Murdoch Children's Research Institute - Mending Broken Hearts

Mending Broken Hearts: Bioengineered Heart Tissue

Mending Broken Hearts: Bioengineered Heart Tissue Patch

Mending Broken Hearts: Our vision is to lead the first in-human clinical trial of stemcell derived heart tissue in children.

A confluence of world leading talent and technology Recent advances in stem cell technologies have the potential to revolutionise clinical care for Congenital Heart Disease (CHD) patients via novel regenerative approaches to repair and replace damaged heart tissue, thus offering a curative approach to heart failure.

With a world class multi-disciplinary team established including expertise in Stem Cell Medicine, Bioengineering and Cardiac Surgery, MCRI are uniquely positioned to capitalise on these recent technological advances to deliver potentially game changing approaches to the clinical management of heart failure in children.

Mending Broken Hearts

Mending Broken Hearts: Bioengineered Heart Tissue Patch

Multi-disciplinary Leadership Stem Cell Medicine

Cardiac Surgery

Cardiology

Associate Professor Enzo Porrello

Professor Christian Brizard

Professor Michael Cheung

A/Prof Porrello is the Director of the Melbourne Centre for Cardiovascular Genomics and Regenerative Medicine (CardioRegen) and head of the Heart Regeneration Group at the Murdoch Children’s Research Institute. His research focuses on the development of regenerative therapies for children with heart failure. A/Prof Porrello has made important contributions to our understanding of mammalian heart regeneration and has pioneered the development of bioengineered heart tissues for drug discovery and regenerative medicine. He is a co-founder and scientific advisor of Dynomics Inc, a biotechnology company focused on the development of new heart failure treatments, which is based on IP developed by his team over the past 5 years.

Professor Christian Brizard is the Director of the Cardiac Surgery Unit at the Royal Children’s Hospital. Leading a dedicated and highly skilled group of medical professionals, Prof Brizard and his team perform 700 heart operations per year, with an emphasis on treatment of neonatal and complex congenital cardiac problems. Prof Brizard’s research interests focus on stem cell delivery to patients with hypoplastic left heart syndrome.

He has published >250 peerreviewed papers and book chapters.

Prof Michael Cheung is the Director of Cardiology at the Royal Children’s Hospital. He has practiced paediatric cardiology for more than 15 years and has trained at world-leading congenital cardiac centres including Great Ormond Street and Royal Brompton Hospital in London, Hospital for Sick Children in Toronto, and The Royal Children's Hospital in Melbourne.

He is the leader of the Heart Research Group at the Murdoch Children’s Research Institute and has published more than 180 peer-reviewed papers and book chapters.

Mending Broken Hearts

Mending Broken Hearts: Bioengineered Heart Tissue Patch

National Collaborators Our internationally leading team of stem cell scientists, tissue engineers, physiologists, cardiac surgeons and cardiologists are exceptionally capable of executing this project. Our team have been at the forefront of cardiac regeneration biology, congenital heart disease research, surgical innovations and development of pluripotent stem cell technologies for over a decade.

Collaborator

Position

Professor Richard Harvey

Co-Deputy Director and Head, Developmental and Stem Cell Biology Division, Victor Chang Cardiac Research Institute; Sir Peter Finley Professor of Heart Research, UNSW Sydney

Associate Professor James Chong

Consultant and Interventional Cardiologist Westmead Hospital, Head Cardiac Regeneration Laboratory, Sydney

Associate Professor James Hudson

Bioengineering Group Leader at QIMR Berghofer Medical Research Institute, Brisbane

Professor Igor Konstantinov

Cardiothoracic Surgeon at the Royal Children’s Hospital (RCH), Professor, University of Melbourne (UoM), and a Senior Research Fellow at MCRI

Associate Professor David Elliott

Heart Regeneration Group Team Leader at MCRI

Associate Professor Joseph Smolich

Principal Research Fellow, Heart Research Group, MCRI

Associate Professor Salvatore Pepe

Senior Research Fellow, Heart Research Group, MCRI

Mending Broken Hearts

Mending Broken Hearts: Bioengineered Heart Tissue Patch

The problem Heart disease is the leading cause of death and disability in children, affecting up to 1 in 100 live births. This equates to approximately 65,000 children and young adults living with a form of childhood heart disease (CHD), such as congenital heart disease, cardiomyopathy, or acquired heart disease. Surgical advances over the past 20 years have dramatically increased survival rates in these patients, with more than 85% of children with CHD now living into adulthood. As a result, CHD is now considered a life-long disease.

An emerging and alarming trend is the sharp rise in the number of children with CHD hospitalised due to heart failure, a condition whereby the heart is unable to pump enough blood to meet the needs of the body.

Currently, heart failure can only be resolved by heart transplantation, but the gap between the number of donors and the number of children with heart failure requiring transplantation is growing. As a result, there are increasing numbers of children on mechanical assist support at RCH requiring heart transplantation.

