Swedish and American authors say a new technique involving the use of an artificial scaffold into which a patient’s own stem cells are inserted, turning it into a fully functional organ, could offer a potential solution to the donor shortage crisis. The review article is one of two papers in a Lancet stem cell series. Below Australian experts respond.

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Professor Wendy Rogers is Professor of Clinical Ethics in Department of Philosophy and the Australian School of Advanced Medicine at Macquarie University

“The promise of stem-cell engineered whole organs and complex tissue is highly attractive on a number of fronts. Not least is the potential to side-step the complex ethical issues associated with organ donation and transplantation from living and cadaveric donors. While Caplan and colleagues are right to draw attention to the current ethical challenges of developing the technology, wider issues are also relevant. This technology has the capacity to alter the landscape of organ transplantation. It won’t be possible to know whether engineered organs are better or worse than transplants from other (living or dead) humans for many years, so that we will stay in the “experimental” phase for a long time until long-term follow up trials have established safety and effectiveness profiles. This creates the possibility that there may be pressure for people who are refused conventional transplants to volunteer for or accept engineered organs. Second, if it seems that life with engineered organs is better (which it obviously has the potential to be, given that no immunosuppression will be necessary) then we may get a two-tier system in which those who can afford engineered organs will get them while others accept organs retrieved from humans.

As with all technological breakthroughs, a focus on innovative treatment takes our attention away from both prevention, and patterns of disease and their underlying causes, so it is important that the science does not dazzle us so that we lose track of, for example, programs to prevent kidney or liver disease.

Finally, there is a great opportunity to perform the necessary research and to make staged introduction of engineered organs an exemplar for the introduction of innovative procedures. To achieve this will require genuine cooperation, transparency, a willingness to act for the greater good, and procedural oversight including registers so that all engineered organs are identified and tracked.”

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Professor Martin Pera is Program Head of Stem Cells Australia and Chair of Stem Cell Sciences at the University of Melbourne

“This article in The Lancet provides an overview of recent advances in rebuilding tissues and organs for transplantation therapy. The authors focus on an approach that exploits nature’s own design templates. Cells for transplantation are seeded onto constructs made not from artificial materials, but from donor or animal derived tissues or organs that have been stripped of any cellular content to leave behind the extracellular matrix, the rich and complex scaffold on which organs in the body are constructed. This decellularized extracellular matrix provides an appropriately shaped structure to which the cells can attach, as well as signals which guide their growth, maturation and integration into the new organ.

The results using this natural approach to tissue engineering are sometimes quite dramatic, achieving significant reconstruction of the key features of the native tissue by grafted cells. However, in order to avoid the use of animal products, and to get around the shortage of human donor tissue, it is likely that future research will focus on mimicking the natural templates with synthetic materials. Moreover, even with the perfect template, an abundant source of the appropriate cells to seed the scaffold is an essential component to organ reconstruction. Future studies will seek to identify the optimal source of cells for each clinical application, whether from patient tissue or stem cell cultures grown in the laboratory.”

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* Engineered whole organs and complex tissues, Macchiarini et al., The Lancet, Vol 379, 2012

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* ‘Embryonic stem cell trials for macular degeneration: a preliminary report’ by Steven Schwartz et al. is published in The Lancet, 23^rd January 2012.

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Professor Martin Pera is Chair of Stem Cell Science at the University of Melbourne and Program Leader of Stem Cells Australia

“The report in the Lancet today from scientists at UCLA and Advanced Cell Technologies provides hope for patients suffering from dry macular degeneration, a very common cause of blindness. Although the work is preliminary, the study shows that replacement of retinal pigment epithelial cells (the cell type that is lost in this disease) by grafts derived from human embryonic stem cells appears to be safe, and may lead to an improvement in vision. This landmark study is the first published account of a human trial of embryonic stem cell based therapy. The authors described results from only two patients, and it is possible that the improvements that they observed may be related to other factors apart from the graft itself. Nonetheless the early findings are most encouraging.

