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Col6.it: with a view to a more extensive, eye-catching and multi-disciplinary profile

Summary of the fourth meeting of the col6.it Group, held on 12th November in the Centro Sociale Ricreativo e Culturale A. Montanari in Via di Saliceto, 3/21, 40128 Bologna

by Ilaria Gregorio & Martina Chrisam

The fourth meeting of patients, doctors and researchers in the col6.it Group was held on 12th November in the Centro Sociale Ricreativo e Culturale A. Montanari in Bologna and, as usual, it turned out to be a unique opportunity for discussion with regard to the variety of real-life situations in the context of

Photo 1 - Cecilia Sorpilli and Dr. Luciano Merlini
Photo 1 – Cecilia Sorpilli and Dr. Luciano Merlini

Collagen VI related myopathies. On this occasion, the scientific debate went beyond the usual confines of the topics most closely linked to the muscular aspects of these pathologies, and saw the participation of experts from various fields of study who gave talks not only on certain biomedical but also on the economic aspects of scientific research. In addition, we also had the opportunity to listen to representatives from UILDM and Telethon, who will offer invaluable assistance to enhance the profile of the Group. Now let’s take a look at the most significant events of the day.

Cecilia Sorpilli, the backbone of the Group and organiser of the event, begins by extending a warm welcome to the participants and gives a brief summary of the situation of the Group, which is constantly growing. Her introduction is followed by a speech given by Dr. Luciano Merlini, who provides us with a detailed explanation of the advantages and disadvantages involved in the Cyclosporine A therapy administered to patients affected by Bethlem Myopathy and Ullrich Congenital Muscular Dystrophy. While being extremely effective in remedying the defects of the energy-producing mitochondria in the muscle cells, this drug however has the by no means negligible disadvantage of considerably weakening the patient’s immune system.

The next person to speak is Prof. Paolo Bonaldo, a researcher who detains the merit of having produced a type of mouse with a deficit of Collagen VI. As illustrated in previous meetings, these animals represent an excellent model for the study of human pathologies deriving from a Collagen 6 deficit, because they mimic the muscular weakness afflicting both Bethlem and Ullrich patients. With the invaluable aid of this animal model, Prof. Bonaldo’s laboratory co-workers are engaged on various levels in the study of the effects of Collagen VI deficit not only on the skeletal muscle but also on other organs and tissues.

The young Ph.D. candidate, Ilaria Gregorio, illustrates part of the study undertaken by Matilde Cescon, a senior post-doctoral researcher in Prof. Bonaldo’s laboratory. This study sheds light on the importance of Collagen VI in maintaining the structure and function of the so-called “peripheral” nerves which, on reaching the skeletal muscle, co-ordinate its activity by conveying the nervous impulses from the brain.

Photo 2 - Prof. Paolo Bonaldo, Ilaria Gregorio
Photo 2 – Prof. Paolo Bonaldo, Ilaria Gregorio

 Matilde has discovered that in Collagen VI deficient mice these nerves are not endowed with the appropriate electrical isolation; this is due to flaws in the structure of the biological isolator, known as the myelin sheath, for which reason the transmission of nervous impulses is slowed down, thus producing a defect in the motor function, as well as in the sensitivity towards external stimuli such as cold and pain. Matilde is also involved in the study of the role of Collagen VI in the structures acting as interfaces between the peripheral nerves and the muscular fibres, namely the neuro-muscular junctions. In this case, too, Collagen VI deficient mice present structurally altered junctions, abnormally fragmented, which lack the power to ensure the correct transmission of nervous impulses to the muscle fibres, thus giving rise to problems in muscle contraction. Not only have these findings clarified the previously unknown role of Collagen VI in tissues that are different from muscular tissue, that is to say the peripheral nerve, but they provide useful insight as regards the effects of new types of therapy for Collagen VI related pathologies.

Ilaria also mentions another branch of research currently pursued in Prof. Bonaldo’s laboratory, namely the experiments conducted on the tropical fish Danio rerio (commonly known as the zebrafish), targeted towards the study of the role of Collagen VI during embryonic development. This study was initially undertaken by a young post-doctoral member of the laboratory, Valeria Trapani, who recently entrusted the task to the new Ph.D. candidate Valentina Tonelotto. The zebrafish offers the advantage of being totally transparent during the initial stages of embryonic development and, moreover, fertilization takes place in the external environment, for which reason these studies require no invasive procedures on the animals themselves. Valeria has been working on the task of producing, with the use of avant-garde technology, zebrafish devoid of Collagen VI and is now collaborating from her new location (Brisbane in Australia) with Valentina in Italy in order to gain a deeper understanding of what happens to these fish. Preliminary data would seem to indicate that even in fish the development of the skeletal muscle is severely compromised in the absence of Collagen VI.

Subsequently Dr. Andrea Vianello, a pneumologist in the Respiratory Physiopathology Unit in Padua

Photo 3 - Dr. Andrea Vianello
Photo 3 – Dr. Andrea Vianello

Hospital, gives an overview of the respiratory complications encountered by patients affected by muscular dystrophies, in particular Ullrich Congenital Muscular Dystrophy. Dr. Vianello illustrates the mechanisms leading to the onset of respiratory insufficiency which, in the case of dystrophy, is not caused by abnormalities in the lungs, but in the respiratory pump, that is to say, the structure formed by muscles, including the diaphragm, which, when in motion, allows air to enter the lungs. Then Dr. Vianello outlines the progress attained in recent years thanks to devices for non-invasive mechanical ventilation, which have enabled doctors to make enormous improvements in the life expectancy of patients affected by dystrophy with respiratory insufficiency, even in the most severe cases, such as in muscular spinal atrophy.

The next speaker to take the chair is Prof. Renzo Orsi, an economist from the University of Bologna, who illustrates the mechanisms whereby certain drugs prove to be particularly expensive. His talk is centred on the drug Sofosbuvir (marketed under the name of Sovaldi), a new drug used to treat hepatitis C. This

Photo 4 - Prof. Renzo Orsi
Photo 4 – Prof. Renzo Orsi

is a drug that is particularly effective in eradicating the hepatitis C virus, but the problem is that in the United States the cost of a four-week course of treatment amounts to 85 thousand dollars per patient, whereas in Italy the cost is approximately 30 thousand euros. It seems clear that, given the elevated number of patients affected by hepatitis C, our National Health Service – which is still among the best in the world – is not in a position to provide all patients with this treatment, with the result that most patients would have to pay out of their own pockets. The Sofosbuvir issue has given rise to heated discussions in and outside Italy, but why is it that it costs so much? Prof. Orsi explains that the high cost of drugs depends on the amount of money that has been invested during their development phase, which generally spans over 10 to 12 years. In the case of Sofosbuvir, the small pharmaceutical company that developed it, and Gilead, the multinational company that subsequently took it over, spent approximately 60 million dollars between the development of the molecule and the pre-clinical and clinical trials. The only way to recover the costs is to increase the selling price; however, this makes the drug inaccessible to many patients, with the risk of the drug remaining unsold. In some countries Gilead has given permission to other companies to produce the drug, although it is still patent-protected, thus promoting its consumption in India, where a course of treatment can be purchased for 400 dollars.

