Using viruses to restore sight – 2017 CSL Florey Medal winner profile

CSL Florey Medal, Embargoed

Professor Elizabeth Rakoczy, the University of Western Australia

Molecular ophthalmologist developing new treatments for eye diseases wins $50,000 CSL Florey Medal for lifetime achievement

 

Professor Elizabeth Rakoczy is modifying viruses to use their powers for good. She’s created a new gene therapy for wet age-related macular degeneration (AMD) that is reversing vision loss in clinical trial patients. Her treatment means one injection instead of several per year.

Modified viruses are gene therapy’s delivery vehicles, taking genes directly into cells. Elizabeth first showed that they could carry a healthy replacement for a mutated gene that causes degeneration of the eye’s retina. She then showed they can deliver instructions for eye cells to form a bio-factory to produce their own treatment for wet AMD, a more complex eye disease.

More than 112,000 Australians have wet AMD—the most devastating form of AMD—and up to 8,000 more commence treatment for it each year. Each injection of the current treatment costs about $2,000, and patients have six to eight per year. Costs will rise with Australia’s ageing population. Gene therapy offers an alternative treatment.

Elizabeth hopes to adapt her bio-factory idea to other diseases to alleviate suffering.

Growing up, Elizabeth was an aspiring gymnast who was briefly paralysed by the polio virus. Viruses would go on to hold a life-long fascination for her.

Jonas Salk’s and Albert Sabin’s development of polio vaccines in the 1950s and the first human heart transplant, performed by surgeon Christiaan Barnard in 1967, captured her imagination. She decided on a career in life sciences instead of medicine, hoping to ultimately help millions of people, rather than thousands of patients, one at a time.

After completing a PhD in theoretical organic chemistry, Elizabeth landed her first job, at the Chemical Research Institute of the Hungarian Academy of Sciences. Her task was to improve the antiviral drug Acyclovir, which was then used to treat herpes, chickenpox and shingles viral infections.

“To learn more about the viruses, I started to study the herpes simplex virus. This was my gateway into the emerging field of molecular biology,” Elizabeth says.

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In the 1980s, Elizabeth moved to Perth, taking up a research role exploring papilloma viruses and their role in cervical cancer at the Microbiology Department of the University of Western Australia (UWA).

In 1989, when the Lions Eye Institute (LEI) was developing its new Centre for Ophthalmology and Visual Science, she convinced its founding director Professor Ian Constable AO that eye research would benefit from expertise in molecular biology. In response, she was tasked with establishing the Molecular Ophthalmology Department.

Elizabeth says the eye is a wonderful target for the development of new treatments: it’s a small, accessible organ; it has defined spaces to deliver medication to with injections; and it’s easy to monitor. The eye also provides a clear outcome: the patient’s vision either improves or it doesn’t.

“Suddenly I was working on inherited eye diseases like retinitis pigmentosa, or those with complex causes, like macular degeneration. There were no viruses to work on. But not for long.”

In the early 1990s, the world’s first gene therapy treatments were taking shape. Gene therapy involves inserting genetic material into cells to replace abnormal genes or to make a therapeutic protein. When Elizabeth heard that modified viruses could be used to deliver genes into cells, it naturally caught her attention.

It would take Elizabeth and her team more than 15 years of solid research—for example, basic research to gain a better understanding of different eye diseases at the molecular level, testing how different modified viruses are tolerated by the eye, and exploring the genetics of healthy and diseased eye cells—to develop what became the world’s first gene therapy treatment for a complex eye disease (wet AMD).

During this period, Elizabeth’s lab produced more than 160 scientific papers and 500 presentations, and had some major achievements.

She was the first in the world to show that stromal stem cells derived from bone marrow can be converted into photoreceptors that become connected and functioning in the eye, pioneering the potential for stem cell therapies to treat degenerative diseases of the eye’s retina.

She also led one of the world’s first large animal gene therapy trials, restoring sight to the eyes of dogs with Leber’s congenital amarousis (LCA), an inherited disease involving severe loss of vision at birth.

Along the way, Elizabeth developed ‘animal models’—test animals that have the condition of interest—that are now helping medical scientists around the world, from Harvard University to the pharmaceutical company Regeneron Pharmaceuticals in USA.

Pre-clinical trials using animal models are important for checking the safety of a new treatment before it progresses to clinical trials with human patients.

Elizabeth developed new mouse models for AMD and diabetic retinopathy, a type of blindness caused by diabetes. These are now the most widely used mouse models for testing drugs, gene therapy, stem cell therapies and other treatments for these diseases, and have been licensed to 11 universities and four pharmaceutical companies.

This is a major contribution to worldwide eye research. It also demonstrates Elizabeth’s nous for research collaboration and establishing strong commercial linkages.

“LCA is a rare and severe form of blindness, caused by a mutation in a particular gene. With the LCA trial, we showed that we can take the infectious power of viruses and engineer them to do something useful, delivering the missing gene into the eye and restoring sight.”

Wet AMD, however, is a complex disease, with causes not yet fully understood. It’s also more common, and a major cause of blindness among the elderly. It occurs when a tiny area at the back of the eye called the macula, which normally doesn’t have blood vessels, starts to develop them in response to an excess of the blood vessel forming protein VEGF in the eye.

If not treated urgently, these leaky blood vessels invade the macula and destroy sight. The current treatment regime involves monthly injections of VEGF inhibitors into the eye.

Elizabeth came up with a novel gene therapy approach to provide a more effective treatment. Instead of periodically injecting medication, why not modify viruses to deliver the code to cells so they become ‘bio-factories’, making their own natural medication on the spot?

Elizabeth’s gene therapy replaces the monthly injections with a single one. Once established within the eye cells, the bio-factories start producing the medication, a naturally occurring molecule that mops up the rogue VEGF. With VEGF removed, the blood vessels diminish and the macula recovers. And because the bio-factories remain operational, potentially for years, the patient’s eyesight is maintained.

This therapy has been licensed to US company Avalanche Biotechnologies Inc., which has raised over $400 million to progress the treatment through clinical trials and bring it to market. This makes Elizabeth one of the few Australians to successfully take a research idea from ‘bench to bed’ and commercialise it internationally.

Further reading

www.lei.org.au/about/our-people/staff/professor-elizabeth-rakoczy

www.aips.net.au/news-events/the-florey-medal

www.scienceinpublic.com.au/floreymedal

Professor Elizabeth Rakoczy

Qualifications

1979                        PhD, Budapest University of Technology, Department of Theoretical Organic Chemistry

1975                        BSc (Biochemistry and Microbiology), Budapest University of Technology

Appointments

2000 – ongoing       Professor of Molecular Ophthalmology

1999 – 2009            Research Director, Lions Eye Institute

1999 – 2009            Research Director, Centre for Ophthalmology and Visual Science

1999 – present       Centre for Ophthalmology and Visual Science, UWA/Lions Eye Institute, Molecular Ophthalmology; Department Director

1988 – 1990            Research Officer, NHMRC, University of Western Australia (UWA)

1982 – 1987            Team leader, Academy of Sciences, Hungary

Honours and awards

2006                        “10 of the Best” NHMRC Award.

1998                        Bede Morris Fellow, Australian Academy of Science

1993                        Lions Save Sight Foundation Service Award

1981                        Honour from the International Heterocyclic Chemistry Committee, Austria

1980                        Honour of the Junior Research Association of the Hungarian Chemical Society of Budapest