CMRI Awarded Multiple Medical Research Future Fund Grants

Children’s Medical Research Institute (CMRI) was awarded multiple Medical Research Future Fund (MRFF) grants to help improve the lives of children living with genetic diseases. The MRFF, which is an initiative of the Australian Government, has funded research projects in cancer, gene therapy, and stem cell medicine at CMRI.

Dr Anai Gonzalez-Cordero, head of the Stem Cell and Organoid Facility and Stem Cell Medicine Group at CMRI, has been awarded the MRFF Stem Cell Therapies Grant to investigate new gene therapies for inherited eye disease.

Dr Gonzalez-Cordero and her team, in collaboration with A/Prof Leszek Lisowski and Prof Robyn Jamieson, Prof Ian Alexander, and Prof John Grigg (of SCHN and CMRI), as well as Dr Carvalho at the Lei Institute in WA, will collect induced pluripotent stem cells (iPSC) from patients’ own cells to generate mini-organs (3-dimensional organoids), specifically of the retina. Thanks to the $498,000 award from the MRFF, Dr Gonzalez-Cordero will be able to test new gene therapies on these retinal organoids and try to reverse the blinding effects of inherited eye disease.

A key tool in gene therapies is the use of adeno-associated virus (AAV) vectors. Where Dr Gonzalez-Cordero will use an AAV vector to treat blindness, Associate Professor Leszek Lisowski, head of the Vector and Genome Engineering Facility and Translational Vectorology Unit at CMRI, will attempt to treat Friedreich’s Ataxia, a genetic disease that causes progressive nervous system damage and movement problems.

A problem with the AAV vector is its difficulty in targeting neuronal and cardiac cells, making them ineffective in the treatment of neurological diseases like Friedreich’s Ataxia. A/Prof Lisowski, in collaboration with Associate Professor Mirella Dottori from the University of Wollongong, was awarded $983,000 to address this major roadblock and develop superior AAV vectors (called ‘SMART AAVs’) that specifically target human cardiac cells, sensory neurons and cerebellar neurons.

Professor Hilda Pickett and her team have long investigated telomeres, the short DNA stretches located at the ends of chromosomes that are important to cancer and aging. Unlike normal cells, where telomeres shorten every time a cell divides, the telomeres in cancer cells maintain their lengths, enabling them to keep growing. There are two methods cancer cells use to achieve this: telomerase and the Alternative Lengthening of Telomeres (ALT) mechanism.

Osteosarcoma is the most common type of primary bone malignancy, with the highest incidence in adolescence. The ALT mechanism is used by nearly 60% of osteosarcomas, yet no ALT-specific treatment strategies currently exist. Courtesy of a $1.48 million grant, Prof Pickett and her collaborators on this project (Prof Roger Reddel and A/Prof Tony Cesare of CMRI) can exploit a newly found Achilles’ heel of ALT cells to create chemical inhibitors toxic to ALT cells, improving treatments for adolescent osteosarcomas.

The Australian Government has contributed $2,961,000 in total to research at CMRI through these MRFF grants, and their support is a huge step towards beating children’s genetic diseases.

Learn more about the MRFF at

Dr Anai Gonzalez-Cordero, A/Prof Leszek Lisowski, Prof Hilda Pickett, Prof Robyn Jamieson, Prof Ian Alexander, Prof Roger Reddel, A/Prof Tony Cesare

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Gene therapy trial success: game changer for children with SMA

New research has shown that gene therapy may provide an effective treatment for Spinal Muscular Atrophy (SMA), a devastating and fatal genetic condition. The first part of the results from the SPR1NT trial were presented at the European Academy of Neurology (EAN) Conference recently. 

What is SMA?

SMA affects the motor nerve cells in the spinal cord, causing progressive muscle weakness and preventing babies from being able to roll, sit up, crawl, walk and eventually breathe. Until recently, it was the leading genetic cause of infant death in Australia, occurring in 1 in every 10,000 births.

Global recruitment site for trial

Sydney Children’s Hospitals Network (SCHN) was the only Australian site selected to participate in the trial and was one of the largest global recruitment sites, with four patients enrolled from SCHN. The trial investigated the use of Zolgensma, a novel viral vector-based gene replacement therapy. Fourteen infants, under six weeks of age and at risk of developing the most common and severe form of SMA, were treated before their symptoms started. 