Then Dr. Massimo Pellegrini from the University of Modena and Reggio Emilia, who was in charge of the organisation of the clinical trial based on the low-protein diet carried out in 2011, illustrates the most important results, published in the scientific review Autophagy a few weeks ago. Dr. Pellegrini shows

Photo 5 - Dr. Massimo Pellegrini
Photo 5 – Dr. Massimo Pellegrini

how a low-protein diet, followed by 7 patients for one year, proved to be not only harmless, but also effective in reactivating autophagy, the system whereby the muscle cells set in motion a self-cleaning process and eliminate damaged components, a process which is deficient in muscles lacking in Collagen 6. Data show that this diet is conducive to a decrease in cell death and to an improvement in the function of the mitochondria, the organelles responsible for energy production in the cells, which seem to be altered in Bethlem e Ullrich patients. Dr. Pellegrini then goes on to describe the characteristics of different types of diet, not only of the low-protein diet, and explains which diets in particular can be exploited to reactivate autophagy, focusing mainly on foods containing greater quantities of spermidine, a substance which, in Collagen 6 deficient mice, has the power to reactivate autophagy and to produce a series of beneficial effects on muscles, including a lower cell death rate and an improvement in mitochondrial function.

Finally Leonardo Baldinu, President of UILDM (Italian Union for the Fight against Muscular Dystrophy) intervenes. He begins by congratulating Cecilia and all the other members of col6.it on having succeeded in forming a small, but active and compact group, constantly on the increase.

Photo 6 - Leonardo Baldinu
Photo 6 – Leonardo Baldinu

Leonardo also commends the Group on its efforts to organize on a regular basis these meetings, which are not only useful to the patients, but also to the doctors and researchers themselves, because they offer patients the opportunity to discover, understand and appreciate the people who are working and studying on their behalf. Pointing out that col6.it forms part of UILDM, Leonardo draws our attention to the various ways in which the group can actively participate in the community. Indeed, the condition of patients affected by muscular dystrophy in Italy can be hugely improved if we work continuously to improve barrier-free accessibility and to guarantee certain fundamental rights, including education up to University level, guarantee of employment and the attainment of as independent a life as possible. Only by defending these rights can we envisage a considerable improvement in patients’ living conditions, at the same time enabling them to contribute to the development of society.

After the lunch break, we are shown a video-message from Telethon. Anna Ambrosini, who is responsible for the Telethon Scientific Committee research programmes, sends us her greetings and assures all the members of the col6.it Group of her support, as well as of Telethon’s goodwill towards the doctors and researchers involved in the study of Collagen VI linked pathologies. Alessia Daturi, who is in charge of the Associazioni Amiche (Friendly Associations) network, namely those associations of patients that accompany Telethon in the battle against genetic disorders, takes over from Anna Ambrosini. Alessia assures us of her willingness to act as a link between patients and the communication team of the Telethon marathon. Then she goes on to explain that, for this purpose, the presence of voluntary spokespersons talking about their life and medical history, via the social or other media, would be indispensable. Alessia concludes her video-message with an invitation to attend the next Friendly Associations conference, to be held on 13th and 14th March in Riva del Garda, with the participation of over 180 associations together with researchers, who aim to inform patients of the progress made to date in the field of research.

At the end of the proceedings, there is a fruitful moment of discussion, during which patients have the possibility to ask doctors and researchers a series of questions: in this way, various topics are addressed, such as funding for research, future clinical trial projects, ways in which to enhance the profile of the Group, as well as other issues.

This meeting, like other previous meetings, proved to be an excellent opportunity for the exchange of information, advice, opinions and explanations. We are fully confident that we are moving in the right direction and that future meetings will prove to be more and more profitable and will further the growth and consolidation of the col6.it Group.

For the full meeting’s photo gallery  CLICK HERE

The fourth reunion of the Italian Collagen VI Group

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front Fourth meeting of italian Collagen VI Group
front Fourth meeting of italian Collagen VI Group

The fourth reunion of the Italian Collagen VI Group will be held on 12th November 2016 in Bologna at the “Centro Sociale Ricreativo e Culturale A. Montanari”.

The meeting is scheduled to begin at 10 a.m. During the course of the day a large number of medical researchers will be illustrating all the new discoveries in the various ongoing research projects, and participants will have the opportunity to watch a video message from Telethon. To conclude, those attending the meeting will have the opportunity to ask questions and exchange ideas and proposals with the rest of the group.

The programme is as follows:

Fourth meeting of italian Collagen VI Group
Fourth meeting of italian Collagen VI Group

Together in col6.it, because united we stand, divided we fall!

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Summary of the third reunion of the col6.it group of patients, doctors and researchers

18th June 2016 c/o Centro Sociale Ricreativo e Culturale A. Montanari, Via di Saliceto, 3/21, 40128 Bologna

