The thousand aspects of Collagen VI research. It proved to be an informative and highly interdisciplinary day, in which updates on the progress of scientific research were accompanied by valuable information on the significance of setting up a patients’ association within UILDM.
In his opening speech, Dr. Luciano Merlini reminded us that research, no matter how rigorously and diligently it is conducted, is not infallible and often leads to erroneous conclusions. But it is at this point that the perseverance and curiosity of researchers step in, and even failures can turn into great discoveries. This is the case with cyclosporine A, initially used as an immunosuppressant to prevent rejection of healthy portions of muscle in patients with Duchenne Muscular Dystrophy. It was only later realised that the transplanted muscle cells were not able to take root and benefit the muscle, but it was cyclosporin A that was mainly responsible for the observed improvements. It is now known that cyclosporine A not only lowers the immune defences, but is also able to prevent the mitochondria from sending alarm signals to the cell, which would result in the initiation of the programme of controlled self-destruction called apoptosis. After an exhaustive explanation of how cyclosporin A works, Prof. Paolo Bernardi updated us on the progress of his studies on NIM811 and Debio025. These two molecules lack immunosuppressive activity, which would be dangerous because it would increase the risk of infection in Bethlem and Ullrich patients treated for long periods of time. At the same time, they are more effective than cyclosporine itself in acting on the mitochondria to prevent the onset of apoptosis, an excessively frequent event in patients’ muscles. Both of these molecules have already been successfully tested on model animals for Bethlem myopathy and Ullrich dystrophy, i.e. the mice and zebrafish that do not produce Collagen VI. As already anticipated in the pages of this site, Debiopharm recently announced in the press that Debio025 will be made available for the treatment of muscular diseases, so we are following the evolution of the events with a view to launching a clinical trial possibly within a year.
A large number of damaged mitochondria must be present in the cell at the same time in order to trigger a sufficiently strong alarm to induce the initiation of apoptosis. In the absence of Collagen VI, an important impetus for apoptosis derives from the fact that muscle cells are unable to break down damaged mitochondria, because the system dedicated to the self-breakdown of damaged or no longer needed parts, i.e. autophagy, is blocked. Prof. Paolo Bonaldo’s talk provided us with a comprehensive overview of Collagen VI research, in which he has been actively involved since the beginning of his career, with particular reference to aspects relating to the modulation of autophagy for therapeutic purposes. Data on the activation of autophagy and the improvement of certain parameters indicative of muscle function in trial participants were briefly shown, and all these data are collected in a paper that is currently being evaluated by a journal for publication. This event will confirm its value in the eyes of the international scientific community, legitimising the continuation of this line of studies. The next step could be the entry into the clinic of spermidine, a molecule naturally contained in the food already mentioned at the previous meeting. The effectiveness of spermidine is demonstrated by studies on mice lacking Collagen VI collected in an article recently published online. Dr. Martina Chrisam, a doctoral student in Prof. Bonaldo’s laboratory who conducted this study, briefly discussed the possible implications: new studies are currently being planned to identify the best method for introducing spermidine in the treatment of Bethlem myopathy and Ullrich dystrophy, either through food containing it or possible pharmaceutical preparations, alone or in combination with other molecules that activate autophagy, such as resveratrol, the famous antioxidant contained in red wine. At present, it is not possible to make a precise time prediction, as there are still many studies to be completed, but we hope that spermidine therapy may also materialise in the near future.
The researchers present at the previous meeting were joined by Dr Patrizia Sabatelli, a collaborator of Prof. Merlini endowed with a high degree of scientific fervour, who outlined in a few words her very recent work aimed at identifying the role of Collagen VI in tendons, structures composed almost exclusively of extracellular matrix anchoring muscles to bones. All the matrix components, interacting with each other, produce one continuous structure that supports and sustains the cells. In order to function adequately, this structure must have a certain elasticity, which decreases in the absence of Collagen VI. Prof. Bonaldo provided us with some information on this, presenting part of a paper conducted in his laboratory and published in 2014, in which the mechanical properties of muscle in the absence of Collagen VI were studied. We are now waiting to see what conclusions this new study, whose focus is on tendons, will draw. Certainly this is ‘basic’ work, more remote from clinical application, but no less important: a deep understanding of how Collagen VI works is the foundation on which new therapies can be designed and developed.