Successful results

The study, which followed each participant until aged 18 months, found that all children achieved the ability to sit independently (with 78 per cent achieving this milestone within the normal developmental window), 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. The trial also showed that following treatment nine children were able to walk independently and all showed fine motor performance similar to babies without SMA by the completion of the study. 

Site-based lead for the study and Paediatric Neurologist at Sydney Children’s Hospital, Randwick, A/Prof Michelle Farrar said the results of the trial was a potential game-changer for both clinicians and families affected by SMA. “These results are extremely exciting and encouraging, not only are these children surviving but with this therapy, most are meeting the developmental milestones of any normal baby, which is unheard of.”

Zolgensma works by treating SMA at its root cause, inserting a functioning copy of the defective gene into the cells.

“By identifying these infants with SMA before the onset of symptoms, early results suggest we may have been able to take what was considered a lethal disease, and turn that around with a one-time, single dose infusion.

“It is giving life back to these babies and hope back to their families.”

Since the introduction of SMA into the newborn screening program in 2018, more than 200,000 babies have been screened, which has helped significantly with early identification of the condition.

In addition to the newborn screening program, the NSW Government has invested $25 million to boost the state’s capability to manufacture viral vectors – the key components of this type of therapy which holds great promise for novel treatments for other genetic diseases.

The second part of the SPR1NT trial, which explored the effect of Zolgensma® in babies with milder SMA, is due to be presented later this year.

Click here for the full media release.

The SPR1NT trial was also supported by Luminesce Alliance and partners including UNSW Sydney.

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CMRI announces new collaboration with Gyroscope Therapeutics

Children’s Medical Research Institute and Gyroscope Therapeutics Holdings, a clinical-stage gene therapy company focused on treating diseases of the eye, today announced they have entered a research collaboration to develop next-generation clinical capsids, the protein shells of viral vectors used to deliver gene therapies.

A team of researchers from CMRI and Gyroscope will work together in the design and screening of capsid libraries to identify novel capsids for enhanced delivery of ocular gene therapies. Under the agreement, Gyroscope has an option to obtain an exclusive licence for ocular uses of capsids developed through the partnership. The CMRI team is led by Associate Professor Leszek Lisowski, Ph.D., MBA, a recognised expert in viral vector-based gene therapy, vectorology and genotoxicity, with more than 15 years of experience in capsid generation and discovery.

“Capsids are one of the most critical components of a gene therapy, however, there are some limitations with the capsids available today,” said Jane Hughes, Ph.D., Chief Scientific Officer, Gyroscope. “We are excited to collaborate with Associate Professor Lisowksi and the team at CMRI to engineer next- generation capsids supporting our goal of developing a pipeline of differentiated ocular gene therapies that have the potential to be administered in the convenience of a doctor’s office.”

“Gene therapies are being studied in many diseases of the eye and capsids play an important role in maximising the potential benefit of these therapies for patients,” said Associate Professor Lisowski. “We look forward to working with the team at Gyroscope to identify novel capsids that may improve upon the current standard for gene therapies for treatment of diseases of the eye.”

Associate Professor Leszek Lisowski will lead Dr Marti Cabanes Creus and Dr Carolin Von Lupin from CMRI’s Translational Vectorology Unit on this project and will also work closely with the Head of CMRI’s Stem Cell Medicine Group Leader Dr Anai Gonzalez Cordero.

Gene therapy project ranked top idea in Australia

A gene therapy project to save infants’ lives has been named the top ranked National Health and Medical Research Council (NHMRC) Ideas Grant for 2020, in what the lead researcher describes as ‘proof that we weren’t just dreamers and symbolic of the power of the genomic revolution’.

Professor Ian Alexander and his team were awarded the 2020 NHMRC Marshall and Warren Ideas Grant Award at the NHMRC Research Excellence Awards Dinner on 16 June.

Professor Alexander is Head of the Gene Therapy Research Unit, a joint initiative of Children’s Medical Research Institute (CMRI) and The Sydney Children’s Hospitals Network (SCHN), and Professor in Paediatrics and Molecular Medicine at the University of Sydney.

His team’s work, over more than 25 years, has made significant contributions to the field of gene therapy and is now leading major advances in treatments for life-threatening genetic diseases.

“The gene therapy field is coming of age and earning the scientific respect that it has increasingly deserved. I thank the NHMRC for this award, which is emblematic of the explosion of therapeutic possibilities – which are unlimited,” Professor Alexander said.