The key word is “together” because the union of patients, doctors and researchers can really contribute to the creation of a new reality, in which patients’ quality of life and awareness of their condition can be definitely improved.
Cecilia Sorpilli, the soul and spirit of the col6.it group, opened the meeting by providing an update on the status of the group: the process of convergence with the UILDM association has now been completed and, thanks to the creation of the www.col6.it site and to Facebook, the profile of the group is gradually gaining more and more visibility. This is of vital importance, as it will enable other patients affected by Bethlem myopathy and Ullrich dystrophy to join our cause.
As on previous occasions, the topics discussed during the reunion ranged from issues concerning Collagen VI research to more specifically medical issues. In his introduction Prof. Paolo Bonaldo explained how researchers came to realise that Bethlem myopathy and Ullrich dystrophy were pathologies deriving from Collagen VI defects. Towards the end of the 1980s, when Prof. Bonaldo was a young researcher, his main concern was to investigate the composition of Collagen VI, and to gain knowledge of how the cells were able to produce and position it in the extra-cellular matrix. There was a total lack of data regarding the function of Collagen VI, nor was it generally considered that it could in some way be linked to human medical disorders. A key event, which represented a genuine turning point in this field of study, was the creation of a mouse, whose cells are unable to produce Collagen VI. It became immediately evident, both to Prof. Bonaldo and his colleagues of that period, that this mouse was subject to problems of a muscular nature and, through the studies conducted by geneticists and neuro-muscular clinicians, it was possible to verify that certain patients with similar muscular problems were deficient in Collagen VI. For the first time, doctors and researchers, together, succeeded in informing Bethlem patients as to the cause of their disorder: a deficit of Collagen VI. This discovery, published in 1996, was followed in 2001 by a further discovery that Ullrich dystrophy is also linked to a Collagen VI deficit. In these two decades, the Collagen VI deficient mice have enabled researchers to make gigantic progress towards their knowledge of the functions performed by this protein. The challenge facing them now is that of understanding the link between the alterations in the matrix, situated outside the cell, and the abnormalities observed within the cell: a reduced cleaning process (known as autophagy), and poor mitochondrial function (the mitochondria being responsible for the cell’s energy production). The scarcity of funding that afflicts Italian medical research makes the challenge even more difficult, but Prof. Bonaldo is fully determined and has every confidence in being able to find both the solutions and the necessary funding.
Prof. Bonaldo’s co-researchers then updated the assembly as regards the most recent developments in the field of Collagen VI research. Dr Silvia Castagnaro provided a brief overview of some of the analyses carried out in the context of the clinical trial based on the low-protein diet, the results of which are to be shortly published and will soon be divulged to the world scientific community. Dr Martina Chrisam illustrated the beneficial effects of spermidine on the muscular condition of mice with Collagen VI deficiency, together with a few recently published data. This study represents a starting point for the formulation of possible novel therapies for patients.
Prof. Luciano Merlini touched upon a topic that represents a sort of bridge between clinical practice and research: the difficulties associated with clinical trials for the testing of effective pharmaceutical products to cure rare disorders. In fact, past experience has taught us that it is very hard to convince the scientific community of the efficacy of a particular therapy on Bethlem and Ullrich patients, due to the fact that the number of suitable patients that can be assembled in one single trial is, generally speaking, decidedly low, given the rarity of these two pathologies. At this point, Prof. Marco Viceconti, who coordinates a research group responsible for “clinical trials in silico” at Sheffield University (GB), intervened. What do we mean by this? Silicon is the main component in computer chips; a “clinical trial in silico” is a computer-simulated clinical trial, in which the patients are virtual and, thanks to intricate mathematical calculations, the effects of a pharmaceutical product on these virtual patients can be predicted. These calculations, however, need to be based on real data, for which reason such a procedure should also include a real-life trial in which doctors and researchers are able to gather as many data as possible to enable Prof. Viceconti and his colleagues to formulate the “super equation”. This strategy, which combines clinical practice and data processing, is at present being applied in various sectors of biomedical research, and hopefully will prove useful in the near future also in the field of research on rare diseases, such as the disorders linked to a deficit of Collagen VI. Another aspect linked to Collagen VI research was outlined by Dr Patrizia Sabatelli, who has recently published two important works on the tendon alterations in mice devoid of Collagen VI and in cells isolated from the tendons of patients affected by a Collagen VI deficit. Tendons function as a link between bones and muscles, and the presence of a defect sheds light on our knowledge of why patients suffer from impaired functional movement. These studies not only demonstrate that the muscle is not the only tissue that needs to be kept under control, but they also lead us to consider tendons as a further objective to concentrate on in order to improve patients’ motility.
The medical team was represented by the contributions of Dr Andrea Fabiani, a lung specialist, and Dr Mariada Perrone, an anaesthetist. Dr Fabiani gave a detailed demonstration of the respiratory process, underlining the importance of the role of muscles during this process. Indeed, the diaphragm and the intercostal muscles are primarily involved in the expansion of the lungs, which enables the introduction of oxygenated air during inspiration and, in the subsequent process of expiration, allows the lungs to expel the air. These movements also favour the removal of pathogenic bacteria which can potentially be embedded inside the lungs and remain entrapped in the mucus. In the presence of reduced muscular function, expiration and also coughing are less effective and this increases the risk of contracting lung infections, because instead of being expelled towards the oral cavity, the bacteria remain in the lungs, where they are likely to proliferate and generate an infection. Dr Perrone’s contribution hinged on the more serious complications, mostly of a respiratory nature, to which patients with a Collagen VI deficit are exposed. The meaning of general anaesthesia was clearly explained, and emphasis was laid on the importance of keeping an equilibrium between the components linked to the respiratory system, the respiratory muscles and tissue oxygenation. With the auxiliary of a video, we were shown how a patient is intubated, a procedure which is indispensable to ventilate and oxygenate a patient under general anaesthesia. In these patients, intubation can be a complicated process, due to the rigidity of the upper airways associated with their morphology, as these can be anatomically different with respect to those of a patient who does not suffer from a deficit of Collagen VI. Information is of the essence, and it is important to be aware of the risks involved in a surgical operation and in the type of anaesthesia employed. Fortunately, nowadays there are other alternative techniques to general anaesthesia, as well as oxygen monitoring systems, which can be taken into consideration in the case of patients affected by this, or other, varieties of myopathy.
This meeting gave us all the opportunity to share a large amount of information, and we are anxious to repeat the experience in the next reunion scheduled for next November.

Third Meeting Collagen VI Group

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Third miting collagen six 6 vi group ullrich bethlem
Third miting collagen six 6 vi group ullrich bethlem
On Saturday 18th, June 2016, the third meeting of the Collagen VI Group was held in the Centro Sociale Ricreativo e Culturale (Recreational and Cultural Social Center) A. Montanari in Bologna.
As usual, it proved to be a day of great scientific interests thanks to the doctors and researchers who delivered their speeches with great enthusiasm and helpfulness. In addition, the day was another opportunity to strengthen the bonds among patients, family members, doctors and researchers and to come to know the new members who only recently have become part of the group. In just over an year, the Collagen VI Group has organized three meetings thus maintaining a stable relationship of collaboration with medical doctors and researchers who deal with these pathologies.
A report of the day will soon be available with all the details regarding the topics discussed, as well as the new photo galleries.
In the meanwhile, the programme of events is as follows:

 

Schedule

10:15 A.M. Introduction: Cecilia Sorpilli and Patrizia Duranti

10:30 A.M. Daily schedule: Luciano Merlini
Omigapil and congenital muscular dystrophies:
Paolo Bonaldo
LPD publication:
Silvia Castagnaro
Beneficial effects of spermidine on mice lacking Collagen VI:
Martina Chrisam
Spermidine and clinical trial in silico, a project of the EU call H2020:
Luciano Merlini, Marco Viceconti
The pulmonary role in muscular dystrophy and its treatment:
Andrea Fabiani

13:00 Lunch break

14.30 UCMD tendons: Patrizia Sabatelli

15.00 Anaesthesia: Mariada Perrone

15.30 Questions, debate and farewell speeches

Summary of the second reunion of patients and researchers

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A multi-faceted approach to collagen VI research.

