A Functional, Mature In vivo Human Ventricular Muscle Patch for Cardiomyopathy

Projektinformationen

5D Heart Patch

ID Finanzhilfevereinbarung: 743225

DOI

10.3030/743225

Das Projekt endete am 31 Mai 2022

EK-Unterschriftsdatum 23 November 2017

Startdatum 1 Dezember 2017

Enddatum 30 November 2022

Finanziert unter

• EXCELLENT SCIENCE - European Research Council (ERC)

Gesamtkosten

€ 2 149 227,50

EU-Beitrag

€ 2 149 227,50

Koordiniert durch

KAROLINSKA INSTITUTET
Sweden

Periodic Reporting for period 3 - 5D Heart Patch (A Functional, Mature In vivo Human Ventricular Muscle Patch for Cardiomyopathy)

Berichtszeitraum: 2020-12-01 bis 2022-05-31

Zusammenfassung vom Kontext und den Gesamtzielen des Projekts

Heart failure is one of the leading causes of morbidity and mortality worldwide and is growing exponentially. While there are many drugs that can slow down the progression of the disease, the only truly curative therapy is heart transplantation, which is severely limited by organ availability. The ability to generate a fully functional heart graft patch in vivo would be potentially transformative for this leading unmet clinical need. Remarkably, the support of the ERC grant has led to the human ventricular progenitors towards approval for the first time in human studies, which will be led and supported by a major Swedish pharma, AstraZeneca.

We have identified that transplantations of human cardiac progenitor cells (HVPs) into acutely and chronically injured porcine hearts can form new heart muscles, reduce scar volume, and prevent heart failure progression. The current project advances our understanding of mechanisms underlying successful cardiac cell therapy using HVPs and brings use one step closer to designing suitable strategies to test these applications in a clinical setting. Our findings clearly support the capability of the HVPs to remuscularize parts of the infarcted heart, which could be of benefit for patients with ischaemic heart disease. It highlights a significant milestone in the potential therapeutic use of HVP cells in the treatment of patients with serious heart failure. It provides new hope for the millions of patients worldwide with end stage heart failure waiting for a heart transplant. We are actively pursuing this with Astrazeneca our industry partner in bringing this to the clinic in 2 years time.

Arbeit, die ab Beginn des Projekts bis zum Ende des durch den Bericht erfassten Berichtszeitraums geleistet wurde, und die wichtigsten bis dahin erzielten Ergebnisse

There were four aims in the initial proposal: 1) To develop a molecular atlas of the sequential steps of HVP muscle patch formation (implantation/survival, migration, expansion, differentiation, vascularization, matrix formation, and maturation); 2) To examine the effects of defined candidate cues which correlate with muscle patch formation 3) To model cardiomyopathy due to genetic disease, a mutation in phospholamban (PLN), a calcium pump regulator; and 4) To optimize HVP ventricular patch formation to rescue cardiac dysfunction following heart attack.

My lab’s 9 publications are the results of our work revolve around these four goals, and all these publications acknowledges the support of my ERC grant. In short, we have achieved the following:

Aim 1:
• Seminal discovery of human muscle progenitor cells can form muscle patches
• Identified the signature at a single cell level of heart progenitor that can be used for development of heart patch with purifications.

Aim 2
• Identified new pathway that control heart progenitor formation during development in a human culture system.
• New pathways that regulate progenitor expansion unique in human vs. mouse.

Aim3
• Described a human based mRNA model system to identify mutations that cause heart failure.
• Described a novel way to improve the function of heart muscle in the setting of heart failure.
• New technology platform with a combination of mRNA to identify and express nanobodies that can improve heart function.

Aim 4
• HVPs ability to sense and migrate to site of injury in pre-clinical pig model
• Capability of large-scale generation of HVPs
• HVPs can form new muscle patches in the recipient heart, while not contributing to arrythmia.
• Cardiac functional improvement following HVPs treatment in acute and chronic settings.

The recent HVP paper published in Nature Cell Biology (Aim 4) was heavily publicized from press releases (Karolinska Institutet, Technical University of Munich, AstraZeneca), on social media (LinkedIn, Twitter), and announced on Swedish network on gene & cell therapy produces. AstraZeneca have put together a video showcasing the publications and our collaborations, and the video was featured on their homepage. The press coverage in turn was picked up by various news outlets. Scientifically, Nature Cell Biology commissioned a New & Views article on our work to coincide with the publication, and editors across Nature Portfolio put together a special issue which showcases research in stem cells published across different journals, and our HVP paper was selected to be featured in that issue. In summary, we have achieved what we have initially planned for the ERC projects, which is to investigate novel therapeutics to treat heart disease. With the generous support from ERC, we have identified a potential new cell type which is progressing towards the clinic.

Fortschritte, die über den aktuellen Stand der Technik hinausgehen und voraussichtliche potenzielle Auswirkungen (einschließlich der bis dato erzielten sozioökonomischen Auswirkungen und weiter gefassten gesellschaftlichen Auswirkungen des Projekts)

Many novel therapies for treating cardiac disorders can be grouped into 1 of 2 categories, cell based therapies or cell-free therapies. To date, many clinicians and scientists stand on one side of this coin, in favor of either cell-based therapies or in favor of cell-free (molecule/chemical) therapies. What is special about our research approach is that we aim to combine cell therapies with small molecules to enhance cardiovascular reparative therapies. This concept is quite novel. We envision that a vascularized muscle graft should enhance long-term survivability and function of the naïve HVP graft. Many pre-clinical studies in large animals have shown transplanting mature cardiac cells in diseased heart models fail to significantly enhance cardiac function. One plausible explanation to these results is because many of the injected cells are pumped out of the heart following transplantation. The remaining cells may maturate into residual small islands of new heart muscle but are incapable of providing a strong global functional effect in the heart. As these islands of newly formed muscle are poorly vascularized, they fail to survive long-term. We have uncovered over the course of the ERC grant period, that HVPs can sense and migrate to the site of injury, and consequently matured into cardiomyocyte and improve cardiac function.

One other aspect of the HVPs is its potential to further develop human cardiac disease modelling. Many genetic disorders linked to cardiac diseases have been modelled in the mouse. Those models despite being useful, do possess strong limitations due to basal differences in between mouse and human cardiac physiology. Therefore, in order to push forward our knowledge in this field and increase translatability of our potential findings we proposed the combination of state of the art generation of human ventricular patches through our HVP technology. We were able to fully utilize that in combination with the large animal pre-clinical model (pig), to validate that our HVPs cells can potentially progress into the clinic.

Schematic of the experimental setup for generation of human ventricular progenitors cells