Thoughts On Stem Cell Research & Treatments

Many will have read about the story earlier this month of a young woman with cystic fibrosis, Roisin Kelleher, who travelled to the Dominican Republic in order to undergo a controversial stem cell procedure. Here, our Chief Executive, Ed Owen, reflects on the difficult issues the case raises and why the Trust cannot recommend others pursue the same course:

There’s been much interest and debate on the use of stem cells as a potential transformational therapy for cystic fibrosis in the wake of publicity around Roisin Kelleher’s story.

Roisin is 20 years old and lives in Kent. She is dependent on oxygen, has been recently diagnosed with pulmonary hypertension and has been told by her clinical team that a lung transplant is probably the only way to prolong her life. Her mum Anntoinette told me when I spoke to her this week, “our lives caved in” at the news and they were desperate to find alternative routes to bring hope for her daughter.

After undertaking a great deal of research on the internet and through other networks, Anntoinette came across the work of a Florida-based physician, Dr Zannos Grekos, who has been promoting a particular stem cell therapy for a range of debilitating conditions, including heart and lung failure. Under his procedure, patients travel to the Dominican Republic where stem cells are introduced into the body intravenously.

Roisin and Anntoinette decided to give it a chance, and raised the funds they needed to travel to the Dominican Republic and undergo the procedure. Roisin is now back home and you can read her personal story on her Facebook page, ‘Breathe Hope for Roisin’.

So what is our view of this particular therapy? It is the question we have been asked by many, including some in the same situation as Roisin who, inevitably, are asking themselves whether they too should seek to undergo this procedure as a way to bring hope of future life.

In answering this question it is important to start by saying that all of us understand the desperation felt by the Kellehers. Theirs is a heartfelt story experienced by many other families touched by cystic fibrosis – and all of us wish Roisin well over the next few weeks and months. Like every other member of the wider cystic fibrosis community, they deserve and should receive full support and love from us all.

But the Cystic Fibrosis Trust does not recommend that others follow their example because it is a procedure that has not undergone the minimum essential procedures to guarantee patient safety. Indeed, the very reason it is carried out in the Dominican Republic is because it is not authorized by the US regulators, the FDA.

I have been in contact with a number of cystic fibrosis experts in the UK and in the US over the last few days, and none believes that this procedure has any scientific or clinical basis. It should also be pointed out that, in 2013, the Florida Board of Medicine removed the medical license of Dr Grekos for committing medical malpractice in performing an “unproven” stem cell therapy on a patient who later died. The board's vote was unanimous and without discussion, although I understand he may be appealing this decision.

I admire Anntoinette’s spirit and deep love for her daughter.  She accepts their decision was a “leap of faith”, and is also keen to point out that Roisin continues to take her existing treatments and is still going through a transplant assessment here in the UK.  She also understands the position the Trust takes on this issue.

And what we all very much agree on is the need for more research into the use of stem cells in cystic fibrosis.

For all the professional scepticism about Dr Grekos’ procedure, there is a great deal of enthusiasm within scientific and clinical circles for the longer-term potential offered by stem cell research. The Cystic Fibrosis Foundation in the US is looking to invest heavily in this field  and we, too, are exploring some innovative areas of work in this area which we hope to announce soon.

This is not work that is going to bring potential clinical therapies soon, and we are some way from even early stage clinical trials. But it is a genuinely exciting area as part of our mission to beat cystic fibrosis for good, and we will not stop until we get there.

In the meantime, our hearts go out to Roisin at this time, and to all those families facing the daily battle to ensure their loved ones remain with them. You are, quite simply, our inspiration in the fight against this cruel condition.

We are continuing to look into this issue, as we do with all developments in cystic fibrosis care and research. Please do keep an eye out on the Trust’s Facebook, Twitter and website, as well as this blog for updates.

SRCs: What’s so good about them?