Gene therapies are ‘genetic medicines’ where healthy copies of genes are delivered into diseased cells to replace or repair faulty genes and therefore treat (or potentially cure) disease. The delivery vehicle for the healthy gene is called a vector (typically modified viruses such as adeno-associated virus (AAV)).

This three-year NHMRC-awarded project aims to exploit immunity to the AAV vector that is stimulated in infants receiving gene therapy for Spinal Muscular Atrophy (SMA), and to use this to engineer the next generation of vectors.

SMA is an inherited neuromuscular disorder, which can be fatal. Babies often die within the first 2 years of life. NSW/ACT are among a few places in the world where there is now pilot newborn screening for SMA, supported by the NSW Government.

The clinical team at SCHN (incorporating experts from The Children’s Hospital at Westmead and Sydney Children’s Hospital, Randwick) has become a leading global centre in using AAV-based viral vectors in gene therapy for infants with SMA, with unprecedented success.

“This award is linked to the fact that we are at the front end of seeing the impact of the genomic revolution,’’ Professor Alexander said.

“It heralds our ability to treat disease by gene transfer. The most stunning example being the treatment of SMA in infants.

“We are now trying to go beyond that. This takes it a step further to improve the technology available to patients – to be able to treat more children, and not just children with SMA. The success of the SMA trials is not the end, it’s just the beginning. There is so much powerful science that can be leveraged by this progress.”

The team is now looking at ways to identify what antibodies the children are producing against the SMA gene therapy vector, recover these antibodies by reverse engineering, and to use these antibodies to guide re-engineering of efficient AAV vectors that can evade immunity. This would help the proportion of children who develop natural immunity to AAV and for whom the original SMA gene therapy is therefore ineffective.

“In this way we can use a child’s immune response to both improve the technology and enhance the treatment opportunities,’’ Professor Alexander said.

“This is a very powerful approach that has many implications, for neurological conditions and beyond.’

“Success breeds success. There is a very fertile interface between clinical medicine and discovery science, and this shows that deep science can emerge from privileged access to clinical material.’’

The project’s other lead investigator is Dr Grant Logan from Children’s Medical Research Institute. Associate investigators are Associate Professor Leszek Lisowski (CMRI), Associate Professor Michelle Farrar (SCHN and the University of NSW), Professor Daniel Christ and Dr Joanne Reed (Garvan Institute for Medical Research), and Dr Denis Bauer (CSIRO).

Listen to ABC Interview

2020 NHMRC Research Excellence Award Winners

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Announcing the establishment of the Australian Genome Therapeutics Centre

Children’s Medical Research Institute (CMRI) and The Sydney Children’s Hospitals Network (SCHN) are announcing the establishment of the Australian Genome Therapeutics Centre (AGTC), a collaborative effort which will transform the treatment of children with serious inherited diseases and contribute to the development of exciting new treatment options for a wide range of other diseases, including cancer, across all age groups.

Genome therapeutics, often referred to as gene therapies, encompass a number of new types of treatment that use genes as medicines, correcting diseases at their source.

Establishment of this Centre represents a major step forward in a journey that began 26 years ago with a small number of clinicians and scientists in the joint gene therapy research program of SCHN and CMRI.

At the start of this journey, many scientists regarded the idea of gene therapy as science fiction. Now, several highly successful gene therapy trials have demonstrated the immense potential of this approach, and SCHN and CMRI have more than 150 researchers working in this revolutionary new area of medicine.

The researchers have made major contributions to the international effort to develop gene delivery systems that are essential for successful gene therapy. These include viral vectors (viruses that have their genetic material replaced by a genetic medicine) and lipid nanoparticles similar to those used to deliver mRNA in the Pfizer and Moderna COVID-19 vaccines.

Chief Executive of SCHN, Ms Cathryn Cox, said that “This unique partnership between clinicians and researchers gives us the ability to make a life-changing difference to the children and families who currently don’t have answers. It gives us the opportunity to offer world-leading clinical trials to paediatric patients across NSW as soon as possible and the potential to develop new treatments, and even cures, that can help children both now and in the future. It is truly a transformational approach to healthcare.”

