Glaucoma Gene Therapy: From Pipedream to Reality

The majority of glaucoma cases can be effectively managed, but what about those who don’t respond to treatment and are left facing the prospect of blindness? Gene therapy may be their best hope – and it might not be far away.

Despite its incurable status, glaucoma is no longer a disease that necessarily resigns patients to a lifetime of blindness or severe vision loss.

In fact, advances in glaucoma care, such as new classes of eyedrop, surgical techniques and laser approaches are helping to ensure a large majority of glaucoma patients avoid sight loss and maintain their quality of life.

While efforts continue to evolve and fine tune these management options, poor adherence, particularly with eye drops, often stands in the way of meaningful results. Today’s surgical options and implants can overcome this issue, but they may prove to be only a stepping-stone towards a truly revolutionary solution.

Centre for Eye Research Australia (CERA) managing director Professor Keith Martin is a researcher at the forefront of a movement focusing on how to stop glaucoma permanently – and even restore lost vision – through gene therapy.

At present, he believes there is no silver bullet that will solve all of glaucoma. Instead he says there are a range of strategies that are effective at different stages of the disease.

“There has been a lot of work developing technologies to lower the pressure inside the eye, but most of these technologies are not particularly revolutionary, they are more evolutionary,” Martin, who is also past president of the World Glaucoma Association, says. “Most of them are probably no more effective than the drugs and operations we already have but are potentially quicker or easier or with fewer side effects.

“I think there is still the need for these options, but most are aimed at people with relatively early glaucoma. At the other end of the spectrum, for people with very severe glaucoma, there is still a need for treatments that work over and above the effect on pressure and, ideally, restore vision once it’s been lost, rather than just slowing the decline.”

Part of the solution could be a gene therapy Martin is helping develop using a recombinant adeno-associated viral vector system. The virus works by introducing therapeutic genes to make retinal ganglion cells more resistant to damage. Initially, it is hoped the therapy would target the 10% to 15% of patients who don’t respond to regular treatment and are advancing towards blindness.

Martin began developing the therapy while at the University of Cambridge before co-founding Quethera in 2016, a Cambridge-based gene therapy company working to bring gene therapy to common eye diseases. That company is now a wholly-owned subsidiary of Japanese firm Astellas Pharma, which acquired the business for £85 million (AU$156 m). The therapy is making good progress towards investigational new drug status, a necessary step before human clinical trials. Martin is still involved in the program and will be continuing related work at CERA and the University of Melbourne.

“We hope to begin clinical trials in the next year or so and it will probably take two or three years for results to come through. We are also thinking hard about who are the most suitable patients,” he says.

“At the start it will be those with more severe and advanced disease where other treatments have failed, but it’s always difficult to give an absolute timescale because breakthroughs and progress don’t occur in a straight line in science.”

Due to the multiple gene defects affecting glaucoma, Martin’s work differs from gene editing techniques being trialled in inherited retinal diseases. However, he is buoyed by an appetite within ophthalmology to progress such therapies into real world care.

An example of this is Spark Therapeutics/Novartis’ Luxturna, which was the first gene therapy approved for an inherited retinal disease (Leber’s congenital amaurosis) by US regulators in 2017 and later in Europe in 2018.

Martin doesn’t need to look far to witness other important work occurring to tackle glaucoma at the genetic level. CERA is working with partners locally and nationally to establish Melbourne as Australia’s leading centre for ocular gene and cell therapy.

Australia, according to Martin, is also well placed to contribute towards personalised treatments that could one day consider the genetic make-up of any given patient. Underpinning this is the fact individual genomes can now be sequenced for a few hundred dollars.

“The likes of ophthalmologists Professor Jamie Craig in Adelaide, Professor David Mackey in Perth and Professor Alex Hewitt from CERA and the University of Tasmania have really made fundamental contributions to the world literature on the genetics of eye disease, including glaucoma,” he says.

“I think the next stage in that will be factoring genetic risk profiling into the way we manage glaucoma patients using the information of these studies to modify how we treat people and targeting more aggressive treatment to those of the highest genetic risk, and less to those that won’t.”

Martin says from a single cheek swab, health professionals can already determine the likelihood of someone getting glaucoma with 75% certainty.

“We are already starting to do that in the research setting, but what we don’t know is how to use that information in clinical practice. We are not at the stage where we recommend everyone does this, but we are starting to envisage this will be something that will be an important part of management – and not just for glaucoma.”

In the absence of a one-off treatment for glaucoma, ongoing treatment and management will continue to place a heavy burden on the health system.

Martin believes the problem could become more pronounced unless more thought is given to the current care model.

“As populations age, the number of people with glaucoma is increasing every year and yet the amount of resource that we have to treat all of these patients is not increasing at the same rate,” he says.

“So the question we are all asking is how do we shift resources away from people who don’t need them to those at the highest risk of life time blindness, and I think that’s a big question going forward.”

This article republished courtesy Insight News. More glaucoma stories here.