The Cystic Fibrosis Trust has just announced it's two newest Strategic Research Centres. Senior Research Manager, Dr Anoushka de Almeida-Carragher explains why they're so great!

Our Strategic Research Centre (SRC) programme is one of the main initiatives which have come about following the launch of our Research Strategy, 'Investing in Research to Change Lives', a couple of years ago. SRCs are virtual centres of excellence made up of a unique consortia of scientists in the UK and overseas, using their wide knowledge and expertise to crack serious problems in cystic fibrosis (CF). SRCs also bring together established academics from different disciplines like chemistry and neuroscience; this much-needed extra set of skills, into CF research, is of profound importance. Not only do SRCs give the opportunity to partner up with pharmaceutical companies, thereby facilitating translating bench science to bedside clinical practice, but they also inspire the next generation of bright, young scientists to focus their research in CF, thus paving the way to a future of global research excellence in CF.

We have recently awarded two world class SRC programmes. Dr David Sheppard at Bristol University will be leading one of them. His multidisciplinary team is made up of renowned scientists from the UK, France and The Netherlands. The team will perform an innovative series of basic science studies which will provide an in-depth understanding of what is going wrong in the cells of CF patients. Specifically, his research aims to promote the development of new drugs to treat the most common cause of CF called F508del.  CF is caused by defects in the protein CFTR that forms a gated pathway for chloride, one part of salt, to cross cell borders lining ducts and tubes throughout the body.  The F508del defect prevents CFTR assembling correctly within the cell.  As a result, few CFTR proteins reach the cell border.  Those that do are fragile; they do not transport chloride properly and they quickly fall apart, losing altogether the ability to do useful work.  The team will investigate the structure of CFTR and learn how it is affected by the F508del defect.  Aided by this knowledge, they will then go on to search for chemicals that repair all the faults in CFTR caused by the F508del defect, so that CFTR is correctly made and delivered to the cell border to form a stable gated pathway for chloride movement.  Thus, the results will inform the development of new drug therapies to benefit the majority of people living with CF.

The second SRC will be led by Prof Di Bilton and her colleagues at Imperial College, London (The Royal Brompton Hospital). Her research team is made up of respiratory medicine experts, epidemiologists, medical statisticians and health economists, widely spread throughout the UK and in Canada. The project will enhance the use of the UK CF Registry data (containing information for over 99% of the UK CF population) so that better use of the information can be made to help answer important CF-related questions. When the data is analysed by cutting edge techniques, the team will be able to identify therapies and make recommendations regarding best use of therapies at critical stages and planning of care, for the increasing adult CF population.

Later this week, we will be inviting researchers to apply for a SRC grant, for the next round. This is a great opportunity for world class research academics in CF research, and other related disciplines, to ‘bang heads’ and work together to answer the critical questions we face in the field of CF, today

Find out more about our existing SRCs at www.cysticfibrosis.org.uk/src

Three Parent Babies and Stem Cells

With three parent babies passed by MPs earlier this week and stem cell treatments in the news, Dr Janet Allen gives insight on how this all applies to cystic fibrosis.

This week there was another landmark decision as MPs approved legislation to help people who carry mutations in a small subset of genes, contained in a part of the cell called mitochondria. This is clear evidence that the UK is once again leading the way in developing and implementing novel approaches that can help people who carry genetic conditions. It is a testimony to the UK’s pioneering work, by thought-leaders such as Dame Mary Warnock, which allows ethical issues to be debated alongside scientific advances. The Human Fertilisation and Embryology Authority, formed in the ‘90s, continues to provide an excellent framework for this debate and ensures new approaches to treatments are introduced in a safe and considered fashion.
  