Macular degeneration is a very promising target for stem cell therapies, because the required cell type can be efficiently produced from embryonic stem cell cultures, and because the eye is easily accessible for surgery and for monitoring the progress of the graft. Centres in California, the United Kingdom, and elsewhere are also progressing towards clinical trials of stem cell therapies in this disease. It will soon be clear whether these preliminary results published today are a harbinger of a new era in cell therapy for this devastating medical condition.”

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Dr Bernie Tuch is Director of the New South Wales Stem Cell Network

“This is a wonderful concept which should be strongly supported. It provides hope that something positive can be done about it for people who are losing their vision.”

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Dr Andrew Laslett is Research Group Leader, Stem Cells, CSIRO Materials Science & Engineering, Victoria

“This report allows cautious optimism that cells derived from human embryonic stem cells may be useful for the treatment of a common cause of blindness, namely macular degeneration. It is very early days and only two patients have been reported on to date but this first ever peer-reviewed report of a human embryonic stem cell-based human clinical trial demonstrated no adverse side effects and both patients showed mild improvement in their vision. The long term hope, based on these results, is that earlier intervention may lead to greater improvements in visual acuity for people with macular degeneration and that these improvements will persist and be safe.”

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Associate Professor Kuldip Sidhu is Director of the Stem Cell Lab and Chair of Stem Cell Biology at the University of New South Wales

“This is an another significant proof of principle that hESC-derived cells have potential in therapeutics if produced carefully avoiding residual hESCs that may cause teratoma – a major concern so far in the use of such cells. In this study a pure population of RPE derived from hESCs were transplanted into the patients eyes diagnosed with macula degeneration. Although only the phase I trials on two patients were carried out and the short term follow up for four months shows cell survival and apparently no adverse effects or tumours formation – a significant way forward in the clinical use of such cells in future. It is too early to conclude that clinical outcome is due to transplanted cells, it may simply be a trophic effects as also pointed out by the authors in this publication. A further long term follow up on these patients is essential to rule out adverse affects if any. Apparently the protocol developed for obtaining RPE from hESCs in Dr Robert’s lab so far involves the use of feeder cells from animals that can be avoided in the future as feeder-free systems are evolving rapidly.”

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Expert response from UK scientists

Compiled by our colleagues at the UK Science Media Centre

Expert reaction to preliminary data on stem cell trial for macular degeneration, as published in The Lancet*

Professor Daniel Brison, Co-Director of the North West Embryonic Stem Cell Centre, Manchester, said:

“This is a very exciting moment for embryonic stem cell therapies.  This is the first peer-reviewed scientific report showing that cells derived from human ES cells can be transplanted safely into a patient with no sign of complications.  Although the study is limited to safety considerations, very small in scope, and at a very early stage, this is nonetheless a ground breaking moment for embryonic stem cell therapies.  It is also very significant for the UK that the second trial of these therapies has now begun in London, only 4 months behind the US trial.  These trials have used human ES cells created at research grade and this was possible as they were transplanted into the eye which is a very localised site in the body.  In order to realise the full potential of ES cell therapies in the future, it will be very important to use the new generation of clinical grade ES cells now being produced in the UK.”

Professor Chris Mason, Chair of Regenerative Medicine Bioprocessing, University College London, said:

“The preliminary data on the two US patients treated using human embryonic stem cell-based therapies in June 2011 is highly encouraging, but is only the start of gathering the necessary safety data before it is possible to test if the therapy will have an impact on patients’ vision. Overall the process of testing for safety and efficacy is likely to take a minimum of 5-10 years before the potential therapy could enter routine clinical practice.

“It is not surprising that the first European human embryonic stem cell-based therapy was carried out in London, given that the UK is a world leader in cell therapy.

“The safety of embryonic stem cell-based therapies in patients is now slowly starting to emerge with both Geron data for spinal cord injury and now ACT for retinal disease. It is still a long way to go before we will have the answer as to whether embryonic stem cell-based therapies will be safe and efficacious, but progress continues to be made towards striving for the ultimate goal of life-changing therapies for patients and their carers.”