Professor Ian Alexander is one of the leaders of the AGTC. He is Head of the Gene Therapy Research Unit, working across both CMRI and SCHN, and is considered a world-leader in this field. “Excellent genomic diagnostic work is being done all around Australia, and we’ve always punched above our weight internationally in this, but the main challenge has been translating that research into the clinic,’’ Professor Alexander said. “Now, finally, we will be able to go beyond offering a diagnosis. It’s very exciting because now we’re working with an increasing number of diseases that are within reach of a treatment or cure.’’

The researchers in AGTC are developing and delivering treatments for conditions including inherited metabolic liver disease, inherited causes of blindness, lung diseases, brain diseases and serious neuromuscular disorders. They and their colleagues also have expertise in development and delivery of CAR T treatments, another form of gene therapy, for cancer.

Future applications of this technology will include treatment of many common conditions such as heart disease, and macular degeneration – a common cause of blindness in older people.

CMRI’s Director, Professor Roger Reddel, said, “this will be a collaborative effort with researchers elsewhere in NSW, other Australian States, and internationally. The researchers in AGTC are providing a complete ‘pipeline’ from design, construction, and testing of gene therapies, through to their production in a small-scale manufacturing facility, and on to treatment of patients with these new therapeutics within SCHN. This effort will be advanced even further by the Viral Vector Manufacturing Facility to which the NSW Government has committed major funding.”

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CMRI expands gene therapy research partnership with LogicBio Therapeutics

Children’s Medical Research Institute (CMRI) is pleased to announce that its partnership with LogicBio Therapeutics to develop the next generation of viral vectors for gene therapy applications has been extended for another two years and two new target tissues.

In 2018, LogicBio Therapeutics, Lexington MA, USA, a clinical stage genetic medicines company, entered into a collaboration with Associate Professor Leszek Lisowski, Ph.D., MBA (Head of the Translational Vectorology Research Unit at CMRI) and Professor Ian Alexander, MBBS, Ph.D. (Head of the Gene Therapy Research Unit at CMRI and Sydney Children’s Hospitals Network) to develop next-generation bioengineered liver-directed adeno-associated viral (AAV) vectors that overcome many of the functional limitations of the AAV vectors in clinical studies today.

The AAV Development Program at CMRI is led by Dr Marti Cabanes-Creus, a global expert in AAV vector biology and vector bioengineering. Dr Cabanes-Creus is originally from Barcelona, Spain, and received his PhD from University College London, UK.

As part of the efforts to develop new and improved vectors compatible with clinical applications, the CMRI team apply a range of advanced genetic and molecular biology techniques ranging from methods based on the 2018 Chemistry Nobel Prize-awarded concept of Directed Evolution to bioinformatics techniques utilizing advanced computational methods, such as machine learning.

Building on the critical insights gained into the mechanisms of AAV vector interaction with primary human cells, and access to proprietary novel highly functional AAV vectors developed during the initial two years of the partnership, the team is now combining advanced computational strategies with access to primary patient cells to develop the next generation of AAV vectors for clinical implementation. Importantly, the tools and strategies developed are not limited to human liver and can be used to develop improved AAV vectors for therapeutic delivery to other human tissues, which enables expansion of the AAV Development Program into other clinically important tissues.

“The outcomes of the project to date have been very exciting,’’ A/Prof. Lisowski said. “The work led to the development of a set of highly functional vectors which we are confident will revolutionize clinical gene therapy applications and will put many more challenging indications within the technological reach, bringing hope to patients and their families. In addition, the collaboration with LogicBio Therapeutics led to three patent applications and two publications in prestigious scientific journals.”

“Because of these promising results, while we extend and expand the AAV Development Program, we are also taking it to the next level. We have learned a lot about which elements of the vector capsid (the outer shell) are critical to its function and now we can take a more targeted approach to get the best results.” Dr Cabanes-Creus said. “We understand better how the viral vectors interact with human cells, what makes the interaction stronger and what weakens it. We are now applying machine learning and artificial intelligence approaches to the best vectors developed during the last two years to further improve their function and manufacturability, and to minimize reactivity with the human immune system.”

“This collaboration highlights how important it is for academic and commercial teams to interact and collaborate to achieve the greatest success” Prof. Alexander added. “We must not compete with each other but rather find a way to work together to increase the speed and efficiency with which new therapies are being developed and delivered to patients”.

