Musculoskeletal affections: The journey from research to clinic

Musculoskeletal affections: The journey from research to clinic
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Professor Dr Martin Flück, of the Laboratory for Muscle Plasticity, discusses the process of translating fundamental research into clinical applications for musculoskeletal affections.

The Laboratory for Muscle Plasticity at Balgrist University Hospital in Zurich, Switzerland, investigates the molecular and cellular mechanisms of clinical muscle plasticity, and towards this end carries out clinical trials on the biological relationships between muscle and clinical endpoints of musculoskeletal disease from molecule to movement – the ultimate aim being to improve current treatments for musculoskeletal affections.

Speaking to Health Europa, the laboratory’s director, Professor Dr Martin Flück, discusses its efforts to translate fundamental research into clinical applications.

What would you say are the biggest challenges in translating fundamental research into the clinic, and how would you like to see the European regulatory landscape change in order to better support this?

It is evident that the musculoskeletal system is a crucial component for bodily health. Musculoskeletal functioning is critical for cardiovascular health, and control of posture and movement. Inactivity-related muscle deconditioning is associated with metabolic disorders and accepted as the largest public health problem of the 21st Century. As such, more needs to be done to understand the metabolic requirements to counteract musculoskeletal deteriorations with individual therapies.

There is also a challenge in the fact that those patients who receive many interventions, aside surgical repair and physiotherapy, such as, for instance, those involved in tendon repair, can take months to fully recover. As such, there is a need to increase awareness about this and, moreover, to highlight the issue that many hospitals in Europe do not yet have the ability to fully invest in translating new therapies as it involves a truly interdisciplinary approach which is, unfortunately, not economically viable for them.

In addition, a considerable problem in translating scientific achievements relates to the nature of control which, of course, is necessary to test the tissue tolerance and longevity of implants. Here, there have been challenges involved in accelerating developments. We are aware that some implants don’t work, of course, but for others it could potentially take years to properly understand how they react to the body. This inhabits innovative approaches for implants, particularly biologic implants such as stem cells, which, while their efficacy has been clearly demonstrated, are not currently being utilised in the way which would fully realise their potential due to problems financing the necessary trials.

Are there, then, additional challenges when it comes to gene therapies? How would you like to see fundamental research and development into musculoskeletal medicine being better funded?

There is quite a lot of data on the potential benefits of, for instance, stem cells. However, there is a sense that some of those working in this field have promised a little too much; rapid progress has been promised by many, but we are yet to see this. That is, at least in part, due to them neglecting the point that stem cells used in therapies have to be administered in relatively small doses, which can take quite a long time. As such, this tends to be something that does not get utilised in a clinical approach as it becomes expensive and hands over responsibility, for instance, to the patient to administer individual doses of the medication. The same is true for gene therapies.

We need to look at the long-term efficiencies from the beginning, and it is crucial that these interventions and their potential therapeutic effects remain connected to reality. Medical professionals will, and rightly so, ask how long it will take for the treatments to work, and they need to have an answer.

That is a big challenge at the moment, and so it is clear we need a fundamental change in how we work. However, it is not yet clear how this could be achieved (or even instigated). Perhaps an initiative in Europe designed to develop disruptive ideas which are being used in bio-hacking, for instance, or in some animal experiments. We need a fundamental change because we need to be able to measure things, we need to change the rules governing this area, to allow incentives, and we need to change how we evaluate the efficiency of a treatment. This final point is particularly important, not least because this can be used to help save resources in the long term, but also to provide more concrete answers on how long a treatment will take from a biological point of view and thus we can see whether we are on the right track to empower the patient with efficient treatments.

Investing in research of this type, which does not necessarily have to be more expensive, could help us to develop treatments which can be used in a patient’s home, independently or with the proper supervision and control, as is for instance the established routine for the diabetic patient injecting insulin.

What disruptive technologies and methods are you utilising, and how you are developing them?

Just a short time ago we have had a publication accepted which described a new gene therapeutic approach to improve muscle regeneration after Achilles tendon rupture. In this experiment we injected a gene for a molecular anchor of muscle fibre growth during repair of experimentally transected Achilles tendon. Within our research into this we have seen very promising molecular signatures that the muscle recovers faster, and we want to build on that work. We have been working on large animal models here, introducing stem cells from the same animal, and we have demonstrated that the degeneration of muscle mass can essentially be stopped.

This nevertheless entails the use of multiple injections, which may mean there are hurdles to translating this to the clinic, but, given that this new approach can result in an animal being able to walk fully again without limping, we want to try to push this forward.

How important is it to keep the patient at the heart of research efforts which are geared towards clinical applications? How do you achieve this in your own work?