Dr Dusko Ilic, Senior Lecturer in Stem Cell Science, Kings College London, said:

“The most important thing is that Robert Lanza and his team at the Advanced Cell Technology get across a message to the media and the public that ongoing clinical trials for dry age-related macular degeneration and Stargardt’s disease with retinal pigment epithelium (RPE) derived from hES cells are safety trials. Even though in preclinical trials, the RPE were capable of extensive photoreceptor rescue in an animal model of retinal disease, resulting in improvement in visual performance without evidence of untoward pathology, we should keep in mind that people are not rats. The number one priority of initial clinical trial is always patient safety. If everyone expects that the blind patients will see after being treated with hES cell-derived RPE, even if the treatment ends up being safe (which is what Advanced Cell Technology are trying to determine in this trial), they risk being unnecessarily disappointed.”

Professor Peter Coffey, Director of the London Project to Cure Blindness said:

“At last seeing fruits of human embryonic stem cell research entering clinical trials. This will help determine the safety of these therapies. I am immensely happy that this has happened in the eye. And will only help those patients with, until now, blinding eye diseases. Hopefully we will be able to enter our own clinical trials using embryonic stem cell therapy soon.”

* ‘Embryonic stem cell trials for macular degeneration: a preliminary report’ by Steven Schwartz et al. is published in The Lancet today, 23^rd January 2012.

Feel free to use these quotes in your stories.  Any further comments will be posted here. If you would like to speak to an expert, please don’t hesitate to contact us on (08) 7120 8666 or by email.

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Dr Stephanie Williams is Chief Executive Officer of The Spinal Cord Injury Network (Available for interview)

“It seems a great loss that a clinical trial that required so much effort to establish and went through a rigorous FDA approval process should falter due to adverse economic conditions. We hope that Geron will be able to identify partners to assist with its stem cell program and indeed complete Phase I of the trial. The spinal cord injury field stood to learn a great deal about cellular therapies in humans from this trial and now much of this huge opportunity has been lost.”

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Prof Bob Williamson is Secretary for Science Policy of the Australian Academy of Science (Available for interview)

“There can be many reasons for abandoning a clinical trial, and people with spinal injury will be very disappointed that Geron has stopped this study.  Because stem cell therapy is such an emotive area with ethical implications, it may be argued that the decision is of great significance.  However, there are always ups and downs in the pharmaceutical industry, particularly when research is being turned into treatment, and Geron may well have thought that its cancer drugs have more chance of making money than stem cells.  There are several other clinical trials under way that use stem cells for therapy, some of which are going well, but the real success of stem cell science has been in helping scientists work out the basics behind the way a one-cell embryo develops into a living human being.  We need to retain the flexibility to use every kind of stem cell to advance our basic knowledge and to apply this for care in the clinic.”

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Dr Megan Munsie is Director of the Education, Ethics, Law and Community Awareness Unit at Stem Cells Australia (Available for interview)

“It is really disappointing that Geron will cease its spinal cord injury trial. We can only hope that Geron is able to identify partners with the necessary technical and financial resources to allow their pioneering stem cell therapy program to continue. Geron invested heavily in their approach and compiled substantial pre-clinical data to meet the rigorous standards demanded by the FDA. Attention of those with SCI who hope to benefit from stem cell therapy will now focus on the progress of the clinical trial by StemCells Inc in Switzerland.”

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Joanna Knott is Co-Founder and Chair of SpinalCure Australia (Available for interview)

“This is incredibly sad and frustrating news for people with spinal injuries and their families. It is devastating for those people who will have a spinal injury and may as a result of this research been cured.

We hope that Geron will be in a situation soon where they can consider funding this project once again.

Perhaps it is time for governments to consider a greater allocation of resources into promising medical research rather than allocating it to the futility of warfare.”

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Below Australian stem cell and legal experts discuss what this decision means for stem cell research on an international scale. There are also numerous comments gathered by our colleagues at the UK Science Media Centre which we hope are useful.

Feel free to use these quotes in your stories.  Any further comments will be posted here. If you would like to speak to an expert, please don’t hesitate to contact us on (08) 7120 8666 or by email.