Summary of the second reunion of patients and researchers, held on 1st November 2015 at the Hotel Ramada Encore, Bologna (Italy)

This proved to be an illuminating and highly interdisciplinary day, during which update on the progress of scientific research was accompanied by invaluable information regarding the importance of creating an association of patients within the UILDM framework.

In his opening address, Dr. Luciano Merlini reminded the assembly that, however rigorously and unsparingly it may be conducted, research is never infallible and may often lead to wrong conclusions. This is when the perseverance and thirst for knowledge of researchers come into play, with the result that even scientific errors can be transformed into great discoveries. This is precisely what happened in the case of Cyclosporin A, initially employed as an immunosuppressor to counteract the risk of healthy muscle portion rejection in patients affected by Duchenne Muscular Dystrophy. It was not until later that researchers discovered that the muscle cells transplanted were not able to take root and bring benefit to the muscle, but the improvements observed were mainly due to Cyclosporin A. Nowadays it is a well-known fact that Cyclosporin A on the one hand weakens the patient’s immune system but, on the other hand, it has the power to prevent the mitochondria from sending alarm signals to the cell, a process which would trigger a process of self-destruction known as apoptosis. Prof. Paolo Bernardi, after an exhaustive explanation of the function of Cyclosporin A, provided us with an update on his research on NIM811 and Debio025. These two molecules are devoid of any potentially dangerous immunosuppressive effect, which would increase the risk of infection in Bethlem and Ullrich patients undergoing long-term treatment. In addition, they are more effective than Cyclosporin itself in its action on the mitochondria to impede the initiation of the process of apoptosis, an event that occurs on an excessively elevated basis in patients suffering from muscular disorders. Both of these molecules have already been successfully tested on animal models for Bethlem myopathy and Ullrich dystrophy, namely mice and zebrafish, which do not produce collagen VI. As already stated in our website, Debiopharm has recently communicated through the press that Debio025 will be made available for the treatment of muscular disorders, thus we are currently monitoring the situation with the prospect of launching a clinical trial, possibly within twelve months’ time.

A large quantity of damaged mitochondria need to be present at the same time in the cell in order to induce apoptosis. When the muscle cells fail to destroy the damaged mitochondria in the absence of collagen VI, there is a high tendency towards apoptosis, due to the failure of the system responsible for the self-destruction of damaged or no longer necessary parts, namely autophagy. Prof. Paolo Bonaldo’s contribution gave a full description of the progress made to date in the field of collagen VI research, in which he has been personally involved since the beginning of his medical career, with particular reference to the issues involved in the modulation of autophagy for therapeutic purposes. He briefly illustrated data regarding the activation of autophagy and the improvement of a few parameters corresponding to muscle function in the patients that participated in the trial. This data body has been included in an article now under review for publication in a medical journal. This will confirm its validity in the eyes of the international scientific community, thus legitimizing the continuation of this field of study. The next step might be the clinical experimentation of spermidine, a molecule naturally present in the food varieties described in the previous meeting. The efficacy of spermidine has been demonstrated in studies on mice lacking in collagen VI, the results of which have been included in an article recently published on line. Dr. Martina Chrisam, a doctoral candidate and member of Prof. Bonaldo’s laboratory team and who is responsible for this project, briefly discussed the possible outcomes. There are new studies, currently in the embryonic phase, oriented towards identifying the best method to introduce spermidine in Bethlem myopathy and Ullrich dystrophy therapy, via foods containing this substance or possible pharmaceutical products, both independently or in combination with other molecules that activate autophagy, such as resveratrol, a well-known antioxidant contained in red wine. At present, it is not possible to make accurate predictions, given that many aspects of this issue are still currently under study, yet we hope that a spermidine therapy will be available as soon as possible.

Also present at the meeting was Dr. Patrizia Sabatelli, a dedicated researcher and colleague of Prof. Merlini, who outlined a recent work of hers based on the role played by collagen VI in tendons, structures composed almost exclusively of extracellular matrix, whose function is to connect muscle to bone. All the matrix components, with their mutual interactions, produce a unique and continuous structure that supports and sustains the cells. In order to function properly, this requires a certain degree of elasticity, which diminishes in the absence of collagen VI. Prof. Bonaldo provided us with information on this issue and explained part of a study, conducted in his laboratory and published in 2014, in which the biomechanics of muscles lacking in collagen VI were investigated. We are now eagerly waiting to see the conclusions of this new study focused on tendons. This is undeniably a “basic” study, slightly removed from clinical application, yet equally as important: an in depth understanding of the function of collagen VI is the conditio sine qua non for the conception and elaboration of new therapies.

Dr. Mariada Perrone, an anaesthetist and pain therapist, gave a talk on the subject of respiratory failure, focusing in particular on a case in which an increased intake of lipids was successful in restoring respiratory function in a seriously compromised Ullrich dystrophy patient. This procedure was elaborated after in depth research into the patient’s pathology, under the assumption that the lipids would constitute an immediate source of energy and could be more easily utilized by the diaphragm muscle. Although a case-by-case evaluation is necessary, this strategy is certainly something to be taken into consideration.

Another topic of general debate was the question of physical exercise: can this be beneficial to Bethlem and Ullrich patients? This is a delicate issue. Research carried out in Prof. Bonaldo’s laboratory confirms that intense and prolonged physical exercise has the effect of worsening the muscular condition of mice that do not produce collagen VI. On the other hand, it is true to say that many patients derive a certain amount of benefit from moderate physical activity and from physiotherapy. There is no contradiction between the two: keeping a muscle in activity is important in order to avoid disuse generating a worsening of the patient’s condition, inducing atrophy, but it is essential not to exaggerate and to avoid excessive fatigue, in which case the damage caused would be difficult to repair.

