Recently we talked about stem cell therapies, which, although radical and risky, are proving to be very effective and can stop and even reverse some of the most common symptoms in patients with severe forms of multiple sclerosis; a condition which many people had proved incurable.
Dr. Paolo Muraro, the Italian neurologist who directs the Neuroimmunology group at the Center for Neuroscience in the Brain Sciences Division, Department of Medicine at Imperial College London, has kindly offered to answer some of my questions.
Dr. Muraro has an exceptional curriculum vitae: he graduated in medicine from the University of Rome “La Sapienza”, he has done his training in Neurology and Clinical Neuroimmunology both in Italy and in the United States, where he worked first as a Senior Research Fellow at the National Institute of Neurological Disorders and Stroke and also as a Neurologist at the National Institute of Health, Bethesda, Maryland. Paolo Muraro is also an honorary consultant neurologist at Imperial College Healthcare NHS Trust and is a member of the UK Multiple Sclerosis Society, as well as the Scientific Committee of the Italian Multiple Sclerosis Foundation (FISM).
His research program aims to understand and develop effective therapies for inflammatory neurological diseases, in particular multiple sclerosis (MS). At this time his research aims particularly to clarify the mechanisms of immunomodulatory treatments and hematopoietic stem cell transplantation in MS. He has published more than 70 peer-reviewed articles in numerous international scientific journals, as well as a number of book chapters, editorial comments and numerous interviews. His research program is funded by the Medical Research Council, the Multiple Sclerosis Society, the UK Stem Cell Foundation, the Wellcome Trust, and the Italian Multiple Sclerosis Society (AISM). It is a great honour for me to be able to ask him some questions.
1. Dear Dr. Muraro, first of all thank you so much for agreeing to this short interview. Let me start by asking what it is you do exactly; I know that you were planning an international study that should have involved 180 MS patients. What is this study? Tell us more about your research.
Hello Stefania. I will gladly respond to your questions. For the project that you mentioned, I had requested a loan from a British publicly traded organisation, which has unfortunately recently been refused. So, as it often happens in this path when you stumble and fall, now we have to start again by changing the research proposal according to the feedback we have received.
In short, this international study sought to test autologous hematopoietic stem cells – HSCT ( usually derived from bone marrow, peripheral blood, or umbilical cord blood)against biological therapies which are highly effective. Although we do not currently have the funding at the moment, this study is not particularly expensive, however the project is currently stopped. The main problem is that this type of study, which does not have a patented treatment, are not funded by pharmaceutical companies. And so the only option is to seek funding from public bodies, which have relatively limited resources and are often extremely difficult to obtain grants from. We estimate that the study we proposed should cost £ 5m. This may seem like a large amount, but in the grand scheme of things it is not a big amount if you consider that a motorway mile costs an average of £ 30 million. So with just 1/6 of a mile we could have done a clinical trial for hematopoietic stem cell treatment on Multiple Sclerosis. Unfortunately, this funding has not yet been approved, so we just have to try again – naturally we are hoping to carry out this study very soon. When carrying out the proposed study, we will definitely be selective in choosing patients with relapsing remitting MS to be sure that there is an inflammatory target in the treatment.
In fact, the autologous hematopoietic stem cells are an anti-inflammatory treatment, not reparative or regenerative for the nervous system, and so they differ from types of treatments which would bring great hope for patients with multiple sclerosis in a more advanced progressive stage.
The hematopoietic transplant therefore, is an ultra powerful anti-inflammatory treatment and works effectively so far on highly inflammatory forms of the disease. It must be said that at present we cannot determine with certainty what will be the precise structural characteristics of the patient population of the study that we will carry out. We cannot of course yet speak of inclusion criteria, because we will have to completely redesign the study. Certainly though, this treatment will be reserved only for highly inflammatory forms of MS.
2. Recently I published an article on my website which took into account the results of the Canadian study which was conducted with an experimental stem cells transplantation in 24 patients. I know you met Mark Freedman, who co-led the research. What do you think of these results?
The results of the Canadian study, which I could personally view with Mark Freedman, are compelling from my point of view. If we focus on the effectiveness, in fact, we can say that this is probably the most powerful treatment for multiple sclerosis that has ever been shown in a scientific publication. The difficulty, however, arises from the fact that there were two cases of hepatic vein thrombosis, of which one in particular resulted in the death of the patient. It is therefore a treatment that carries a certain risk, in particular considering this type of toxicity.