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Professor Martin Pera is Program Head of Stem Cells Australia and Chair of Stem Cell Sciences at the University of Melbourne

“The decision yesterday by the European Union Court of Justice will slow or halt the translation of advances in stem cell research into treatments for patients.

Though the ruling does not affect Australia directly, we have to recognize that progress in this field depends on international collaboration, particularly in clinical trials.  European stem cell scientists are leaders in the field, and everyone will suffer if there are barriers to such collaboration.

Engagement of the pharmaceutical and biotechnology sectors is critical to bringing stem cell therapies to the clinic. Such engagement depends on the ability to protect intellectual property.

Clinical trials of cell therapeutics derived from embryonic stem cells are already underway in the United States for spinal cord injury and macular degeneration, and more are on the way. These trials depend on private sector investment and technological capability. The ruling will make it very difficult to pursue similar work in Europe.”

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Dr Debra Yin Foo is the Partner in charge of the Biotechnology Department at Phillips Ormonde Fitzpatrick Intellectual Property Attorneys

“This is a disappointing decision and goes against a purpose of the Patent System. The Patent System rewards innovation and encourages dissemination of information by disclosure of the invention in a Patent.  For that disclosure, the applicant receives a period in which they can exploit the invention at the exclusion of others. This gives some certainty to a company associated with the granting of a Patent.

With limited and reduced protection of the research and discoveries surrounding an invention, companies, not only in Europe, will be discouraged from publishing their findings and inventions and hence will keep that information secret. We need to have systems that encourage the dissemination of information, particularly in the area of embryonic stem cell research. Suitable replacements for embryonic stem cells are not certain and research in this area should be encouraged and shared.

If there is no system to protect inventions in Europe then companies may also decide not to file in other countries, such as the US, which would otherwise disclose their inventions to the public. Once disclosed and published with no protection in Europe, others are able to commercialize the invention in Europe without reward to the patentee. There would be many negative flow-on effects for both companies and individuals.

Finally, the judgment is binding on EU member states, and the European Patent Office (EPO) is also expected to bring its practice into line with the judgment.  In practice this means that the validity of any patents relating to uses of human embryonic stem cells that have already been granted in the EU can now be challenged on the ground of exclusion from patentability, although they will remain in force until such a challenge is made.  With regard to the examination of pending applications, we expect that the EPO and countries of the EU will revise their current practice in line with the judgment.  Therefore, we think that chances of obtaining patent protection for pending applications are, at best, very slim.

We escaped a bullet with the gene debate and I hope that this backward approach to patenting of ES cells, especially for the new technologies, will not have the impact that we all are concerned about.”

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UK Science Media Centre Rapid Reaction

Expert reaction to European Court of Justice decision on patents on Embryonic stem cell research

See: http://curia.europa.eu/jcms/jcms/P_81409/

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Dr Celia Caulcott, Director of Innovation and Skills, BBSRC said:

“Whilst the full consequence of this ruling is yet to be understood, it is important to BBSRC to ensure that a clear path to commercialisation is maintained for researchers working across our remit.  For fundamental research to reach its full potential for social and economic impact in the future, we need supportive regulatory and business environment.

“BBSRC funds researchers who are investigating the basic biology of stem cells. For these researchers, perhaps more so than those working closer to commercialisation, we must ensure access to the widest variety of avenues through which to explore the potential of their science; it would be a shame if this were jeopardised by this ruling.”

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Ben Sykes, Executive Director, UK National Stem Cell Network, said:

“The detail of this judgement, published today on the ECJ website, warrants further consideration by the legal profession. The initial impression is that the decision is disappointing and will have implications for European companies investing in hESC research as well as the exploitation of world class European research in the field on other continents such as Asia and North America. There might also be unintended consequences arising from a restricted environment for commercialisation of this research within Europe, though we must await further scrutiny to see precisely how limiting this judgement is.”

