degeneration of the optic nerve. And we found that many of the genes that map to the genomic loci associated with risk for developing primary open angle glaucoma, enrich for expression in microglia cell types in the retina and around the optic nerve — so these are cell types that support the metabolic supply and structural support of the retinal ganglion cells that you know that may be affecting itself and ability to survive.

So it suggests that we did not see actually genes enriched for expression in the retinal ganglion cells themselves, suggesting that, you know, thinking about in the future different developing new therapies might be important to think about targeting the neuronal support cells in addition to maintaining the health of the retinal ganglion cells.

Next steps for the research

The next step we're planning on kind of following up on these results, seeing if they replicate, reproduce in an independent secondary study both of single nucleus RNA-sequencing of additional healthy eye tissues from from donors; as well as in an even larger population-based study looking for genetic risk factors associated with primary open angle glaucoma, that looked at maybe over 10,000 additional cases, and identify now over 300 genomic loci.

So we're planning on doing this analysis with an even larger set of risk factors for glaucoma together with the single cell data and see if the results stand. And we can learn more about the underlying genes and biological processes. And then down the line we're interested in, in collaborating with experimental biologists here at Mass Eye and Ear to test some of the hypotheses of what genes and pathways may be functioning in particular cell types.

What this can mean for patients

This work suggests that there may be both what is better understood, you know, pathophysiological path that's affecting a risk of POAG through regulation of intraocular pressure, and it's suggesting certain cell types in the front of the eye, some that have been more well established, and others were suggesting particular genes.

So the hope is, currently there are medications that reduce IOP but my understanding is that some patients they might not be as effective. So having maybe this knowledge of the particular genes that are perturbed and in the particular cell types might help design even better intraocular pressure reducing medications.

And the other thing is a kind of uncovering the potential role for particular cell types such as the neuronal support cells in the retina and the optic nerve head. This might open a new avenue for developing drugs that will will be helping the neuro protection of the retinal ganglion cells so could open a new avenue for therapies that are for helping treat patients that develop primary open angle glaucoma. And that is not dependent on the intraocular pressure being elevated, but maybe more has to do with the sensitivity of retinal ganglion cells. But that's that's uh, you know, there's work here at Mass Eye and Ear and trying to study the genetic predisposition to what we call normal tension glaucoma.