In Research
Subscribe to this blog
Find out when new entries are posted the instant they are published on Action Duchenne via RSS.
Disclaimer
The Action Duchenne website aims to offer a unique forum for sharing information and ideas in the search for a cure and better medical care for Duchenne and Becker and will at all times attempt to ensure postings are accurate, scientifically peer reviewed and not offensive to individuals. Action Duchenne, however, cannot take responsibility for personal opinions, information and the content of links to other websites. It is essential that you always contact your clinician or GP before taking any course of medication, therapy or supplement.
Stem cells and muscular dystrophy
Every few weeks or so, there is a report of a new stem cell that will cure a whole range of diseases. The more responsible of these reports include a statement that it will be some years before any actual therapies are available. It should also be pointed out that development of a practical therapy within the foreseeable future is far more likely in some tissues than in others. The reasons for thinking this are discussed below.
The first problem lies in making sure that the stem cells turn into the cell type in which we are interested: in the case of DMD we want them to turn into the cells which construct and repair skeletal muscle. These are called myoblasts. Myoblasts that can enter a resting state, so as to be available for repairing our muscles throughout life, are called satellite cells and these do seem to be a sort of stem cell that is largely restricted to making muscle. If we start with stem cells that can make a wider range of tissues - any tissue in the case of embryonic stem cells – then we need to be sure that we can turn them into muscle stem cells very efficiently and that none of them remains in an ‘undecided’ state where it might produce a cancer. It is this second point that is difficult – it only takes one cell to cause a tumour.
We can also learn a lot from the tissues in which stem cells work well. In fact stem cells capable of replacing the bone-marrow cells that make all of our blood cells have been in use for many years. More recently skin stem cells have been used to replace skin in severe burns patients and earlier this year, a patient’s own genetically modified skin stem cells were used to correct a genetic disease of the skin. In both cases, the tissue being treated, is one in which stem cells are in constant use for its day-to-day maintenance and so have in place mechanisms for incorporating these stem cells without any need for special tricks on our part. Unfortunately, most other tissues use stem cells far more rarely or possibly not at all once we have stopped growing. Muscle appears to be one of these tissues in which the stem cell population is rarely called into serious action. The satellite cells in muscle seem capable of doing quite a good repair job but it is not perfect and each time they are called into action the repair is not quite as good as the last time. These defects build up over time and the muscle gradually loses its ability to work efficiently. However, if we could replace the satellite cells of a DMD boy with cells carrying a good copy of the dystrophin gene, then the muscle they repaired would not break down and need repairing so often.
Perhaps the big problem with using stem cells on muscle is that we cannot deliver them very accurately to the places in which they are needed. The stem cells of the bone marrow work well because they pass through the blood and home to the right places. Skin stem cells can be delivered fairly easily to the parts of the body surface where they are needed. When we transplant myoblasts they do not move more than a few millimetres from the site of injection and so are very difficult to deliver to even a proportion of the body musculature. What we need is a muscle stem cell that we can put into the blood and that can get out into the regions of muscle where it is needed for repair. Up to now the only stem cells that have been demonstrated to be capable of doing this at all efficiently are the Mesoangioblasts being studied by Cossu’s group in Milan. These may be the same as some other muscle stem cells but they are the only ones that have been demonstrated to be distributed via the blood. The fact that they can do this is more important than whether or not they are stem cells. There remain some questions about mesoangioblasts: in particular they do not seem to replace the satellite cells in the muscle and so would have a limited period of effectiveness. Also, their behaviour is different in the two species in which they have been studied. In the mouse they mostly enter the muscles immediately downstream in the artery into which they were injected whereas in the dog they seem to escape this local trapping and become distributed more generally around the body. How they will behave in man, remains to be seen. There are advantages and disadvantages to each pattern of behaviour. If they are trapped in the muscle immediately downstream of the injection site, it means that they would have to be administered separately to all of the main muscle groups of the body. If they distribute more broadly, then we may worry about where they get to apart from the muscles and whether they could do any damage if they lodged, for instance, in the brain or the kidneys.
As an overall message, matter of whether this, that, or the other cell is a stem cell, is less important than whether the tissue we are targeting has in place the mechanisms to incorporate them properly and efficiently into its structure. More effort is need on the development of this aspect of stem cell therapies.