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Alexander Denoon, Lawyer at Lawford Davies Denoon (law firm specialising in life sciences), said:

“While this is an unwelcome decision, this is not catastrophic for the sector for a variety of reasons:

(1) Despite the plea not to undertake skilful drafting to circumvent the decision, I suspect that inventors and patent attorneys will find ways around some of this. In fact, inventors and patent attorneys have known about this concern for some time and have been drafting to try to take account of this issue.

(2) It is possible to obtain patents for these types of inventions in most other countries in the world, including the US.

(3) It should be possible to obtain patents on allied technologies, such as biomarkers and diagnostics related to the particular therapy.

(4) Under the current regulatory framework, it will be virtually impossible to convince a regulator to approve a generic (technically a biosimilar as the threshold for biologicals is higher than normal generics), thus the regulatory protection for approved medicines will be very high.

(5) This affects the sector generally and not European scientists or patients disproportionately.

(6) Finally, we still await the decision of the Federal Patent Court in Germany (Bundespatentgericht) and subsequent guidance from patent offices.”

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Dr Tony Peatfield, director of corporate affairs at the Medical Research Council:

“While the full impact of the European Court of Justice Ruling will need to be considered, this seems to be a very disappointing conclusion.

“The MRC expects to invest over £130m in research to promote the application of stem cell and related technologies for regenerative medicine over the next four years, and strives to ensure that the UK remains a world leader in this area of research. Patents have an important role to play in encouraging and protecting industry investment in human embryonic stem cell research, and in effecting the delivery of stem-cell based therapies in the longer term. It’s likely this decision will hamper inward industry investment.

“The MRC is committed to working hard with its partners to provide as supportive an environment as possible within this new patent era.”

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Prof Sir Ian Wilmut, MRC Centre for Regenerative Medicine, University of Edinburgh, said:

“It is very much to be regretted that the Court has taken this view. It will unfortunately make it less likely that companies in Europe will invest in the research to develop treatments to use embryonic stem cells for treatment of human diseases.

“Once a fundamental discovery has been made in the laboratory further research is required to produce a clinically safe and effective product. This is a particularly expensive part of the entire process. Companies in Europe will now be less likely to invest in this stage of the research with embryo stem cells because they would be unable to protect their procedures.

“Sadly this judgement may mean that initial research carried out in Europe in some cases with European funds will be more likely to be developed and used in other parts of the world.”

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Prof Austin Smith, Wellcome Trust Centre for Stem Cell Research, University of Cambridge, said:

“This unfortunate decision by the Court leaves scientists in a ridiculous position. We are funded to do research for the public good, yet prevented from taking our discoveries to the market place where they could be developed into new medicines. One consequence is that the benefits of our research will be reaped in America and Asia”

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Prof Pete Coffey, Institute of Ophthalmology, University College London, said:

“This is a devastating decision which will stop stem cell therapies use in medicine. The potential to treat disabling and life threatening disease commonly using stem cells will not be realised in Europe.

“I have just won an international prize from the New York Stem Cell Foundation for translating stem cell research into clinical practice, yet I now find that Europe, the continent in which I am doing this research, is basically calling me immoral. I cannot produce a medicine, I can give a therapy, I can show how it works in a small group of patients, but we need the companies to commercialise this work. This decision will be a major barrier to patients actually receiving these treatments.”

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Prof Oliver Bruestle, Director of the Institute for Reconstructive Neurobiology at Bonn University, said:

“With this unfortunate decision, the fruits of years of translational research by European scientists will be wiped away and left to the non-European countries. European researchers may conduct basic research, which is then implemented elsewhere in medical procedures, which will eventually be re-imported to Europe. How do I explain this to my students?”

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Prof Robin Lovell-Badge, MRC National Institute for Medical Research, said:

“The issue of patents in biomedicine, especially where they involve human material, is often contentious and is one where there perhaps needs to be a bigger debate about how to ensure the involvement of biotech and other companies and rewards to them and inventors can be managed in way that is equitable and, critically, of maximum benefit to patients. But given the limitations of the current system, any decision taken now needs to take the moral imperative of maximising the likelihood of benefits to patients. If this requires individuals and companies having some degree of patent protection on materials and methods developed from human embryonic stem cells, otherwise they will not invest in finding treatments, then so be it – this is what is needed.