The news of the three-parent babies debate has received a lot of press attention this week. So what is meant by three-parent babies? It is really a misnomer. There are 37 genes that are found in specific organelles called mitochondria, inside cells. These organelles have been referred to as ‘the power battery for cells’.  Their role is to provide the energy to allow cells to function. Mutations in this small number of genes lead to dysfunctional mitochondria and so genetic conditions. Mitochondria are present in the human ova (eggs) but lie outside the cell nucleus and are not involved in the fertilisation process at conception. In contrast there are over 20,000 genes found in the cell nucleus, which are derived from the father and mother and come together during fertilisation to form the genetic make-up of the child. This fact is unchanged by the recent news.

Stem cells have also been in the news this week. The use of these cells in tissue repair processes is the subject of much research. Initially, stem cells were derived from embryonic sources (eSC) but this was very controversial and restricted their application. In recent years, a new source of stem cells has been identified, known as inducible pluripotent stems cells or iPS or iPSC.  These iPS cells can be derived from mature blood cells.

So what are iPSCs? Normally, when a blood cell divides it creates more blood cells of the same type. However, scientists have worked out how to convert a blood cell to a stem cell in the lab. Once an iPS stem cell, it can then be converted in to another cell type, say a liver or lung cell. So for any one individual, their own blood cells can be converted to the specific cells required for tissue repair. In the context of CF, it is important to understand that this process alone will not fix the gene mutation, cells that carry the CFTR mutation following this process will continue to carry the CFTR mutation. We have just started to fund a research programme where we will aim to correct the mutation in these iPS stem cells. Only then will it be possible to use stem cells as a therapy for cystic fibrosis. Achieving this in the laboratory is relatively straightforward. The big challenge is how to convert this to help people directly.

Stem cell therapies hold enormous promise for the future.  However, at the moment, the work is still at an experimental stage and is not available as a routine.  It is very important that any claims for success are properly evaluated and subject to critical review by independent experts.  Stem cell therapies need to be scrutinised as rigorously as any new treatment for cystic fibrosis.  After all, no one would accept that a new drug be used in people with cystic fibrosis without the proper safety and efficacy measures required by the European Medicines Agency and the Food and Drug Administration in the US.  These agencies have been set up to protect us all and ensure any new treatments, including stem cells, are used appropriately.
If you want to learn more about how three parent babies work, you can find some good lay explanations over on the BBC, The Independent and Buzzfeed. 
 

Genotype Matters

Yesterday we launched 'Genotype Matters', allowing people with cystic fibrosis to learn more about their genotype, and how it is important in the era of personalised medicine. Dr Janet Allen, Director of Research & Care, has been overseeing the project at the Cystic Fibrosis Trust and here gives some background to it.


I am delighted to announce that we have launched our Genotype Matters campaign. We have been working with the CF centres in this area for a while. We ran a very successful pilot last year where we were able to pay for some of those whose genotype was unknown to have a blood test, and now we are able to extend the offer to all those who have a question mark about their genotype in the CF Registry. Cystic fibrosis is a clinical diagnosis made by expert CF specialists. In the past, the genotype information was provided afterwards and recorded in the CF Registry. However, the early genotyping panels only covered three or four common genotypes. As our knowledge of cystic fibrosis has increased, it has become clear that there are many different CF-causing mutations and not all of these are on the most recent standard test as they are very rare. So, we know that there are about 900 patients in the CF registry (out of just over 10,000) where the genotype record is missing for one or both genes (entered as ? or ??). In the past, knowing the exact genotype was not a high priority as treatment had nothing to do with knowing the genotype.

However, the picture changed with the appearance of ivacaftor (Kalydeco) which is prescribed for people who carry the G551D mutation. This is the first genotype-specific treatment and we anticipate that others will appear in the next few years that are targeted to other mutations. What’s more, it has become clear that ivacaftor (Kalydeco) can have beneficial effects on some people with a limited number of very rare mutations (so called non G551D gating mutations) and is already being used in the US for these very rare mutations. So it now becomes important that everyone wherever possible knows their genotype. Clearly, for the vast majority of people with CF this information is available and in their medical notes. We believe it is your right to know this information, and if you don’t we urge you to ask at your next clinic visit. If your doctor says the record in the registry says “?” or “??”, then we will cover the costs of the most up-to-date test that covers the rare genotypes. This is quite an expensive test so we are asking your doctor to double check with us and the CF Registry to make sure we don’t waste this opportunity.