The cost of treating childhood heart failure is growing, with the annual total inpatient cost for heart failure in Australian paediatric hospitals estimated to be $118,796,830 in 2016, representing 2% of overall paediatric hospital costs in Australia. Current treatment options are clearly inadequate and new approaches to radically change patient trajectories are imperative.

Current treatment options are clearly inadequate and new approaches to radically change patient trajectories are imperative.

Whilst mainstream cardiology and cardiac surgery focus their efforts on disease management, there is little emphasis placed on underlying causes and novel treatments.

There are no clinically approved therapies that can restore function to the failing heart in patients with CHD. Frontline pharmacological therapies for heart failure provide symptomatic relief and slow down disease progression but are not curative. Heart transplantation is a last resort for many patients, and even today only offers medium-term palliation with a high mortality rate. Furthermore, CHD patients have a worse long-term survival post-transplant than other recipients.

Compounding the problem is the low donor rate in Australia (21.6 donors per million), which means that many children are forced to wait long periods on mechanical support as a bridge to transplantation, thereby increasing the risk of thrombosis and stroke. In addition to improving clinical outcomes for patients, a therapy that reduces the need for mechanical circulatory support and transplantation would ease the economic burden of childhood heart failure on the healthcare system.

The bioengineered heart tissue patch proposed here has the potential to prevent, delay or even reverse heart failure in CHD survivors and thus has the potential to completely transform the lifelong trajectory of children with heart disease and associated burden on the healthcare system.

Mending Broken Hearts

Mending Broken Hearts: Bioengineered Heart Tissue Patch

Where are we now Three critical scientific milestones have been achieved by the project team, creating excitement and a strong foundation to pursue this bold vision.

This project has the potential to completely transform the lifelong trajectory of children with heart disease.

The three milestones achieved are:

1. Industrial-scale production of human cardiac cells Over the past 10 years, the project team have developed and patented cardiac differentiation protocols for the derivation of bioengineered heart tissue from human pluripotent stem cells. Our team have developed methods for the generation of miniature organoids for drug screening and disease modelling, as well as larger tissues for regenerative medicine applications.

Most recently, with the support of an Australian government grant, the team have scaled-up their cardiac differentiation protocols in line with industrial standards such that they can now consistently produce ~200 million cardiac cells per batch.

2. Creating Bioengineered Heart Tissue Patches Over the past 18 months, our team have developed novel, completely defined protocols for the generation of large, bioengineered heart tissue patches for children with heart disease.

Working together with our surgical team, we have developed patches that are of clinically relevant dimensions for implantation in children.

[Figure above: A schematic overview of cardiac differentiation and tissue engineering protocol.]

Mending Broken Hearts

Mending Broken Hearts: Bioengineered Heart Tissue Patch

3. Testing the patch in surgical models Building on over 30 years of experience in large animal models of congenital heart disease, our team have developed a novel model of paediatric heart failure in lambs. Sheep are a gold standard animal model for translational studies as their cardiovascular physiology and anatomy closely mirrors humans.

Over the past 18 months our team have established the surgical feasibility of implanting a bioengineered heart tissue patch. This major achievement gives us great confidence we are on the right track and we are now seeking to accelerate our progress.

(Figure on right: Bioengineered Heart Tissue Patch)

Pathway to Success Whilst this highly ambitious project has already completed some significant milestones, it continues to be a high risk, high stakes undertaking. The budget below breaks the project into tranches, each indicating a critical stage required for the project to culminate in Stage 5, partnering with industry to deliver the first in-human clinical trial of stem-cell derived heart tissues in children.

It is estimated that total funding required to bring the project to Stage 5 is between AU$10-15million. We are currently seeking visionary philanthropists to join the team as they embark on Stage 2 of the project.

Completed Yrs 1-2 so far

Yrs 3-5

Yrs 5-10

Stage 1

Stage 2 - $2M

Stage 3 - $5-10M

Stage 5 - TBA

Established the surgical feasibility.

Evaluation of safety and efficacy.

Expansion of pre-clinical testing to include use of clinical grade tissues.

• Clinical Trial with Industry partner.

[Update: July ’21: We have sourced AU$1M of this funding via an Australian Government MRFF grant]

Concurrent work streams will be established with leads across (i) Stem Cell Biology, (ii) Bioengineering and (iii) Surgery Learnings in one stream will inform approaches in other streams to accelerate the project

Partnering with industry will provide the resources and infrastructure required to manufacture clinical grade tissues and to conduct large-scale clinical trials.

Stage 4 - $3M Establish a world-class bioengineering group at MCRI with capability in cell manufacturing, scale-up and tissue engineering.

Mending Broken Hearts

Mending Broken Hearts: Bioengineered Heart Tissue Patch

Contact details If you would like to discuss this exciting initiative, please contact: Matthew Hannan Head of Department Engagement and Philanthropy Murdoch Children’s Research Institute, Melbourne E: matthew.hannan@mcri.edu.au T: +61 3 8341 6359

Mending Broken Hearts