Australia’s first gene therapy for genetic eye disease

Children’s Medical Research Institute and Sydney Children’s Hospital Network were pleased to hear the announcement that the Therapeutic Goods Administration (TGA) has registered a drug known as LUXTURNA® for the first gene therapy for inherited retinal diseases in Australia. One of their senior scientists, Professor Robyn Jamieson, has been involved in the process to get to this exciting stage.

It will be used for the treatment of patients with inherited retinal dystrophy caused by pathological biallelic RPE65 mutations and who have sufficient viable retinal cells as determined by the treating physician. LUXTURNA®, is injected under the retina and carries a functioning RPE65 gene to replace the faulty one.

“The availability of LUXTURNA® for the first time provides a treatment for people with inherited retinal diseases. LUXTURNA® is the first gene replacement therapy for blinding eye conditions and one of the first gene replacements for any human disease. This heralds a new era in transforming the lives of these people who otherwise have a life of blindness ahead of them. Although this treatment is for a rare genetic form of retinal dystrophy this therapy will be the first of many providing hope and treatment for many people,” said John Grigg, Professor and Head, Discipline of Ophthalmology, Save Sight Institute, The University of Sydney.

“This is ground-breaking news in Australia, the first eye gene therapy soon to be available for clinical use. This one is for RPE65-related retinal vision loss. It is a revolutionary change for people with genetic retinal disorders like retinitis pigmentosa, because it provides real hope for therapies for this whole group of conditions,” said Robyn Jamieson, Professor of Genomic Medicine, Head, Eye Genetics Research Unit, Children’s Medical Research Unit and Sydney Children’s Hospitals Network, and Head, Discipline of Genomic Medicine, University of Sydney.

Children and adults born with a mutation in both copies of the RPE65 gene can suffer from a range of symptoms, including night blindness (nyctalopia), loss of light sensitivity, loss of peripheral vision, and loss of sharpness or clarity of vision,6 potentially progressing to total blindness. Research shows that vision impairment and blindness in children frequently cause social isolation, emotional distress, loss of independence, or hazards such as falls and injuries.

“Inherited retinal diseases are a group of conditions that disproportionally affect children and young adults and lead to blindness. In Australia, one in every 1,500 children is born with an inherited retinal disease. The patient burden is extremely high and the impact on family and friends can also be devastating. Retina Australia welcomes the news of this new targeted gene therapy that has the potential to improve vision and prevent progression towards total blindness for people with mutations in the RPE65 gene. This life-changing therapy brings hope to more than 15,000 affected Australians that treatment for all forms of inherited retinal disease may be possible. Retina Australia looks forward to learning how patients respond to LUXTURNA®,” said Leighton Boyd, Chairman, Retina Australia.

“Leber’s amaurosis is a devastating diagnosis for a child and their family. Gene therapy using LUXTURNA® now offers some children with Leber’s amaurosis associated with the RPE65 gene, the opportunity to improve and retain their functional vision. This will allow the child to lead an independent life,” said Frank Martin, Clinical Professor in the Department of Paediatrics and Child Health and Ophthalmology at the University of Sydney.

“The TGA registration of the first gene therapy in Australia, LUXTURNA®, marks a milestone in reimagining medicine and has the potential to bring real value to patients in Australia living with inherited retinal dystrophy, their families and society as a whole,” said Richard Tew, Country President, Novartis Australia and New Zealand. “At Novartis, we bring together our heritage in ophthalmology and our investment in accelerating gene therapy to deliver on our commitment to help transform eye care for patients suffering from a variety of rare ophthalmic diseases including inherited retinal dystrophy.”

CMRI – SCHN Formalise Agreement

July 2020

Children’s Medical Research Institute (CMRI) is Australia’s oldest paediatric research organisation and Sydney Children’s Hospitals Network (SCHN) is the largest paediatric healthcare entity in Australia: it incorporates The Children’s Hospital at Westmead, Sydney Children’s Hospital, Randwick, Bear Cottage, the Newborn and paediatric Emergency Transport Service (NETS), the Pregnancy and newborn Services Network (PSN) and the Children’s Court Clinic. Decades of past collaborations between CMRI and the SCHN have helped to bridge the gap between biomedical research and clinical application, and our organisations continue to work closely across a number of research areas.

Last month CMRI and SCHN finalised an overarching ‘Umbrella Agreement’ to facilitate the anticipated increase in combined research activities in the next few years and to simplify the documentation requirements for all new projects. This agreement marks an important milestone towards even greater collaboration.