Helping stem cells overcome degenerative muscle disease

The ENDOSTEM project has made noteworthy advances in the use of endogenous stem cells to tackle degenerative muscle disease. Although the team has faced various difficulties, its findings lay the groundwork for novel therapy strategies.

Muscular dystrophy (MD) is a type of degenerative muscle disease. One of its most known forms, Duchenne muscular dystrophy, affects 1 in every 3 500 boys worldwide according to the FP7-funded scientist partnership EuroStemCell. Affected patients progressively see their muscle mass and function decrease and eventually lose the ability to walk. There is no cure, and the available treatments are only able to slow down the degeneration process.

The biological mechanisms behind this disease resemble a tug-of-war: normally when a muscle fibre is damaged, the stem cells it contains communicate through a chemical signal, change themselves into muscle fibre and create copies of themselves until the muscle is healed. But since muscular dystrophy inflicts constant damage to the muscles, the repair burden placed on these cells is so big that they get exhausted and eventually lose their ability to copy themselves. Degeneration overcomes regeneration, and damaged muscle fibres are replaced by fat cells and scar tissue.

Until recently most scientists thought that the best solution to MD lied in delivering healthy stem cells to muscles, so that they could generate new muscle fibres to replace the damaged ones. But for Dr. David Sassoon and his team, this solution is not efficient and too complex. Their project launched in 2010, ENDOSTEM (Activation of vasculature associated stem cells and muscle stem cells for the repair and maintenance of muscle tissue), aims to identify an agent capable of ‘boosting’ stem cells already present in muscle tissue for a more efficient tissue repair.

In this exclusive interview with the research*eu results magazine and a few months before the project’s end date, Dr. Sassoon discusses the project’s successes and the reasons why him and his team will not be able to reach all of ENDOSTEM’s objectives.

What was the main objective of ENDOSTEM?

The overall objective was to identify new therapies for muscular dystrophy and muscle degenerative diseases. The idea of ENDOSTEM was to figure out a way – instead of genetically altering the tissue through cornea or viral DNA transfer, or taking out stem cells or putting in stem cells – to mobilize or encourage the stem cells that are already there to actually do their job.

The project was based on the observation that there is a period of time during which the patients are sick but they don’t show much in terms of symptoms. It is known that during that time the regenerative mechanisms in young kids are highly activated and this capacity can keep up with the degenerative mechanisms.

By mobilizing the endogenous stem cells we thought we would be able to keep that regenerative capacity very high so that the stem cells are able to repair the tissue, thereby ensuring that the symptoms of the disease are held in check.

Your approach doesn’t involve extracting stem cells from the patient’s muscle tissues. How is this more effective?

The major problem with taking someone’s stem cells, repairing them and putting them back is that it is very complex. In this scenario the stem cells are considered as a medication, and as such they are submitted to very complex rules in terms of how they can be used. On the other hand putting in a more standard pharmacological medication such as a growth factor or saccharide – although it still has to go through the appropriate approval and trials – represents significantly less hurdles than using living cells. Moreover, you don’t have to suppress the immune system.

How did you come up with this idea?

Before the project started various groups and researchers had started talking about working together. When I looked at the landscape of what was actually going on, that is, the introduction of genetic material and/or engraftment of stem cells, I thought maybe there is a better approach. At that time the question of whether we could augment the endogenous regenerative capacity had not really been considered.

What would you say are the project’s main achievements?

One of the essential findings that emerged during the last five years was that information has a very positive effect on regeneration and that we can actually manipulate those signals to further augment regeneration. We also have become more aware that multiple progenitors are activated in the response entry and all these progenitors are talking to each other during the process of regeneration. But if the balance between different groups of progenitors is disrupted, then instead of rebuilding muscle tissue the process creates a fibrosis. We now know much more about the processes that lead to this, thanks to work from groups within the project.

So the project is set to meet all of its objectives?

Unfortunately not. With the crisis Europe went through the market took a massive hit, which created immense difficulties for some of the companies that we were dealing with – one of which eventually had to drop out in the middle of a very promising clinical trial. We found a replacement in an Italian company looking at epigenetic modifying drugs that augment the recruitment of muscle cells into the regenerative process, but bureaucratic issues with the Commission caused a lot of delays. Now we are in a situation where we cannot be granted a one-year extension – notably because of the launch of Horizon 2020 – and won’t be able to perform the last two clinical trials we had foreseen by the time the project ends.

So you won’t be able to pursue your research?

A significant amount of basic research has been accomplished, two clinical trials, pre-clinical work and we successfully identified an agent that increases the number of progenitor cells in muscle tissue, but key steps like trials on pigs won’t be completed in time, meaning that companies are likely to find it too risky to invest in our findings at this stage.

We could be applying for Horizon 2020, but we would have to identify a suitable call and this would cause delays while research keeps marching ahead. Of course I think some of the interactions will continue and obtaining the funds is achievable, but the clinical trials are never easy to do. You have to deal with local authorities, EC authorities, quality control, delivery, then of course you have to obtain the consent of patients. A project extension would have been the most viable solution for us.

You said you were able to identify an agent that augments the number of progenitor cells in muscle tissue, which was the project’s key deliverable. How advanced are you with testing this agent?

We have identified an agent called Cripto which was developed in Italy and tested in mice. It appears to be very promising in terms of amplifying the number of progenitor cells. The major obstacle was how to deliver this peptide to muscle tissue in a way that won’t trigger an immune response. We tested three approaches, and the next step was testing on large animals – pigs in this case. Unfortunately that’s part of the work we will not be able to do.

In light of your difficult experience, what are your hopes for Horizon 2020?

I think it will be really important for the EC to increase the level of flexibility in case of unforeseen events, which was one of the weaknesses of FP7 in my opinion. But there are some very positive things to say about EC funding: it helped us achieving numerous publications in high impact journals, providing the project with an important following outside the network. This also helped us bring young researchers together with established ones, and other collaborative projects are either foreseen or already ongoing.

What’s you next challenge?

The fundamental research is almost never completed. We still need to understand the nature is of the signals transmitted between progenitor cells, and another question that has become more important to me is why regeneration ultimately fails as part of the ageing process.

For more information, please visit:

ENDOSTEM
http://www.endostem.eu/