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Discovery & Development Drug Discovery, Formulation

IOP Control – with Gene Therapy

Glaucoma is a common eye condition, affecting approximately 80 million people globally. If left undiagnosed and untreated, the condition can result in permanent vision loss. A team at the Smurfit Institute of Genetics – in collaboration with the biotechnology company Exhaura – have stepped outside the traditional confines of intraocular pressure (IOP)-lowering eye drops and minimally invasive glaucoma surgery to explore the potential of a gene therapy-based approach. Using a single injection of a viral vector, the team were able to increase the flow of aqueous fluid from the front of the eye and lower pressure in pre-clinical models. Here, Matthew Campbell, Professor in Genetics and Head of Department at the Smurfit Institute of Genetics, Trinity College Dublin, Ireland, explains in more detail.

What was the starting point for this IOP-lowering gene therapy?

Our research began by exploring the role of matrix-metalloproteinases (MMP) in the aqueous of the eye and its relation to glaucoma. Glaucoma is caused by the build-up of unwanted proteins in drainage channels at the front of the eye. The resulting increased IOP can damage the optic nerve and lead to irreversible blindness. After many years of research, we were able to sequentially identify an MMP – namely, MMP-3 – that was able to digest away built-up proteins, increase the outflow of aqueous, and thereby decrease this IOP. In short, we package a gene that codes for the MMP3 enzyme into a viral vector.

For those less familiar with viral vectors, could you explain in a little more detail?

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

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

It’s a proven platform – but presumably not straightforward in application… 

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

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

Why is an industry collaborator, like Exhaura, so important in this kind of translational research?

Ultimately, the major thrust in academic research is the acquisition of new knowledge. However, when we identify a novel therapeutic target we need to move towards clinical deployment – and that’s where our collaborations with industry are critical. The skills required to operationalize gene therapy for use in humans are vastly different to those required to run a research lab. Not only are there complex manufacturing needs, but there are also regulatory and legal considerations required. For academic research, establishing close relations with industry is absolutely essential. 

What other areas of genetic research spark your interest?

Without a doubt, CRISPR-based gene editing approaches to treating disease will see a whole range of developments in the future. The concept of making permanent genetic changes to cells/tissues to prevent or treat disease is the focus of a number of start-ups – and there are already drugs in clinical trials. 

I also see mRNA-based approaches to treatment as major drugs of the future. The concept of introducing genetic materials into cells in the body to transiently make the drug themselves is incredibly exciting and something to watch out for in the future.

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