Fishing for biomarkers for Rett syndrome

Researchers around the world are desperately looking for a treatment for Rett syndrome, a severe genetic disease that causes babies to lose movement and communication. It affects one in 10,000 children, mainly girls, including 430 in Australia.

Rett syndrome is hard to diagnose and is often confused with autism or mitochondrial disease as girls with Rett syndrome have symptoms that overlap with characteristics of these disorders.

Our project is sifting through more than 700 chemicals found in the blood and urine of girls with Rett syndrome to see whether they are different from those in children without the disease.

These chemicals, called metabolites, could one day be measured in a simple test that would help doctors in their diagnosis, and test whether the disease is progressing, or treatment is working.

Our findings will be invaluable for scientists around the world who are looking for treatments for Rett syndrome, by providing a reliable measure of whether their therapy is working.

It often takes around four years for families to receive an accurate diagnosis of Rett Syndrome. There is no effective treatment for the condition, despite numerous national and international clinical trials.

One of the reasons clinical trials have failed is that no clinically useful biomarkers have been identified for Rett syndrome. 

Luminesce Alliance funding is being used to analyse blood and urine samples from girls with Rett syndrome to find biomarkers – molecular indicators of the disease’s severity and progression.  

The study is searching for biomarkers among more than 700 metabolites (chemicals) in the samples, using state-of-the-art technologies that can identify any disruptions in these chemicals in one test.  

Dr Wendy Gold, Head of the Molecular Neurobiology Research Laboratory at Kids Research, says the ultimate aim is for clinicians to be able to test for these biomarkers to aid in the diagnosis, and for scientists and pharmaceutical companies to have a reliable measure of disease improvement in clinical trials.  

“We would like to find a biomarker that is expressed at a different level between Rett patients and non-Rett patients. Then we can measure whether it changes with disease progression and treatment.”

As well as this ‘fishing expedition’ to look for biomarkers, Dr Gold and her team are studying two specific biomarkers known to indicate mitochondrial stress, which they believe from laboratory tests could also indicate disease progression in Rett syndrome.

The project will determine whether these biomarkers can help diagnose the stage and severity of Rett syndrome in girls and whether they can predict the course of the disease.

“Traditionally, research funders don’t like fishing expeditions – they want to see preliminary data first. Now we have shown there are fish out there, and hopefully, this funding will enable us to catch them.”



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Growth of ‘mini organs’ to aid study of neurological disease of the eye and brain

The growth of brain and retina organoids from stem cells in a laboratory dish could improve the study of neurological diseases of the eye and brain.

The “exciting” discovery was made by researchers at the Luminesce Alliance-funded Stem Cell Medicine Group, based at the Children’s Medical Research Institute, in Westmead.

Led by Dr Anai Gonzalez Cordero, the team has perfected the culturing of organoids from induced pluripotent stem cells, which are generated using a patient’s blood or skin. Often referred to as mini organs, organoids are morphologically similar to actual organs, providing opportunities to learn about how they behave in the lab.

Dr Gonzalez Cordero said that as her team were growing retinas in a dish, they noticed cells similar to those found in the brain were growing nearby.

The team were able to verify that they had produced brain organoids in the retinal cultures through collaborating with researchers at CMRI’s Synapse Proteomics Group and Computational Systems Biology Group.

“It is a great start,’’ Dr Gonzalez Cordero says. “This work is all about improving how we study some neurological diseases, so it’s very exciting. The next step is to optimise the process.

“It is also a great example of the collaborative approach to research that we have at CMRI.’’

The research is published here in Stem Cell Reports. Authors on this publication included Milan Fernando, Scott Lee, Jesse Wark, Di Xiao, Hani Kim, Grady Smith, Ted Wong, Erdahl Teber, Robin Ali, Pengyi Yang, Mark Graham, and Anai Gonzalez Cordero.

Read more here


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Are some children predisposed to cancer?

A Luminesce Alliance-funded trial looking at the genomic sequencing of patients diagnosed with childhood cancers is providing vital insights into whether some children are predisposed to develop the disease.

When children and adolescents present to hospitals with cancer, we often suspect it may be caused by changes in their DNA that damage the genes they were born with. But we do not know why some children get cancer, how many of them have an underlying genetic abnormality that predisposes them to cancer, or what this means for the future management of these children and their families.

Our pilot program allows all children diagnosed with cancer in New South Wales access to family-based DNA testing. The PREDICT study will help give the world a much clearer picture of how changes in genes we are born with contribute to the risk of developing childhood cancer and help us find ways of managing it.

We have already recruited more than 100 families to the study.