In the pilot study, we found it was not always possible to identify the genotype even with the most modern test, because for technical reasons the test isn’t able to cover the entire gene. So our aim this year is that everyone with cystic fibrosis knows their genotype based on the most up-to-date test but recognise that for a small number of people this information will still remain unknown.

Why does this matter? Ivacaftor is the first of a new generation of treatments that help certain genotypes. However, even more exciting is the possibility to correct the mutation in the person’s own gene – so called genetic editing. For this, the precise genotype information is required. The approach works in the laboratory but as usual it will take some time before this lab-based work becomes reality.

You can find out about your genotype, or if you don't know it, learn how to get tested for it, at www.genotypematters.org 

Trials Week: Postcard from the European Clinical Trials Network conference in Barcelona

This week, Dr Janet Allen, Director of Research & Care at the Trust, has swopped frozen England for sunny Spain, and the European Clinical Trials Network conference as part of the Cystic Fibrosis Europe meeting. Here’s what’s been going on.

Every January, the research-active organisations across Europe that represent people with cystic fibrosis (so the Cystic Fibrosis Trust in the UK) come together to share experience and knowledge under the umbrella organisation known as Cystic Fibrosis Europe (CFE).  At the same time, we meet with colleagues in the European Clinical Trials Network or ECTN. This network was set up by CF physicians to coordinate clinical trials across selected centres in Europe. By working together, we can increase the number of trials running in Europe and attract international global companies to bring their clinical studies to Europe.  

It’s the end of January, so where better to have a meeting than in Barcelona, or more accurately a town just outside Barcelona:  to swap cloudy, windy, cold Bromley for blue skies and a slightly warmer environment! However, before anyone gets carried away, I can say we have been stuck in a stuffy room all day and the blue skies have not been seen as we debate methods to increase access to clinical trials, standardisation of protocols and better ways of getting protocols adopted through many different languages. The commitment and passion of the ECTN members to improving access to clinical trials across Europe is remarkable, especially when I realise that all the discussions are in English, even though for the vast majority, English is not their native language.

The ECTN has been running for a number of years and initially involved 25 centres across Europe; five of which are in the UK – Belfast, Birmingham, Royal Brompton, Leeds and Nottingham. The Cystic Fibrosis Trust provided financial support to help form the ECTN over the last three years.  

The ECTN has been very successful and there are now plans to expand the number of participating centres by 10. They have been tracking the number of trials and can show an increase over the last few years. In addition, the ECTN has been instrumental in assisting in trial design and doing feasibility studies. 

Trials Week: Clinical Trials: clearing up some common misconceptions…

As part of our week raising awareness about clinical trials in partnership with CF/Aware, we asked our very own Senior Research Manager, Dr Anoushka de Almeida-Carragher, to look at two of the key myths around trials.

Clinical trials have a profound impact on our lives, and there are a couple of myths associated with them that are worth clearing up.

Myth: “A clinical trial, which has shown a particular drug to be ineffective, is a failure
A completed clinical trial that has shown a particular drug to be ineffective should not necessarily be regarded as “unsuccessful”, and therefore a failure. 

Quite often, the drug just wasn’t effective enough or suitable for the purpose for which it was tried, under the conditions tested, and purely knowing this , is, in itself, very informative. In fact, the drug may actually be beneficial in other ways. A classic example is Viagra, which was initially tested as a treatment for angina but the trial results were disappointing. Pfizer was about to pull the plug on this “unsuccessful” trial, when it was reported that it had a surprising alternative function… Viagra is now one of the most commonly prescribed drugs, globally.