The meeting was also heightened by the contribution of Dr. Anna Ambrosini, Head of the Research Programme Area of the Telethon Scientific Medical Committee, who provided us with an overview of Telethon’s efforts to promote scientific research on muscular dystrophy. First and foremost, she illustrated the various typologies of research conducted in the laboratories financed by Telethon, which study the mechanisms underlying neuromuscular disorders or work on the development of new therapeutic approaches in animal or cell models. Dr. Ambrosini then proceeded to give a more detailed description of the investments made by Telethon on the clinical front. This initiative is the result of an alliance between Telethon and UILDM, which in 2001 led to the launch of a competition notice dedicated exclusively to clinical research on the quality of life of patients suffering from neuromuscular disorders. This was subsidized by the Telethon marathon, which sees UILDM joining forces with Telethon every year in order to raise funds. Anna Ambrosini underlined the fact that, over the years, this investment has promoted the growth of a network of clinical centres that participate in multicentric studies with a duration of two or three years. In this way, encouraging results have been able to be obtained, for instance the provision of a reliable diagnosis for many less widespread neuromuscular disorders, the collection of precious data regarding the progress of the various pathologies, the so-called natural history, as well as the possibility of implementing the instruments currently at our disposal to slow down the course of disease, or to reduce the symptoms and complications, and improve standards of care. The guidelines regarding the management of healthcare services have, in recent years, improved the condition and quality of life of neuromuscular patients in Italy. These activities have also given clinics the opportunity to tackle new therapeutic trials and to place Italian clinical centres on the international scene. At the same time, Telethon offers concrete support in the creation and management of patient registers. These are an extremely important issue: Dr. Ambrosini provided us with an overview of the various typologies of registers and their mechanisms, which should also guarantee patient privacy and safeguard personal data, while consenting the sharing of data in aggregate, and on an anonymous basis, with researchers that require them for their research projects and/or clinical trials. It is essential that the registers be integrated with highly detailed information regarding the genetic diagnosis and the clinical conditions of the patients registered, also with the support and collaboration of the medical authorities responsible, and that these be maintained over time and properly handled. With a view to launching new clinical trials, it is important that the registers be as exhaustive as possible to speed up the identification of the most suitable patients to participate in them. Bethlem myopathy and Ullrich dystrophy patients are already included in the CMD (congenital muscular dystrophy) list. At present this is a database compiled by Italian clinicians and is used primarily for research purposes. Further information can be found on the website www.registronmd.it on the CMD register page. There are plans to convert this database into an official register, which can be accessed directly by patients. Still on the subject of registers, Anna Ambrosini illustrated the important role played by UILDM in the creation of the Register Association, the legal representative that protects patient data, and underlined the importance of uniting our efforts within UILDM, in order to avoid a dispersion of energies and resources.

The col6.it website is becoming richer in content and Dr. Chrisam, who is responsible for some of the texts included, described how the “research and publications” section will be structured. This will be articulated in five paragraphs dealing with the structure and genetics of collagen VI, the model organisms that are indispensable for carrying out research, the role of collagen VI in tissues other than muscle and the projects that have contributed to the elaboration of possible therapies for Bethlem myopathy and Ullrich dystrophy. Any suggestions for additional topics are welcome.

The location of the meeting and the quantity and quality of the information made this a really memorable day and our sincere thanks are due to Cecilia Sorpilli for undertaking to organise the event. The next meeting is expected to take place in approximately 6 months’ time.

Anaesthesia recommendations for patients suffering from Collagen VI-related myopathy

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Disease name: Collagen VI-related myopathy
ICD 10: G71

 

Synonyms – Spectrum of phenotypes:

Mild: Bethlem myopathy/ benign congenital muscular dystrophy
Intermediate: Limb-girdle muscular dystrophy; myosclerosis myopathy
Severe: Ullrich myopathy/ congenital atonic sclerotic muscular dystrophy

First described by Ullrich in 1930 and Bethlem in 1976 respectively [1]. Caused by mutations in any of the 3 genes which code for collagen type VI synthesis, COL6A1, COL6A2 and COL6A3 [2]. Collagen VI is a major contributor to stability of the extracellular matrix. The remaining function of Collagen VI determines the clinical severity of the disorder [3,4]. Considered different entities in the past, Bethlem and Ullrich myopathy are now considered extremes in the spectrum of Collagen VI myopathy. Both inheritance (mostly autosomal recessive) and de-Novo mutations (mostly autosomal dominant) are possible, the latter is more common. Combined prevalence is estimated at approximately 1 in 100,000 births (Varying data for subtypes). Diagnosis relies on muscle biopsy and molecular genetic testing. There exists no causative treatment.


warning-iconMedicine in progress Perhaps new knowledge Every patient is unique Perhaps the diagnostic is wrong

Find more information on the disease, its centres of reference and patient organisations on Orphanet: www.orpha.net


 

Disease summary

In Bethlem myopathy, patients will experience moderate muscle weakness, peripheral joint laxity and proximal joint contractures. Onset of symptoms will take place in late childhood or adolescence. Mobility will diminish over the years but usually still be present in advanced years. No valid data on life expectancy. Overall benign course.

In Ullrich myopathy, muscle weakness and muscular contractures are noticed at birth or in early infancy. Neonates may present with congenital hip dislocation and general hypotonia whilst infants may present with difficulty climbing stairs. Even where independent ambulation is achieved in childhood, most will be wheelchair-bound from early adolescence. Affection of respiratory muscles is frequent and ventilation support may be necessary intermittently (nocturnal) or permanently. The clinical course may be complicated by recurrent pulmonary infections. The phenotype will be characterized by hypermobility of peripheral joints and contractures of proximal joints as well as scoliosis and kyphosis. Affected individuals may present with a round facies with long thin limbs and muscular wasting. Muscular weakness may also prevent adequate mastication and may lead to underweight.

Impaired Collagen VI function can also lead to follicular hyperkeratosis resulting in impaired wound healing and keloid scar formation.

Collagen VI is not found in the CNS and thus cognitive ability is unaffected. There is no sensory component. Cardiac function seems to be normal in Ullrich disease. Data for Bethlem myopathy is conflicting with isolated reports of mild cardiomyopathy and a unclear relevance for anaesthesia practice [5]. Serum creatine kinase may be slightly raised as a biochemical marker.

 

Typical surgery

Surgical correction of musculoskeletal, especially spinal deformities – e.g. scoliosis correction [6]. Distraction osteotomy – growth rod insertion. Contracture release.

Tracheostomy, Gastrostomy and pressure ulcer repair in the most severe cases.

Scar revision surgery.

 

Type of anaesthesia

There is no data to indicate the superiority of either intravenous or volatile anaesthetics [7]. Literature and pathophysiology suggest no connection to malignant hyperthermia. Depolarizing muscle-relaxants should however be avoided in the context of patient immobilisation.

Little information is available in literature regarding neuro-axial blockade and regional anaesthesia in these patients. The presence of a scoliosis and/ or kyphosis can present a significant technical challenge. Regional anaesthesia may be beneficial in patients with impaired respiratory capacities but also present with severe challenges due to contractures and difficulties in positioning and anatomical access. Be aware that some reports indicate that minimal tissue injury can cause severe subcutaneous haemorrhage.

 

Necessary additional diagnostic procedures (preoperative)

Respiratory function needs to be robustly assessed prior to the administration of general anaesthesia. Even more than a chest X-ray, lung function tests should be performed to assess respiratory impairment. This includes an arterial blood gas analysis.

Although cardiac function seems unaffected by the disease per se, there may be evidence of right heart failure as a consequence of prolonged respiratory involvement and therefore an ECG and an Echocardiogram is advisable, if right heart involvement is suspected. The significance of single reports of very mild and clinically irrelevant cardiomyopathy in Bethlem myopathy is not yet clear.