Dr. Mariada Perrone, an anaesthetist and pain therapist, briefed us on respiratory insufficiency by presenting a case in which increased intake of lipids enabled recovery of respiratory function in a severely impaired Ullrich patient. This procedure was developed following extensive research into the patient’s pathology, predicting that lipids would provide an immediate source of energy more easily exploitable by the respiratory muscle diaphragm. Although a case-by-case evaluation is necessary, this strategy should certainly be taken into account. Another topic of general discussion was the issue of exercise: for Bethlem and Ullrich patients, can it be beneficial? The question is a delicate one; research conducted in Prof. Bonaldo’s laboratory tells us that intense and prolonged exercise severely worsens the state of the muscles of mice that do not produce Collagen VI. However, many patients benefit from moderate physical activity and physiotherapy exercises. There is no contradiction between these two issues: keeping a muscle in exercise is important to prevent disuse from worsening it, thus leading to atrophy, but it is imperative not to overdo it and avoid fatigue as this would result in damage that would be difficult to repair.
This day was complemented by the contribution of Dr. Anna Ambrosini, Head of the Research Programmes Area of Telethon’s Scientific Directorate, who gave an overview of Telethon’s commitment to promoting scientific research dedicated to muscular dystrophies. First of all, she illustrated the various types of studies conducted in Telethon-funded laboratories, which carry out research into the mechanisms underlying neuromuscular diseases or work on the development of new therapeutic approaches in animal or cellular models.
Dr. Ambrosini then described in more detail the results of Telethon’s investment on the clinical neuromuscular front. This initiative stems from the cooperation between Telethon and UILDM, leading to the launch in 2001 of a public project dedicated exclusively to clinical research on the quality of life of people with a neuromuscular disorder. The proceeds of the call for proposals are the fruit of the fundraising campaign conducted every year by UILDM together with Telethon during the Telethon TV Marathon. Anna Ambrosini pointed out that, over the years, this investment has allowed a network of clinical centres in Italy to grow, enabling them to collaborate on multicentre studies lasting two or three years. This is how it has been possible to achieve encouraging results, such as ensuring the diagnosis of many less widespread and less known neuromuscular diseases, collecting valuable information on the evolution of the various pathologies, the so-called natural history, intervening with the means currently available to slow down the progression or reduce symptoms and complications, and improving the standard of care. It is precisely the dissemination of these care management guidelines that has changed the condition and quality of life of patients with neuromuscular diseases in Italy in recent years. These activities have also prepared clinics for new therapeutic trials and placed Italian clinical centres on the international scene.
In parallel, concrete help for research comes from Telethon’s commitment to setting up and managing patient registers. The issue of registers is both delicate and very important: Dr. Ambrosini provided us with an overview of the types of registers and how they work; these must at the same time guarantee the privacy of patients and the protection of sensitive data, allowing aggregated and anonymised data to be shared with researchers who need them to conduct research projects or clinical trials. It is important that the registers be supplemented with very detailed information on the genetic diagnosis and clinical condition of the registered subjects, also with the help of competent physicians, and that they be maintained over time and properly managed. With a view to initiating new clinical trials, it is advisable for the registers to be ready and as complete as possible so as to speed up the identification of those patients who are eligible to participate.
As regards patients with Bethlem and Ullrich myopathy, the reference register already exists and is known as the Congenital Muscular Dystrophies (CMD) register. It is currently a database compiled by clinicians in the Italian network and is mainly used for research purposes. More information can be found at www.registronmd.it on the CMD registry page. It is now being considered to convert this database into a full-scale register that patients can also access by direct registration.
Also on the subject of registers, Anna Ambrosini illustrated the important role that UILDM has played in creating the Registry Association, the legal authority representing the patients’ data, and gave her views on how important it is to have a critical mass within UILDM in order to work as a group and not to dissipate energy.
The website of the col6.it group is being enriched with content and Dr Chrisam, who is editing some of the texts, described the structure that the ‘Research and Publications’ section will have. It will consist of five paragraphs, which will describe the structure and genetics of Collagen VI, the model organisms essential for conducting research, the role of Collagen VI in tissues other than muscle, and the studies that have provided insights into therapies for Bethlem myopathy and Ullrich dystrophy. Suggestions for further topics are of course welcome.