So, if a trial doesn’t show the results we want to see, it doesn’t mean it is a failure. In the world of medical research, acquiring knowledge, even from negative results, is invaluable. As Thomas Edison once said, “I have not failed; I’ve just found 10,000 ways that won’t work”.

Myth: “A Clinical trial testing a brand new drug is more important than one studying an existing drug.”
Of the two main types of clinical trial, one may test a new drug, while the other might look at a new combination of existing treatments, or test whether administering a known drug in a different way can increase its efficacy and/or reduce its side effects. When it comes to patients signing up for clinical trials, some patients are put off based on the type of trial being carried out. For instance, a clinical trial testing a shiny new drug may seem more appealing, purely for the possibility of a new life-changing intervention, whereas any other type of trial involving existing treatments would not have that air of novelty and anticipation. 

What we must not overlook is that trials of this type are also invaluable, especially those where comparisons are made between existing treatments, like the current TORPEDO trial. This trial compares the administration of two existing treatments of the Pseudomonas aeruginosa lung infection in people with cystic fibrosis, (ie it compares intravenous vs oral antibiotics). This is a good example of a trial which doesn’t involve a brand new drug but which, once completed, will give us the valuable info we need to decide which method of administration works better, and is more beneficial to the CF patient in the long run.

It is vital, therefore, not to discriminate between the different types of trial; all clinical trials, irrespective of the category they fall in to, are equally important.

You can see more about Trials Week by following the hashtag #trialsweek on Twitter.

Trials Week: The Cochrane Collaboration – Evidence and practice

It may surprise you to learn that what takes place in the lab or on the ward is only the tip of the iceberg. As part of our joint Clinical Trials Week, today we and our friends at cf/Aware are each offering an insight into the vital work that goes on elsewhere to inform and sometimes form the basis for, a clinical research project.

Here Nikki Jahnke, Managing Editor of Cochrane Cystic Fibrosis & Genetic Disorders Group, talks about the work of the Cochrane Review. 

There are thousands of clinical trials being run across the world, so how can your doctor keep up with all their findings and make sure you get the best treatment? It would mean reading hundreds of articles in so many journals that there wouldn’t be any time to see patients! This is why we work to include the findings from randomised controlled trials - the best type of trial design for establishing whether a treatment works or not – in systematic reviews.

Why are they called systematic reviews? Because we work systematically through databases and journals to make sure we capture all the available evidence for a particular topic, like ‘inhaled antibiotics for pulmonary exacerbations’. Once we identify the relevant trials, two independent authors record all the information they need from the trial reports and collate it in a single review. By combining data from a number of similar trials we can be more confident that our findings really are due to the effects of the treatment and not just chance. Our reviews also consider if there are factors that might affect the results of the trials. We make recommendations for doctors and other healthcare workers to use in daily practice, which can inform patients when discussing treatment options with their doctors.

If we don’t find any trials that help us answer our research question, we add a plan to our review describing how we think trials should be designed to provide us with the information we need. Many agencies ask for a systematic review to be undertaken before they agree to fund new trials. The review will show if the trial needs to be run, ie because there is either no or little evidence, and indicate how it should be designed. An example of this is the review looking at antibiotic strategies to eradicate infection with Pseudomonas aeruginosa in people with cystic fibrosis. Our original review found some trials, but the findings were not conclusive. So we recommended that a new trial should be run with more people. The TORPEDO trial is now underway and when it is finished we will be able to update our review with the results.

Finally, how do we decide on what questions to ask and which topics to investigate? For this we rely partly on our volunteer authors (doctors and other healthcare workers), but we also ask people who have CF to tell us what questions they want answered. This is where you can really get involved in driving research that will directly affect you. Take a look at the 75 CF reviews we have published so far and let us know what we should look at next.

Visit cf/Aware's Facebook page this afternoon to hear from Rebecca Cosgriff, Registry Lead at the Cystic Fibrosis Trust, about the work of the UK CF Registry.