Our findings will show whether routine family-based germline testing of children with cancer is feasible and beneficial, what percentage of children with cancer have a genetic predisposition, and what the implications are for them and their families and how they are managed.

About 8 per cent of childhood cancers may have a genetic cause. But whole genome sequencing of children with high-risk, aggressive cancers who were enrolled in the Zero Childhood Cancer Program (ZERO) over the past five years, found that double that number as many as 16 per cent had reportable genetic variants thought to be responsible for their cancer.

To understand the full spectrum of these genes and variants and the contribution of heritable germline variants in the development of all paediatric cancer, it is necessary to broaden genomic germline sequencing to all children with cancer.

Luminesce Alliance funding has been used to develop and launch the PREDICT trial, which involves whole genome sequencing of the germline of every child diagnosed with cancer in NSW.

Understanding the genetic predisposition to cancer will have several benefits for the child and their extended family, says Dr Luciano Dalla- Pozza, Director of the Cancer Centre for Children at The Children’s Hospital at Westmead.

For example, it will influence treatment recommendations and play a role in determining outcomes, such as whether a child may respond well to radiotherapy or certain medications.

It provides the opportunity of personalising surveillance programs and implementing early intervention and lifestyle changes to prevent or treat cancer at an earlier stage.

“It also provides valuable information to patients and their families to help them make choices about future pregnancies, to understand how to minimise their own cancer risk and that of any future children they may have,” says Dr Dalla-Pozza.

Ultimately, if the PREDICT trial indicates that this work is feasible and useful, it will inform the roll-out of a national cancer predisposition pilot screening program through the Zero Childhood Cancer Program’s clinical network.

In the long term, that program will provide the opportunity to personalise surveillance and treatment plans for children and their families who are found to be at risk of cancer due to heritable germline variants.



Hope for children with Spinal Muscular Atrophy

Children newly diagnosed with the devastating genetic condition Spinal Muscular Atrophy (SMA) now have access to novel new gene therapy, Zolgensma®, free of charge, after it was listed on the Pharmaceutical Benefits Scheme.

Announced today by Federal Health Minister Greg Hunt, Zolgensma®, which normally costs $2.5 million per treatment, now joins two other publicly funded therapies on offer for SMA – Nusinersen and risdiplam.

The devastating genetic motor neurone disease, spinal muscular atrophy (SMA), quickly paralyses babies, who survive on average 9 to 10 months. While their brains remain unaffected, they lose the ability to move, feed and ultimately breathe. SMA affects one in 10,000 births and was once the leading genetic cause of infant death.

Patients at the Sydney Children’s Hospitals Network participated in the global SPR1NT trial, which investigated the use of Zolgensma®. The study, funded by Luminesce Alliance, followed each participant until aged 18 months, found that all children achieved the ability to sit independently, all were alive and free of permanent ventilation and all had normal swallow function and were fed exclusively by mouth by 18 months of age.

Since the addition of SMA to the NSW Health funded newborn screening program almost four years ago, more than 330,000 babies have been tested for the condition free of charge and given quick access to treatment and support.

Read more: A success story of translation: screening babies nationally for spinal muscular atrophy

“We know that early identification is vital in the treatment of SMA and that is what the newborn screening program has allowed us to do. It has radically shifted our model of care and we are now in a position where we can rewrite the history of SMA,” says Associate Professor Michelle Farrar, paediatric neurologist at Sydney Children’s Hospital and the University of New South Wales, Sydney.

Read more from Sydney Children’s Hospital Network


A success story of translation: screening babies nationally for spinal muscular atrophy

In a collaborative effort supported by Luminesce Alliance, clinicians and researchers have worked together to introduce a molecular test for a previously untreatable disease that paralyses babies.

The devastating genetic motor neurone disease, spinal muscular atrophy (SMA), quickly paralyses babies, who survive on average 9 to 10 months. While their brains remain unaffected, they lose the ability to move, feed and ultimately breathe. SMA affects one in 10,000 births and was once the leading genetic cause of infant death.

We supported a successful pilot that added the first genetic test to the Newborn Screening Program in NSW and the ACT. All babies are now screened for SMA and inherited immune disorders.

New treatments are also revolutionising the outlook for babies with SMA. However, the treatment is most effective when given before a baby develops symptoms – by this time they may have already lost 90 per cent of their nerves. The best way to identify babies who need the treatment is to screen at birth.

“Every day counts. Any delay could be the difference between a child living in a wheelchair or not,” says Associate Professor Michelle Farrar, paediatric neurologist at Sydney Children’s Hospital and the University of New South Wales, Sydney.

