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expert reaction to a study using stem cell therapy to regenerate damaged primate hearts

Transplants often fail because of immune reactions of the patient against the donated organ or tissue. A paper published in the journal Nature has described attempts to use modified transplanted stem cells to regenerate the damaged hearts of five monkeys.

All our previous output on this subject can be seen here.

 

Prof. Nilesh Samani, Medical Director at the British Heart Foundation, the UK’s leading independent funder of cardiovascular research, said:

“This research represents tantalising progress in our attempts to harness the potential of stem cells to treat the damage caused by a heart attack, which can lead to heart failure.

“The findings provide more evidence of the potential of stem cells, but there are still many challenges to overcome before this approach can be used to treat people with heart failure. For example, the study shows that the injected cells can trigger dangerous heart rhythms.

“The BHF is committed to funding research that will change the lives of people with heart failure. We have established research centres focused on the potential of stem cells and, with the public’s support, invested over £27 million into regenerative medicine research since 2010.”

 

Prof. Martin Evans FMedSci, Director of the Cardiff School of Biosciences, University of Cardiff, said:

“The article by Shiba et al. marks an interesting step forward in the progress to use stem cell therapy to repair hearts damaged following a heart attack.

“Cellular therapies are transplants; and the ideal would be to use exactly matched “autologous” tissues prepared especially from each individual patient. There are, however, clearly practical and logistic problems in this approach.

“One attractive alternative possibility would be to use sources of cells just matched in the major histocompatibility locus (MHC) and a way forward would be to have pre-prepared sets of such cells. Each patient will typically have two different types of MHC.  This study tests this approach by making the cells from an individual monkey which just one type of MHC (homozygous) and using these to treat monkeys matching in one of their two sets. This limits them from reacting against the introduced cells.

“This study used cynomologus monkeys. This is important because the major immunological barrier to transplants – the  MHC system – is very similar to human. A stock of induced pluripotent cells (iPSC’s) were established and from these cardiac muscle cells were isolated. These were then injected into the hearts of monkeys two weeks after a heart attack.  The injected cells did indeed become incorporated into heart muscle in the affected area of the heart and were shown to be working in synchrony with the host heart.  The major downside was that in all cases the treated hearts showed abnormal episodes of irregular beating. This is a serious complication which has been seen in some previous studies and deserves further study.

“There are numbers of challenges ahead before we can look forward to this becoming a regular safe human clinical procedure (practical, logistic, economic, regulatory) but this comprehensive study is moving in the right direction.”

 

Dr Dusko Ilic, Reader in Stem Cell Science, King’s College London, said:

“In this study, 4×108 induced pluripotent stem cell (iPSC)-derived cardiomyocytes, homologous for MHC-class I and II, were injected via 10 injections intra-myocardially into infarct and border zones, 14-day post experimentally induced cardiac infarction in five monkeys. The cellular therapy resulted in integrated graft survival and improved cardiac contractility for at least 12 weeks. However, as a consequence of cellular therapy, the animals suffered from transient non-lethal ventricular tachycardia suggesting that this therapeutic approach is still not ready for clinical application.

“I found it a bit odd that the authors are not even referring to the world-first hESC-based trial for the heart repair commenced in autumn 2014 in France under the sponsorship of the Assistance Publique – Hôpitaux de Paris (APHP; http://www.aphp.fr).  Instead of injecting the cells directly into heart, the French scientists transplant a fibrin patch embedding hESC-derived cardiac-committed CD15+ ISL-1+ progenitors into epicardium of the infarcted area and cover with an autologous pericardial flap. According to initial reports, the treatment was successful and the patient did not suffer from issues described by the Japanese group. Therefore, it is likely that the side effects seen in monkeys are a consequence of a poorly chosen strategy for application of the cells rather than the cells per se.

“Regardless, the study is an important step forward in bringing cellular therapy to patients suffering of threatening heart disease.”

 

Dr Stephen Minger, stem cell biologist and independent consultant (Director of SLM Blue Skies Innovations Ltd), said:

“With the possible exception of iPS cells as the source of the cardiomyocytes, I don’t think this study adds much to what we know. Chuck Murry’s group in Seattle showed a couple of years ago that dissociated ES-derived cardiac cells performed in a similar way to the present study in non-human primates (i.e. integrated morphologically but also promoted arrhythmia) but several studies have shown if the cells are seeded on a “patch” and transplanted they can integrate functionally into the normal rhythm of the heart. The cardiac folks might have a different opinion but I think we knew much of this before this study.”

 

Prof. Sian Harding, Professor of Cardiac Pharmacology and Director of the British Heart Foundation Cardiovascular Regenerative Medicine Centre, Imperial College London, said:

“This paper represents a significant step forward: by Implanting allogeneic iPSC-derived cardiomyocytes in a species close to human, they strengthen the case that a bank of pre-prepared matched iPSC could be used to treat patients, without relying on the long process of reprogramming and differentiating the patient’s own cells.

“This makes iPSC therapies much more feasible and potentially less expensive.  The improvement in heart function seen with iPSC-derived cardiomyocytes in this study is a step forward from previous work using non-human primates, and the integration is convincing.

“The arrhythmias were seen in a previous similar study, but in neither study did they prove fatal and both suggested that they would decrease with time.  Clinical strategies for preventing sudden cardiac death from arrhythmia, such as implantable cardiodefibrillators, may therefore be necessary as adjunct therapy for some months after implantation.”

 

Prof. John Martin, Professor of Cardiovascular Medicine, University College London, said:

“This article describes some good basic science but I think there is very little chance of it improving patient care in the future.

“The latest thinking among clinician-scientists in the field is that the objective of regenerative medicine in the heart should not be to make new heart muscle from transplanted cells but rather to induce the production of paracrine factors (chemical messengers) which go from stem cells to the malfunctioning heart cells to help them.

“Also, I note that the transplanted cells caused change in heart rhythm in the recipient heart. Such changes can be fatal in patients and led to the stopping of clinical experiments with similar technology a decade ago.”

 

Dr Tim Chico, Reader in Cardiovascular Medicine, University of Sheffield, said:

“There are thousands of patients suffering from heart failure in the UK who are desperate for new treatments to improve the function of their heart. It is important this current study, although scientifically important, does not give them false hope.

“Many doctors and scientists around the world are working hard to try to turn the promise of stem cell treatment into a reality, but there remain many obstacles and challenges to overcome. The current study does give cause for very cautious optimism that eventually stem cell treatment for heart failure might be possible, but it also highlights the potential to cause serious heart rhythm problems.

“I do not think stem cell treatment for heart failure will become a reality for many years, except for the essential clinical trials that help to advance our understanding of what might be possible.”

 

Allogeneic transplantation of iPS cell-derived cardiomyocytes regenerates primate hearts’ by Yuji Shiba et al. published in Nature on Monday 10th October. 

 

Declared interests

Dr Stephen Minger: I am the Director of SLM Blue Skies Innovations Ltd and provide expert technology assessment to the biotech and investment communities.  I am a Scientific Advisor to BioLamina in Sweden and FloDesignSonics in Boston, as well as Senior Consultant to GE Healthcare in Cellular Sciences and Regenerative Medicine.

Prof. Sian Harding: No conflict of interest apart from membership of the NCOB working party.

Prof. John Martin: I have no conflict of interest to declare.

Dr Tim Chico: “I am a committee member and Treasurer of the British Atherosclerosis Society, a charity established in 1999 to promote UK atherosclerosis research.”

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