Bridging the gap between diagnosis and treatment of genetic conditions

The genomic revolution is changing the face of modern medicine. In this new era, Sydney Children’s Hospitals Network (SCHN) is focused on bridging the gap between the ability to diagnose and the ability to treat rare genetic conditions – and the results are life changing.

Rare genetic diseases, although individually uncommon, affect about five percent of the population and for the majority there is no cure. But breakthroughs in genomic research have proven to be effective for previously untreatable diseases, transforming the lives of children with rare genetic and acquired disorders.

Researchers at SCHN, with their partners, have already made major contributions to the international effort to drive genome therapeutics. Key achievements include the global SPR1NT trial, which investigated the use of Zolgensma® to treat Spinal Muscular Atrophy (SMA), as well as the Australian-first delivery of ocular gene replacement therapy.

The establishment of  the nation’s first viral vector manufacturing facility  at Westmead Precinct has also enabled the Network to drive advancements in gene transfer technology. The facility will manufacture GMP grade AAV and lentiviral vectors. This is a vital component for gene transfer (carrying the new genetic information into the cells to correct the functional defect at its source) and genome editing and a major piece of the puzzle in solving genetic diseases in the future. 

Professor Ian Alexander is Head of the Gene Therapy Research Unit, a joint venture between the Network and the Children’s Medical Research Institute (CMRI). He says the ability to use gene transfer technology will transform the landscape of healthcare.

“The technology is moving in the direction from gene addition to gene editing. Just like the way you’d edit a computer document, we can start doing that with the human genome,” Professor Alexander said.

“That’s the journey we’re on and we could only dream that was possible five years ago. The capacity to repair a faulty gene at that level is now with us.

“One of the difficult steps is going from the laboratory into the clinic, but this initiative with NSW Health [the viral vector lab] to manufacture those gene transfer formulations will help Australia take that step. It’s an area in which we’ve got significant traction.”

Professor Alexander’s main interest is in virus-mediated gene transfer, specifically focussing on metabolic liver disease and primary immunodeficiency.

The liver performs a large number of metabolic functions so it is common in metabolic disease for the liver to be the primary location of the problem, or to be the source of other issues throughout the body.

“If we can cure these diseases [through gene therapy], we’re going to have big benefits for the kids who’ve got them. These kids currently need liver transplants but instead of them having a new liver with all the surgical risks and life-long immunosuppression, the idea is we can go in and repair their own liver,” Professor Alexander said.

This starts with targeting challenging conditions like urea cycle defects, a group of conditions which affect how the body removes ammonia from the blood, the waste product from breaking down protein.

“Urea cycle defects are particularly challenging for the technology. If you think about all the diseases like fruit on a tree, they’re not the low hanging fruit. We’re reaching quite a way up the tree because we think we have the technology to do it,” Professor Alexander said.

“If we can pick some of the high hanging fruit, then not only is that good for the piece of fruit and those who have that disease, but it also implies the technology will be able to filter down to the rest of the fruit on the tree.”

Professor Alexander believes urea cycle diseases hold the key to unlocking a world of new treatment options and thinks results for this may be seen sooner than later.

“We’re on the cusp of robust therapeutic success in the treatment of metabolic liver disease. I believe if we succeed in urea cycle defects, which I don’t think is far off, then this is going to herald an explosion of possibilities for many other metabolic diseases.”

While gene therapy holds enormous potential for the future treatments of metabolic diseases, this is dependent on early intervention. This is where carrier and newborn screening comes in.

Both areas have a vital role in detecting many inborn errors of metabolism and other genetic conditions, helping families make informed choices for commencement of care and treatment as soon as possible.

Established in 1964, the NSW Newborn Screening Program is hosted at The Children’s Hospital at Westmead and is one of the most innovative laboratories of its kind in the world.

It was the first publicly funded laboratory globally to incorporate tandem mass spectrometry to analyse samples, which led to the detection of more than 40 inborn errors of metabolism, including urea cycle defects.

The introduction of SMA testing to the program in late 2018 helped drive the SPR1NT trial. Through this trial, it was found that gene therapy can provide an effective and life-changing treatment for children born with the previously fatal condition.

“The major aim for the pilot program was to position the Network in a place where it could aid with gene therapy and clinical trials,” Associate Professor Veronica Wiley, Director of the NSW Newborn Screening Program, said.

Each year the program screens more than 100,000 babies and detects about 150 who need urgent assessment and treatment. The next step for the program is investigating ways to minimise the number of false positives associated with the tests, like they’ve achieved with Cystic Fibrosis (CF).

“We’ve added additional markers to the variants we look for with CF. We used to only look for one and then we increased it to four, and then a couple of years ago to 139 variants. It helps us find the cases of CF and minimises the number of false positives associated with it,” A/Professor Wiley said.

“We need to make sure we’ve providing the best possible service we can for all babies with equity across the state, in the most reliable way we can. This means updating our tests with new markers as new research becomes available.

“By doing this, we can ensure we don’t have too many families worried but also that the babies who need treatment and intervention, get this as early as possible. An early diagnosis for some of these genetic conditions can be life-changing and more importantly, lifesaving.” 

Furthering the work of genetic screening is Professor Edwin Kirk, who is a Clinical Geneticist at the Sydney Children’s Hospital, Randwick. He is one of three leads of Mackenzie’s Mission, a three-year research study that is screening more than 8,000 couples across Australia for approximately 750 childhood-onset genetic conditions.

“The idea is that you can screen a couple before they have an affected child, then those who are found to be carriers have choices about what to do with that information, with the range of options depending on whether there is already a pregnancy,” Professor Kirk said.

“The reason this is possible at all relates to the new genetic technology, which is being used widely all over the world. It allows you to use one test to read the sequence of many different genes all at once, up to the level of a test that reads the sequence of all of the genes – this is called exome sequencing”.

The combination of genetic screening carrier screening and new genetic therapies could one day mean it is possible to identify a baby affected by a rare genetic condition before birth, and use a targeted treatment soon after the baby is born – or perhaps even before.

The start of this journey has already begun in Australia, with the Federal Government adding five new items of pre-implantation genetic testing (PGT) of embryos to the Medicare Benefits Schedule this year.

From November 1, Australians are able to claim a rebate within the existing IVF process for testing of conditions including CF, SMA, muscular dystrophy, fragile X syndrome, neurofibromatosis and Huntington's Disease.

Between the work of Ian, Veronica, Edwin and their teams, the future of genetics is filled with possibilities that will change the narrative for children and their families both in and beyond the Network.

“I think gene therapy is a big part of the future, it sits in a constellation of things that will be developed. There’s going to be a lot of clever developments coming out of different fields of medicine and gene therapy is very exciting,” Professor Alexander said.

Our research is supported by Luminesce Alliance, the Ministry of Health, OHMR and CRMI.

Professor Ian Alexander, Associate Professor Veronica Wiley and Professor Edwin Kirk will discuss their leading research this week at the prestigious International Congress of Inborn Errors of Metabolism. Find out more.