Blood analysis may highlight polycythaemia (respiratory impairment) or concurrent (airway/pulmonary) infection. Urea, creatinine and electrolytes will help to rule out any renal end organ damage as a result of the pre-existing scoliosis and is helpful to refer to following surgery in the prone position.

 

Particular preparation for airway management

In cases accompanied by the typical facial stigmata, micrognathia and a high arched palate can lead to difficult intubation conditions. Preparations for difficult airway management are advisable.

 

Particular preparation for transfusion or administration of blood products

Literature does not indicate any increased requirements resulting from the myopathy per se. However, corrective spinal and extensive musculoskeletal surgeries have inherent procedural risks of major blood loss.

 

Particular preparation for anticoagulation

No information on specific disease related pathophysiology. As mentioned above: Remember the procedural risks of major musculoskeletal/spinal surgery.

 

Particular precautions for positioning, transport or mobilisation

Previous immobilisation, contractures and underweight may be marked and careful patient positioning is crucial in order to avoid pressure ulcers and nerve entrapment syndromes.

This condition is associated with respiratory insufficiency and whilst the prone position (for spinal surgery) can be helpful with gas exchange, extra care should be taken for adequate positioning.

Ullrich myopathy is associated with follicular hyperkeratosis which leads to keloid scar formation, impaired wound healing and increased skin and soft tissue vulnerability. Extra caution is advisable with bandages, eye pads and other adhesives.

 

Probable interaction between anaesthetic agents and patient’s long-term medication

Children with Ullrich disease may be on prophylactic antibiotics, which may alter the choice of antibiotics used for surgical prophylaxis.

Cyclosporine A may be of benefit in Ullrich disease and children on this drug may display its side effects including gingival hyperplasia and hypertension.

 

Anaesthesiologic procedure

Inhalational and TIVA techniques may both be used. Little evidence surrounds the use of neuro-axial anaesthesia and regional anaesthesia. Invasive procedures may lead to significant cutaneous and subcutaneous bleeding.

 

Particular or additional monitoring

Invasive arterial catheters seem useful to assess ventilation and gas exchange both during surgery and in the post-operative period.

In Cases of pulmonary hypertension and/or right ventricular dysfunction, advanced hemodynamic monitoring (Swan-Ganz-catheter, Intra-operative-TEE) should be considered.

 

Possible complications

Skins lesions and reactions may be seen as a result of the use of dressings, eye tapes and ECG pads.

Pressure ulcers may develop due any difficulty with the positioning of patients.

 

Postoperative care

In severe cases (typically Ullrich myopathy) respiratory failure may complicate the postoperative course. Those patients should be handled in an intensive care or highdependency environment.

Information about emergency-like situations / Differential diagnostics

caused by the illness to give a tool to distinguish between a side effect of the anaesthetic procedure and a manifestation of the disease

Iatrogenic causes of respiratory failure should be avoided including the overuse of opiate analgesia, prolonged action of neuromuscular blocking drugs, hypothermia and residual anaesthetic agents.

 

Ambulatory anaesthesia

Due to the complex and rare nature of this disorder and the risk of possible postoperative respiratory failure in severely affected patients, ambulatory anaesthesia should only be considered in the mildest of phenotypes.

 

Obstetrical anaesthesia

Literature does not provide any data regarding parturient patients with Collagen VI myopathies. Neuro-axial procedures may be complicated by anatomical difficulties and skin/soft tissue vulnerability (haemorrhage!).

 

Literature and internet links References

1. Bethlem J, Wijngaarden GK. Benign myopathy, with autosomal dominant inheritance. A report on three pedigrees. Brain: A journal of neurology. 1976;99(1):91-100 2.
2. Lampe AK, Flanigan KM, Bushby KM, Hicks D. Collagen Type VI-Related Disorders. Pagon et al., GeneReviews (R): University of Washington, Seattle; 1993 (FREE FULL TEXT).
3. Bonnemann CG. The collagen VI-related myopathies: Muscle meets its matrix. Nat Rev Neurol. 2011;7(7):379-90
4. Gilbreath HR, Castro D, Iannaccone ST. Congenital myopathies and muscular dystrophies. Neurologic clinics. 2014;32(3):689-703,viii
5. Finsterer J, Ramaciotti C, Wang CH, Wahbi K, Rosenthal D, Duboc D, et al. Cardiac findings in congenital muscular dystrophies. Pediatrics. 2010;126(3):538-45
6. Takaso M, Nakazawa T, Imura T, Okada T, Ueno M, Saito W, et al. Surgical correction of spinal deformity in patients with congenital muscular dystrophy. Journal of orthopaedic science: Official journal of the Japanese Orthopaedic Association. 2010;15(4):493-501
7. Grosu I, Truong D, Teodorescu S, Mousny M, Veyckemans F. Anesthetic management of a child with Ullrich myopathy. Journal of anesthesia. 2012;26(4):636-7.

 

 

Internet links

CURE CMD (Support group based in the USA; content in English; containing links to further online resources for non-physicians in social media).

MUSCULAR DYSTROPHY UK (Charity based in the UK; content in English; umbrella organisation for over different conditions of muscular dystrophy).

Prof. Paolo Bonaldo’s lab

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When many cells are making up a living organism, they need an organized scaffold that holds them and helps them to work together in order to form tissues and organs: this scaffold is the extracellular matrix, the main focus of the laboratory of Paolo Bonaldo. The extracellular matrix is composed by different macromolecules, which are precisely balanced and differently organized in the different tissues in order to fulfill the specific needs of each organ. Many discoveries suggest that these macromolecules are very important: indeed, if they are missing or altered, organs do not work well.

The major interest of Bonaldo’s lab is collagen VI, a protein of the extracellular matrix that forms a distinct microfibrillar network and supports cells in many organs, especially those in skeletal muscles. Unfortunately, there are persons whose organs do not produce collagen VI at all, or produce it in a version that does not work, leading to several problems, especially in muscles. Actually, the detailed characterization of the structure and function of collagen VI is essential for opening new therapeutic venues and understanding what to do when collagen VI is defective. In addition, animal models that do not produce collagen VI not only offer the possibility to get further insights into what happens in humans affected by collagen VI-related diseases, but also provide a valuable tool for evaluating the effects of possible therapies.

Another research topic of the lab is the study of a family of extracellular matrix proteins called “Emilins”, which were found to be particularly important in the matrix surrounding the blood vessels. To date, it is not known if there are human disease caused by alterations of these proteins, but this possibility is very likely to be found soon.