All sub-types of autologous hematopoietic transplants use high-dose immunosuppressive therapy and, therefore, have risks related to immunosuppression and toxicity. This Canadian Protocol, in particular, used forms of immunosuppression and cytotoxicity which were particularly intense, called “myeloablative“. This is one of the most intense forms of immunosuppression of this type and therefore causes major toxicity. For this reason, and considering what I perceive from the environment in which these scientific studies are carried out, I do not think that at this time this exact transplant treatment is going to take root readily in other centres. There is indeed the doubt that even with extreme effectiveness reduction of the MS symptoms, this treatment has also a high toxicity which makes the protocol too risky. At the moment, therefore, the Canadian study comes, if you want, in contrast, to other specialized centres, including the Chicago research team of Dr. Richard K. Burt, for example, and the Swedish centres. They have already for a long time been using almost exclusively the non-myeloablative treatment, and thus a treatment a little softer and therefore less toxic. No one really knows what would be the ideal system to do the transplant, and this will be one of the studies that we must do in a trial, comparing a more intense regime with a lighter regime, in order to understand what is the best compromise in terms of both efficiency and security.
3. Recently I read an article in the Mail Online on a case outlining a miracle cure which surely you will have heard: it is the story of Eric Thomson (link on the bottom of the page), a man hit by a very aggressive form of MS, which was treated in Mexico with stem cells obtaining sensational results. I wanted to ask your medical opinion on this.
I have had several patients, not treated personally by me, but which have been referred to me by their GP or other neurologic colleagues, who have been or who are planning to go to Mexico to travel to these centers for stem cell treatment. The most important problem is that these centers have no transparency on what they do exactly and they do not interact with the scientific community in an open way. These are private centers that give a course of treatment which, in some cases, is not even completed. As you can imagine, a treatment from a private center that does not provide data on their protocol and does not publish their results at a scientific level, creates problems. The media, moreover, often sensationalise the results.
It must be said, though, that it is not new that patients who have malignant forms of multiple sclerosis and undergo a course of aggressive altering treatment, had also frankly surprising reactions to immunosuppression and hematopoietic transplantation. There are also cases reported in the scientific literature by the Swedish research groups, and in Italy by Prof. Mancardi and his team at Genoa. The difference is that in those cases we know all the details to understand what was the clinical evaluation of the patients and then their response to treatment is measured scientifically. In these media cases, however, they lack that kind of detail. In general, one can say that when there is the recovery of function due to a treatment, generally there is still a current or recent neurological damage. In fact, the article quoted that the patient was diagnosed in 2011, and has “only” five years of disease history, therefore relatively recent.
His improvement, or rather his response to immunosuppressive treatment also at the functional level, is therefore plausible for what was probably exaggerated by the media. What causes confusion, in fact, is how the media report the news. If is published an article about a man in a wheelchair who takes a miraculous treatment and is able to walk again, a patient who has been in a wheelchair for 20 years with a disability unfortunately consolidated by a damage to the nerve cells, reading this article may think that he/she can have the same kind of benefit. This creates false hopes which is very harmful to the people who nurture them. It is a a very sensitive subject and certain media unfortunately do not understand the need for moderation and accuracy in reporting such stories.
4. What will be the future developments and how much research is there to do before the treatment is available for all patients?
Future developments of the research will be, first of all, a randomized controlled clinical trial transplant with hematopoietic stem cells compared with highly active approved therapies such as natalizumab (Tysabri), Ocrelizumab and Alemtuzumab (Lemtrada). A possible future study could also compare the different types of transplantations, myeloablative and non-myeloablative, to observe the efficacy and safety. If the autologous transplantation shows effectiveness and safety for the inflammatory relapsing remitting multiple sclerosis, we could then also try to extend the study to progressive forms of MS that still have an inflammatory component.
We will need, then, a few more years of work. Unfortunately, the current lack of funds which I have already mentioned, slows the research. For a comparison, the clinical trial for Ocrelizumab was sponsored by a pharmaceutical company who spent 600 million dollars, while we were not able to obtain 7. It is clear that we will not be sponsored by a pharmaceutical company, and so the timescales for our research are much longer, precisely because of the limited funds. However, we continue to work with the funding from public institutions and charitable organizations, including the Italian Multiple Sclerosis Foundation (FISM) and the UK Multiple Sclerosis Society“.
To learn more about Dr. Paolo Muraro and his many publications:
If you want to read the story of Eric Thomson here’s the link:
We will return to this article soon in another post because I was able to contact Eric Thomson a few days ago. See you soon!