Glaucoma is a common eye condition, affecting an estimated 80 million people worldwide. If left undiagnosed and untreated, the condition can cause permanent vision loss. A team from the Smurfit Institute of Genetics, in collaboration with biotech company Exhaura, has moved beyond the traditional confines of intraocular pressure (IOP)-lowering eye drops and minimally invasive glaucoma surgery to explore the potential of a therapy-based approach gene. Using a single injection of a viral vector, the team was able to increase the flow of aqueous fluid from the front of the eye and lower the pressure in preclinical models. Here, Matthew Campbell, professor of genetics and head of department at the Smurfit Institute of Genetics, Trinity College Dublin, Ireland, explains in more detail.

Our research began by exploring the role of matrix metalloproteinases (MMPs) in ocular water and its relationship to glaucoma. Glaucoma is caused by the buildup of unwanted proteins in the drainage channels at the front of the eye. The resulting increase in IOP can damage the optic nerve and lead to irreversible blindness. After many years of research, we were able to sequentially identify one MMP, namely MMP-3, which was able to digest accumulated proteins, increase aqueous outflow and thereby decrease this IOP. Briefly, we package a gene encoding the MMP3 enzyme into a viral vector.

We use adeno-associated virus (AAV), a non-replicating virus that has been used extensively in clinical trials. There are already approved drugs based on this technology, such as Luxturna, which is used to treat a rare form of blindness called Leber’s congenital amaurosis. The AAV is basically a protein shell, in which we package our gene of interest.

Once injected into the anterior chamber of the eye, AAV will enter cells and begin producing MMP3, which can degrade the accumulated proteins causing blockage of drainage channels. In fact, it’s a one-time injection that could potentially negate the need for invasive surgery.

We performed countless experiments in cultured cells, redesigning the gene, and working with small and large animal models to develop an AAV that could produce sufficient amounts of the MMP3 enzyme to persist over time. So not simple.

And that’s why getting the first datasets from nonhuman primate models was an incredibly exciting moment in this research. The nonhuman primate eye is an ideal model for the human eye as it is nearly identical in an anatomical sense, but on a slightly smaller scale. These animals are also genetically much closer to humans than other smaller animals, so we have high levels of confidence that our technology will translate very effectively to humans.

Ultimately, the main thrust in academic research is the acquisition of new knowledge. However, when we identify a new therapeutic target, we need to move towards clinical implementation and this is where our collaborations with industry are key. The skills required to operationalize gene therapy for use in humans are very different from those needed to run a research laboratory. Not only are there complex manufacturing needs, but there are also regulatory and legal considerations required. For academic research, establishing close relationships with industry is absolutely essential.

No doubt, CRISPR-based gene editing approaches to treating disease will see a whole host of developments in the future. The concept of making permanent genetic modifications to cells/tissues to prevent or treat disease is the focus of many start-ups, and there are already drugs in clinical trials.

I also see mRNA-based approaches to treatment as the major drugs of the future. The concept of introducing genetic materials into the body’s cells to temporarily produce the drug itself is incredibly exciting and something to look out for in the future.

#IOP #control #gene #therapy

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