Our facility is located very close to a hospital, which has a lot of advantages for us. Indeed, this means that we are close to very skilled surgeons who are able to provide us with information and knowledge on particular syndromes, and that can enable us to formulate our questions around what is actually needed.

However, there seems to be a lack of communication in some areas. For instance, successful approaches have been developed to prevent muscle loss with tendon rupture within the rotator cuff which stabilises the shoulder; and yet they are not being fully utilised in the clinical setting. Here, we know that medication which worked was, for some reason, stopped for reglementary causes, and so we now need to establish fundamental research into this so that we can properly understand why this happened, as well as why the therapy actually worked, although only to an incomplete extent. These medications are readily available, and yet regulatory recommendations don’t allow this, and we need to find out why.

Being located close to a hospital also means that we can gain access to patient data, for consented clinical trials, which enables us to conduct efficient evaluations in terms of numbers. Indeed, we have recently concluded a clinical study which has identified potential biomarkers that should allow us to implement practical changes to several existing interventions. Of course, we still have to test this approach, but thus far the results are encouraging.

It should also be highlighted that the hospital’s surgeons are also incredibly helpful when it comes to the animal work, and that they also bring their students to the table and, together, they can often offer new and different technical approaches which help us to develop our work in sometimes unforeseen ways.

Of course, there is also a financial aspect attached to this, in that they help us to establish a greater level of trust in the approaches we develop and, as such, this can help to secure investment into disruptive applications, some of which might require long-term financing.

However, there is also a sense that some surgeons remain reluctant to use very novel methodologies if they feel they are too far away from applications, which is not the case in areas applying a new brand of medication termed biologicals, for instance in the USA. Thus, there is perhaps the need for a more progressive approach to be taken in Europe moving forwards, and working closely with hospitals and their teams can certainly help here.

How important is industry collaboration in your work?

It is very important, and, in a general sense, it works very well, though the level of success can depend on the area. For instance, industry collaboration works very well in areas such as imaging, where associated industries are quite heavily involved, to quantify muscle composition, for instance, with non-invasive means, which would also be compatible with other approaches directed to monitor implants.

When it comes to the biology side of our work, however, the scene is a little different. That is, while initially there was quite a lot of interest on the part of industry, they began to feel that this area was not open enough to different viewpoints, and so this interest began to wane.

On the physiological side, there have been industry activities, such as the development of new drugs by pharmaceutical companies such as Novartis. However, their specificity means that they also have quite significant side effects, which means that, currently at least, they can only be used in a very small window of application. This can also mean that companies are, for the time being, less willing to collaborate.

We hope that the gene therapies industry will be interested in working with us in the future. However, these experiments are relatively expensive and so typically require a collaborative relationship with foundations – such as the French Dystrophy Association, which has the capacity to generate those tools with us – rather than an industrial approach.

How will your own research efforts continue to focus on the translation of fundamental research results moving forward?

In recent research we have been able to identify potential biomarkers for the prediction of rehabilitative improvements with post-surgery tendon reattachment, and we are set to publish papers describing the potential of these biomarkers. As we move forwards, we hope to be able to develop that further.

We also hope to further explore the relationship between the musculoskeletal system and cardiovascular rehabilitation. We know that muscle health is crucial here, and we want to gain a better understanding of how and why. We have recently had a paper accepted for publication in this area, which outlines how we have defined a genetic signature that is able to predict what people may best respond to in terms of training, and this is just a first step in the work we hope to conduct in the future.

I am also looking to secure further funding for research into gene (and potentially stem cell) therapies, where I hope to specifically develop a new/different approach to fully allow the regrowth of atrophic muscle by multiple injections in a given surgical timeframe relevant to the disease.

An interest group which recently held its first meeting is also enabling us to pull together a lot of expertise on the kind of problems being faced in clinics, both in terms of specifics but also in terms of the impact that ageing has on the individual. We hope that this will help to form the basis of clinical criteria for long-term treatment, as well as perhaps a shift towards effective ways of treating a much broader range of conditions and diseases.

When it comes to research funding, we have thus far been unsuccessful in winning finances from the European Commission via the framework programmes. However, we do hope to be able to submit proposals to Horizon Europe for gene therapies and stem cell therapy – which could become a crucial addition to future diagnostics.

The awareness of the importance of the muscle system is growing across disciplines, and so I am incredibly positive when it comes to what the future holds.

Professor Dr Martin Flück
Laboratory for Muscle Plasticity
University of Balgrist
+41443863791
mflueck@research.balgrist.ch

Please note, this article will appear in issue 9 of Health Europa Quarterly, which is available to read now.

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