To carry out science at the best level, a team work is mandatory. Bonaldo’s lab works with many national and international groups, experts in extracellular matrix, muscle, and several other aspects that cannot be effectively addressed without experience in particular fields. These collaborations include the lab of Marco Sandri, expert in muscle; Raimund Wagener and Mats Paulsson, at the University of Cologne, with whom it is useful to exchange different views on topics related to the extracellular matrix; and Paolo Bernardi, who helped to identify defects in the mitochondria (the energy suppliers of the cells) of cells from muscles lacking the collagen VI.

Members of the lab:

Prof. Paolo Bonaldo, Full Professor

Prof. Bonaldo has devoted a large part of his life as scientist to study collagen VI, investigating almost every aspect of the structure, production and function of this large and complex extracellular matrix protein. He is the leader of a dynamic young team and supervises the whole lab, in which the pathological consequences due to the absence of collagen VI are being examined in depth, with a unique passion and enthusiasm. Actually, many of these studies were made possible thank to the mouse model lacking collagen VI, produced by Prof. Bonaldo himself.

Prof. Paola Braghetta, Associate Professor

Prof. Braghetta is an expert in laboratory mouse model. Currently, she is actively involved in the generation of different mice with altered versions of collagen VI, which, undoubtedly, will be a valuable tool to investigate the function of this important matrix molecule. In parallel, studies of these animals will help to identify new therapies for diseases caused by the deficiency of collagen VI.

Dr. Dario Bizzotto, Research Technician

The lab has no secrets for Dario: he shares his broad scientific and technological experience, enriching the work of all the scientists in the lab. He is very skilled in the mouse work and tools, and, therefore he helps Paola Braghetta in the generation of animals, making possible new studies upon different aspects of the collagen VI. In addition, he is actively involved in the fascinating study of the protein family known as “Emilins”.

Marianna Spizzotin, M. Sc., Lab Manager

Marianna is the angel of the lab: she’s always cheerful and willing, and carries out essential tasks by preparing reagents, communicating with the administrative offices and managing animals and cells. At the same time she maintains order and discipline, essential to work better in the lab.

Dr. Matilde Cescon, Senior Post-Doc

Matilde is maybe the strongest and tenacious person of the lab. She is carrying out a number of studies aimed at understanding the effects of collagen VI deficiency in the nervous system and in the neural transmission. Her work allowed understanding that skeletal muscles are not the only organs suffering from the lack of collagen VI. Indeed, when collagen VI is defective, also nerves, which direct the necessary instructions for the movement of muscles, struggle to function properly.

Dr. Francesco Da Ros, Senior Post-Doc

The dynamic Francesco has only recently approached the study of the collagen VI. Nevertheless, he is providing a large number of ideas to clarify how this protein that is normally out of the cells can profoundly influence the processes occurring within the cells. In parallel, Francesco is studying the Marfan syndrome, a very debilitating genetic disease linked to extracellular matrix, with the aim of better clarifying how it develops and in order to developing strategies to counteract it.

Dr. Silvia Castagnaro, Junior Post-Doc

The cheerful and positive Silvia is an expert in cell cultures and manipulations. Essentially, she isolate cells from muscles and other tissues and grows them on specific plastic supports, in order to study how the lack of collagen VI alters the cell behaviour at the molecular level. Those cells are from animals that lack collagen VI and from biopsies of patients with Bethlem myopathy and Ullrich Congenital Muscular Dystrophy.

Dr. Francesca Gattazzo, Junior Post-Doc

The topic of Francesca’s research is the futuristic field of tissue engineering. Actually, she is generating microscopic three-dimensional structures with the biodegradable fruit extract of gardenia, called “genipin.” Within these structures, cells are cuddled and helped to build portions of functioning muscle. In the future, these studies will allow the repair of large portions of damaged muscles in disease or trauma conditions.

Martina Chrisam, M.Sc., Ph.D. Student

The cleaning systems of cells, in particular of those in muscles, constitute the main interest of Martina. On one hand, she is looking for new strategies to reactivate these systems in mice that lack collagen VI. On the other hand, she wants to understand how a healthy cell can adjust such cleaning systems depending on cell’s needs. These two aims are closely linked, as a deep understanding of how to regulate these cleaning systems is key to understand what to do when they are not working as they should.

Sibilla Molon, M.Sc., Ph.D. Student

Nowadays, it is well known that collagen VI is critical to the function of those muscles that allow us to move. Conversely, little is known about its role in other muscles, in particular in those present in the gut that allow the food to proceed along the digestive tract. Moreover, the intestine is composed of a large number of cells with different functions: some of them absorb nutrients, others repair damage, and others provide instructions through electrical stimuli. Sibilla is passionately dedicated to the understanding of how the lack of collagen VI alters the function of these cells.

Valeria Trapani, M.Sc., Ph. D. Student

The Valeria’s faithful co-workers are small tropical fish called “zebrafish”. The advantage of these fish is that they are almost totally transparent throughout their growth, from the moment of fertilization, which occurs in water and not in the womb, until they reach adulthood. Therefore, studies in zebrafish provide an important insight whether collagen VI has a role during the development of living organisms, and will also allow throwing light on the molecular pathways that transduce within the cells the signals generated by collagen VI and other extracellular matrix proteins.

Debiopharm International SA and Solid Biosciences, LLC, announce a collaboration to explore the use of Alisporivir (Debio 025) in muscular dystrophy.

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Debiopharm to start pre-clinical animal studies in Duchenne Muscular Dystrophy (DMD) with Solid Biosciences, a DMD-focused biotech company.

Lausanne, Switzerland, and Cambridge, USA – September 8, 2015 – Debiopharm International SA (Debiopharm), part of Debiopharm Group™, and Solid Biosciences, LLC, are proud to announce the start of preclinical studies of Alisporivir, in the rare disease Duchenne Muscular Dystrophy (DMD). The objective of the collaboration is to reinforce existing preclinical proof of concept data in additional DMD animal models. This preclinical work, fully funded by the Lausanne-based company, will then lead to Debiopharm initiating the clinical development of this new and promising therapeutic for DMD at its own expense in the near future.

Alisporivir is a non-immunosuppressive cyclophilin inhibitor, with multiple potential indications and has already been tested in more than 1500 patients during clinical development for hepatitis C, demonstrating an acceptable safety profile. Alisporivir is able to prevent mitochondrial-dependent muscular cell death and has shown promising activity in preclinical models of DMD but also Limb-Girdle and Ullrich-Bethlem myopathy. The aim of this collaboration is to confirm the efficacy of the compound in a new model of DMD that more closely resembles the human pathology and to enable the start of clinical development in this indication.

“We are delighted to start development in muscular dystrophy”, said Thierry Mauvernay, Delegate of the Board of Debiopharm Group. He added: “We are very pleased to be able to work with Solid Biosciences on this program, combining our deep understanding of Alisporivir with their great expertise and network in DMD and their focus on finding solutions for these young patients suffering from this terrible disease.”