7 Comments
-
- Carl Tilson (Living with DMD)
- December 11th 2007
- 13:01pm
I think we have to start on humans now because eventually we will need to know - sooner rather than later! Safety is important I agree but there will always be risks you have to take, learn by your mistakes and then you gain experience. Also I think there should be a case where an adult 18+ can make a decision where if he wants to take part and risk himself in a clinical trial for stem cells he's entitled to and can sign a disclaimer, so then there is no case for compensation issues. While we are waiting for treatments the more we deteriorate!"I'd rather die trying.. Than die without trying!"
-
Hello Terry, Do you agree with the following quote?
-
Sorry accident pressed button !! So to continue: Terry do you agree withe the following quote: Prof Dominic Wells, of Imperial College London, who is developing gene therapies to combat muscular dystrophy, said: "There is a huge amount of paperwork and that is very difficult to match with the pace of scientific change. "Each time we find a new way of doing something, we have to go through a complex process of getting it approved by the Home Office. This makes us non-competitive." He also goes onto complain that the legislation protecting Rats and mice ie. temperature control hinders progress! I consider the best way to get around this problem would be to forget the mice/rats and lets get out of the labs and into human trials, it needs someone somewhere to be brave after all this is a Terminal Disease with no hope of survival ...we as parents,people living with DMD and of course the Scientists and clinicians must start to adopt the 'can do' attitude to research and trials, I have been hearing 'we must do more work' for years now and my son has not got any better.I would be interested to hear your views on this and how you would like to see things change to speed up the route to treatments. Kindest Regards Paul
-
I agree with Prof Dominic Wells views, a lot of paperwork and lots of work to do - too much workload! I think it should be focused on the actual treatment working or trial their testing rather than paperwork - actions speak louder than words. As Paul says his son is not getting any better, either am I and everyone else with DMD - years and years of research after research, I think it's time to forget the mice and move on to humans like Paul said. The more we wait, the more ill we become, the more people we lose its horrific! It will always be a risk of life or death, everything is thats life but if we don't we'll never know. Please post your views. Thank you for your time, Carl
-
I agree with Paul - its all very well showing therapies such as stem cells are beneficial in mice but it doesn't help those living with DMD, many of whom would be willing to participate in such trials like yesterday! Terry you say the biggest barrier to developing a stem cell therapy in humans is the lack of an effective systemic delivery method, I think work on this needs to be made a priority particularly as several types of suitable stem cells have already been identified. In the meantime clinical trials could be performed in humans by injecting stem cells into individual muscles such as the diaphragm. I for one would take at least being able to breathe unaided without a ventilator for a start! Obviously I realise we can't just throw caution to the wind as the safety of individuals participating in trials needs to be ensured but unless stem cells are tried in humans how we will ever know. What is your view on this? Thanks and best wishes, Mark
-
I apologize for not having responded sooner. I had though I had written a comment before Christmas but it seems not to have been received. First, I do agree with Dominic Wells on the extraordinary difficulty of conducting research in the UK. Unfortunately, this domination by bureaucracy over practical experimentation seems to have been one of the UK's more successful exports and is becoming an impediment to research here too. If it operated to the benefit of the animals, it would be more defensible but as it operated in the UK it just slows things down while someone takes 3 months to approve a minor alteration to an experimental schedule. It is also the case that many of us would like to move to human trials more quickly. The animal work is necessary to ensure that a particular idea actually works at all at non-toxic doses, as for instance in the case of the exon-skipping work that currently looks most promising. There is a limit, however, to the amount of useful information we can get from experiments in mice and dogs and in the case of the agents that produce exon-skipping and the mesoangioblast stem cells of the Italian group, we do need to actually take the risks of trying them out on human volunteers. This must be done cautiously, both because we do not want anyone to suffer and because a really bad outcome, like a death, would shut down the entire research program for years and prevent the development of what might still be a potential therapy. My personal view is that we need to become less averse to risk if we are to make progress but we do need to proceed in a sensibly thoughtful fashion and be less hidebound by the standard procedures - perhaps this view will become less unfashionable in the next few years as we accommodate to it. In the case of exon-skipping we will in effect conduct our tests of toxicity studies on the volunteers and there is no other sensible way of doing this. Much the same is true of the mesoangioblast strategy - the only way in which we will find out if it is dangerous to inject these cells into man is to try them - but very cautiously. Unfortunately, the first local injections will not be into inaccessible muscles like the diaphragm because they will want to take biopsies to see how they are behaving. If all went well with local injections, then perhaps they might try to target the diaphragm by injecting into the blood vessels that supply this muscle.
-
Just a thought, you say targeting the diaphram would be difficult, because biopsies would be needed etc.. well what about intercostal muscles between the ribs, i thought they help with breathing too, better access to those is available.