“Families now have two birthday parties – one to mark the day the child was born, and the other the day they got their treatment. Before it was uncommon to celebrate first birthdays.”

The power of working together

In a collaborative effort supported by Luminesce Alliance, specialists from Sydney Children’s Hospital Network and the University of  New South Wales universities have worked together to have a molecular test for SMA included in the newborn screening test offered to all 100,000 babies born in NSW and the ACT each year.

Newborn screening involves taking three drops of blood from a newborn baby’s heel. This is then analysed using biochemical tests for more than 25 medical conditions.

International gene therapy trial

The impetus to test newborns for SMA was boosted by an international gene therapy trial, including NSW children, which indicated a single dose of gene therapy could potentially reverse the disease.

With world-leading expertise in SMA, newborn screening and gene therapy, the members of Luminesce Alliance realised there was an opportunity to show international leadership in this space. They launched a pilot of the first genetic test to be included in the newborn screening program.

The new test involves extracting the baby’s DNA from the heel prick test and looking for genetic variants that indicate SMA as well as some primary immunodeficiencies. The test is highly specific and sensitive and can be conducted on-site at Westmead.

If a baby’s genes suggest they may have a form of SMA, further tests can be conducted to confirm the diagnosis and start life-saving treatment.

Making the test available to babies throughout Australia

The two-year pilot was completed in 2020 and was then continued with NSW Health funding. The data were analysed by the Federal Government, which recently recommended that newborn screening for SMA should be implemented nationally.

The pilot boosted the case with implementation and health economic data that showed newborn screening for SMA was value for money, led by Prof Georgina Chambers from the National Perinatology Epidemiology and Statistics Unit.

A/Prof Farrar says this work would not have been possible without the connections, reputation and organisational support offered by Luminesce Alliance.

Read more: Testing & treating newborns for spinal muscular atrophy: saving lives & healthcare costs


Illuminating paediatric outcomes … together

By Kathryn Greiner, Luminesce Alliance Chair

A few years ago, patients presenting every year to our children’s hospitals in Australia with serious inherited conditions often resulted in no diagnosis or cure.

The international explosion in genomic medicine has offered new hope of identifying the genetic cause of these diseases and finding targeted therapies to treat them – an advance called precision medicine. But there needs to be an organised, systematic way of introducing this model of care into the health system.

Luminesce Alliance was funded in 2018 by the NSW Government to create a paediatric translational research hub delivering twenty-first-century precision medicine for the families of NSW.

We brought together NSW’s leading paediatric medical research institutes with our children’s hospitals network and universities to combine strengths and capabilities, creating a competitive advantage in paediatric research that was previously lacking in NSW.

With a strong translational focus, we have been able to fast-track discoveries in the laboratory into treatments for patients with rare diseases and cancer, sometimes in a matter of months.

Medicine that uses the power of genomics can be astonishingly successful. Rather than the incremental benefits we would normally expect from medicine, these new therapies have the potential to completely cure children of their condition.

The strength of Luminesce Alliance is in the collaborations it nurtures – collaborations between fiercely competitive research institutes and clinical campuses, between different research teams, between clinicians and scientists, and between people from a wide range of disciplines. The way these teams are now working together is, perhaps, our greatest achievement.

NSW is now at the international vanguard of paediatric precision medicine – but there is still so much more we could do. We want to develop new treatments in NSW for our children and families, and export them to the world. Through nurturing paediatric research, our modelling shows we can attract even more investment to NSW, create jobs, and generate government cost-savings through the rapid diagnosis and treatment of childhood disease.

The discoveries being made will have impacts far beyond child health. Improving diagnosis and treatment of children will support families and communities, boost the economy through saving on health expenditure in later life, and lead to new understandings that will be applied to many common adult diseases in future.

Learn more about our research projects


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Breakthrough for genetic eye disease

New opportunities towards gene therapy and diagnosis for the blinding eye disease, retinal dystrophy, may now become available following work done by the Eye Genetics Research Unit at the Children’s Medical Research Institute.

The team looked at the RPGR gene which is involved in maintaining healthy photoreceptor cells. Variants in this gene are the main contributor to eye disease such as rod cone dystrophy and gene therapy for this condition is now in clinical trials.

The research, published in the Journal of Personalized Medicine, was partly supported by Luminesce Alliance funding.

The team worked closely with collaborators at the Department of Clinical Genetics and Sydney Genome Diagnostics, Western Sydney Genetics Program, Sydney Children’s Hospitals Network (SCHN), and the Rare Diseases Functional Genomics Laboratory, SCHN, and CMRI, and Save Sight Institute, Faculty of Medicine and Health, University of Sydney.


Find out more about this research