“We, at Solid Biosciences, are proud to be partnering with Debiopharm”, said Ilan Ganot, founder and CEO of Solid Biosciences. “Alisporivir has exciting efficacy potential in DMD and we look forward to put to work our expertise in this condition to help advance Alisporivir to patients afflicted with DMD. I am particularly grateful to Bob McDonald and Ed Mascioli whose personal and professional commitment to DMD patients is reflected in this relationship.”

About Duchenne Muscular Dystrophy (DMD)
Duchenne Muscular Dystrophy (DMD) is a severe X-linked form of muscular dystrophy that affects approximately 1 out of every 3500 males. DMD is caused by the absence of dystrophin, a structural protein critical for protecting skeletal and cardiac muscle against contraction-induced injury. Characterized by progressive and pervasive muscular degeneration, patients with DMD lose the ability to walk in the early to mid teens and progress to full loss of upper body function. DMD patients suffer from progressive cardiopulmonary complications, which are the primary cause of mortality, typically in the early to mid 20’s. To learn more about DMD visit: www.parentprojectmd.com

About Debiopharm International SA
Debiopharm Group™ is a Swiss-based global biopharmaceutical group of four companies active in drug development, GMP manufacturing of proprietary drugs, diagnostics, and investment management. Debiopharm International SA is focused on the development of prescription drugs that target unmet medical needs. The company in-licenses and develops promising drug candidates. The products are commercialized by pharmaceutical out-licensing partners to give access to the largest number of patients worldwide.
For more information about Debiopharm Group™, please visit: www.debiopharm.com
We are on Twitter. Follow us @DebiopharmNews at http://twitter.com/DebiopharmNews

About Solid Biosciences, LLC
Solid Biosciences is a Cambridge, MA based biotech company committed to developing therapies for Duchenne Muscular Dystrophy. Solid is currently developing small molecules, gene therapies and medical devices, all targeting the many facets of DMD.
For more information about Solid Biosciences, please visit: www.solidbio.com

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Debiopharm International SA Contact
Christelle Tur
Communication Coordinator
christelle.tur@debiopharm.com
Tel: +41 (0)21 321 01 11

Solid Biosciences, LLC Contact
Joel Schneider, PhD
Director of Research and Development
joel@solidbio.com
Tel: +1 857 209 2654

Additional Media Contacts
In London
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Muscular Disorders linked to a Type VI Collagen Deficit: Current State of Research

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Report on the assembly of patients and researchers held on 2nd June 2015, in Sasso Marconi (BO), Italia

by Prof. Paolo Bonaldo and his team

Dietary modulation and Debio 025: these are the main targets which research is currently focusing on, in order to combat the progression of muscular disorders due to a genetic type VI collagen deficiency.

Type VI collagen is a component of the connective tissue that holds the cells and tissues together, the so-called extracellular matrix. It plays a crucial role in providing anchorage and support for cells, especially in the skeletal muscle where it is highly abundant and forms a net around the muscular fibres, thus facilitating their contraction. The information needed to produce type VI collagen is contained in the DNA and the disruption of this information due to a deletion mutation may result in inefficiency or even a total lack of type VI collagen. A deficit of functional type VI collagen triggers a series of reactions causing significant damage within the cells. An important objective in the field of research is to shed light on the exact sequence of events leading to this damage, as well as to identify the impaired structures and find a way of repairing them.

The year 2003 marked an important discovery in the laboratories of Prof. Paolo Bonaldo and Paolo Bernardi, who were able to demonstrate that a type VI collagen deficit causes damage to the muscle cells’ energy centres or powerhouses, namely the mitochondria. The team coordinated by Prof. Bernardi, specialized in the study of mitochondria, is investigating the possibility of identifying possible drugs to specifically target the mitochondria in order to restore their normal function, thus improving the efficiency of the whole muscle. Cyclosporine A, tested on animals (mice lacking in type VI collagen) in Prof. Bonaldo’s laboratory and clinically employed by Dr. Luciano Merlini (in a pilot clinical trial on a small group of Ullrich and Bethlem patients), has proved to be highly efficient in restoring damaged mitochondria. However, the drug has the effect of suppressing the immune system, making it unsuitable for long-term treatment. Therefore interest is now being focused on two molecules similar to cyclosporine, which have the additional advantage of not affecting the immune system: NIM811 and Debio 025. To date, both drugs have passed all tests performed in order to exclude possible side effects, and in parallel they have proved useful in improving mitochondrial efficiency in laboratory animals devoid of type VI collagen. Following a series of consultations with a few pharmaceutical companies, there now exists a possibility that Debio 025 may be made available as a cure for human myopathies linked to a type VI collagen deficit. This may be confirmed as soon as the report drafted at the end of 2014 by Prof. Bernardi’s research team is evaluated by the pharmaceutical company that produces the drug.

Yet what causes the presence of these impaired mitochondria in muscular fibres devoid of type VI collagen? In 2010 Prof. Bonaldo’s team gave a reply to this question: there is insufficient cleaning inside the cells. The process defined as “autophagy” (from the Greek “αυτος”, self and “φαγειν”, eat), whereby the cell removes its own damaged components and recycles their constituents, is impeded in mice with a deficit of type VI collagen. This gives rise to an accumulation of abnormal mitochondria. Reactivation is possible, and preliminary experiments performed on laboratory animals have enabled the researchers to ascertain that in this way there is a notable improvement in the efficiency of muscles with a type VI collagen deficit. Among the strategies that can be adopted to reactivate autophagy, there is one which is particularly suited to therapy on humans, namely the low protein diet. A group of patients under the supervision of Dr. Merlini agreed to follow a very strict diet over a twelve-month period; the results of the trial, which are soon to be published, have shown that it is possible to reactivate autophagy according to this method and, moreover, this is accompanied by a corresponding improvement in the efficiency of the muscle. In the meanwhile, studies are being performed in the laboratory in order to identify the substances – naturally present in various types of food – that can stimulate the reactivation of autophagy with a view to treating the pathology. In this connection, a study demonstrating the efficacy of spermidine will soon be published. Spermidine is a component of many foods, being particularly abundant in mushrooms, soya and in citrus fruits. A less restrictive low-protein diet with respect to the previous diet, but enriched with foods containing spermidine, may prove easier to follow, without any danger for children or underweight patients who are obliged to consume rather elevated daily quantities of protein. Diet and spermidine appear to be the ideal balanced combination to obtain the desired effect, and the identification of the most suitable protocol remains an absolute priority in the field of research.

Our hopes are based on the fact that this approach will enable us to significantly improve the quality of life of patients diagnosed with a type VI collagen deficit. In the meanwhile, research continues in order to shed more and more light on the effects produced by this deficient protein, thereby discovering more and more effective ways of treating the pathology.

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