“In this respect I am very disappointed in the European Court of Justice’s decision not to permit patenting in this area. To prevent a lack of investment in this research, we urgently need to come up with alternative methods that will allow this type of science and its application to progress.”

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UK scientists were able to treat liver disease in mice with a combination of stem cells and genetic correction therapy. The research, to be published in Nature, demonstrates the feasibility of combining human induced pluripotent stem cells (iPSCs) with genetic correction to generate clinically relevant cells for cell-based therapies. The scientists edited the genome in human iPSCs taken from patients with a protein deficiency. These corrected iPSCs were given to mice where they were able to colonize their livers, restoring normal structure and function.

*Targeted gene correction of a1-antitrypsin deficiency in induced pluripotent stem cells, Yusa et al., Nature, doi:10.1038/nature10424

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Dr Andrew Laslett is Research Group Leader, Stem Cells, CSIRO Materials Science & Engineering

“This paper demonstrates for the first time the feasibility of combining gene therapy approaches with iPS cell technology to correct a simple genetic mutation that causes human liver disease. The corrected cell lines produced will require stringent safety and stability testing and the removal of all non-human proteins before they would be suitable for human clinical safety trials. This approach may be applicable to other human diseases which have a known and simple genetic mutation.”

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Dr Bryce Vissel is Head of Research into Neural plasticity and Regeneration, Garvan Institute of medical research

“This exciting study from Allan Bradley and Ludovic Vallier offers enormous hope for recovery for people suffering from genetic disorders. The study demonstrates for the first time that it is possible to take skin cells from a person with a genetic liver disorder, turn those skin cells into stem cells (called IPSCs) and then fix the genetic defect. Quite amazingly, the repaired cells could be turned into functionally corrected transplantable liver cells that have potential to correct the original liver defect. This amazing discovery builds on extensive studies over recent years of the potential of IPSCs. This study offers the possibility not only to repair genetic disorders of the liver but possibly also to repair numerous types of genetic disorders. As with all scientific progress, there will be major challenges to overcome before we see this new technology widely applied to people. It is important to note that the study does not yet cure a human condition; in this study the exciting result was shown in mice. Also there were important problems raised in the study. It will take scientific rigour, persistence, patience, perhaps even some failures, to overcome the challenges from here and achieve an outcome in people. Nevertheless, the study is an important step towards the goal of treating disease with stem cells. We are on the edge of a revolution in medicine – regenerative medicine – that could help people worldwide.”

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Dr William Sievert is Director of the Gastroenterology and Hepatology Unit, Southern Health and Professor of Medicine, Monash University

“Patients with alpha-1 antitrypsin (A1AT) deficiency develop serious lung disease such as emphysema because of low blood levels of A1AT; some also develop liver disease because the A1AT protein gets trapped in liver cells and damages them. Currently the only treatment available for people who develop serious liver disease is transplantation but what if you only needed to transplant normal liver cells instead of the whole liver? These investigators have taken skin cells from people with A1AT deficiency and done two things – corrected the genetic mutation in those cells that caused low levels of A1AT and changed the skin cells into liver cells (hepatocytes) that now make normal levels of A1AT. So this is a giant first step to treating this important genetic disease with cells (rather than an entire liver) that will continue to grow in the patient without the need for drugs to prevent rejection (since they came from the patient in the first place) and will provide the patient with enough A1AT to protect their lungs and liver.

The next steps will be to take this discovery from the laboratory, where it was tested in mice, to clinical trials where safety and effectiveness can be properly evaluated in people. There will be many challenges to overcome such as how to make enough cells to treat a person, in understanding at what age to start treatment for this genetic disease, determining how long the cells will continue to function and which individuals are most likely to benefit. Long-term safety considerations, such as whether tumour formation will occur, are very important. If these questions can be answered, then someday people with serious liver damage from other causes, such as viruses, alcohol or obesity, might benefit from this process of making skin cells into functional liver cells that could support or even regenerate a damaged liver, rather than having to replace it.”

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