col6.it: widespread, more visible and multidisciplinary
Report of the fourth group meeting of the col6.it group – 12 November 2016 c/o Centro Sociale Ricreativo e Culturale A. Montanari in Via di Saliceto, 3/21, 40128 Bologna
by Ilaria Gregorio & Martina Chrisam
The fourth group meeting between patients, doctors and researchers belonging to the col6.it group was held on 12 November at the A. Montanari Recreational and Cultural Centre in Bologna and, as usual, it proved to be a unique opportunity for interaction among the different realities involved in Collagen VI pathologies. On this occasion, the scientific discussion transcended the topics more strictly related to the muscular aspects of these pathologies, and experts from different disciplines took part, presenting a few biomedical, but also economic, aspects of scientific research. In addition, we also listened to talks given by representatives of UILDM and Telethon, whose help will be invaluable in enhancing the group’s profile. Let us now retrace together the events of this day.
Photo 1 – Cecilia Sorpilli, Dr. Luciano Merlini
Cecilia Sorpilli, the cornerstone of the col6.it group and organiser of the event, greeted those present with a warm welcome and a brief summary of the state of the group, which is in continuous growth. This was followed by a talk by Dr Luciano Merlini, who gave an exhaustive explanation of the advantages and disadvantages of cyclosporine A-based therapy for patients with Bethlem Myopathy and Ullrich Congenital Muscular Dystrophy. This drug has, in fact, an excellent ability to remedy defects in the energy centres of muscle cells, i.e. the mitochondria, but has the major disadvantage of significantly lowering immune defences.
Prof. Paolo Bonaldo, a researcher credited with producing a mouse model with Collagen VI deficiency, then made his contribution. As already discussed at previous meetings, these animals represent an excellent model for studying human pathologies stemming from Collagen VI deficiency, as they mimic the muscle weakness condition of Bethlem and Ullrich patients. With the valuable aid of this model animal, the members of Prof. Bonaldo’s laboratory are engaged at various levels in studying the effects of Collagen VI deficiency, not only on skeletal muscle but also on other organs and tissues.
Photo 2 – Prof. Paolo Bonaldo, Dr Ilaria Gregorio
Young PhD student Ilaria Gregorio illustrates part of the work recently conducted by Matilde Cescon, a senior post-doctoral researcher in Prof. Bonaldo’s laboratory, showing the importance of Collagen VI in maintaining the structure and function of the so-called ‘peripheral’ nerves, which reach the skeletal muscle and orchestrate its activity by conveying nerve impulses from the brain. Matilde discovered that, in mice lacking Collagen VI, these nerves do not possess good electrical insulation, due to defects in the structure of the biological insulator known as myelin sheath, so the transmission of nerve impulses is slowed down, resulting in a defect in motor function but also in sensitivity to external stimuli such as cold and pain. Matilde is also studying the role of Collagen VI in the structures that act as an interface between peripheral nerves and muscle fibres, i.e. the neuromuscular junctions. Again, mice lacking Collagen VI have structurally altered, abnormally fragmented junctions that are unable to ensure proper transmission of nerve impulses to the muscle fibres, leading to problems in muscle contraction. These findings have not only clarified a previously unknown role of Collagen VI in a tissue other than muscle, i.e. the peripheral nerve, but also provide insights into the effects of new types of treatment for disorders due to Collagen VI deficiency.
Ilaria also introduced another branch of research in Prof. Bonaldo’s laboratory, namely the use of the tropical fish Danio rerio, commonly known as zebra fish, to study the role of Collagen VI during embryonic development. This work was initiated by a young post-doc in the lab, Valeria Trapani, who recently handed over to new PhD student Valentina Tonelotto. The zebrafish offers the advantage of being completely transparent during the early stages of embryonic development, and moreover fertilisation takes place in the external environment, so these studies do not require any invasive interventions on animals. Valeria has been involved in the generation of Collagen VI-free zebrafish using state-of-the-art technology, and is currently coordinating from her new location (in Brisbane, Australia) with Valentina here in Italy to investigate what happens in these fish. Early data indicate that even in fish, skeletal muscle development is severely impaired in the absence of Collagen VI.
Photo 3 – Dr Andrea Vianello
Then, Dr Andrea Vianello, a pulmonologist in the respiratory pathophysiology department of Padua Hospital, describes the respiratory complications that patients with muscular dystrophies, including Ullrich congenital muscular dystrophy, can suffer. Dr. Vianello explains the mechanisms that lead to the onset of respiratory insufficiency which, in the case of dystrophies, is not caused by alterations to the lungs, but to the respiratory pump, i.e. the structure composed of muscles, including the diaphragm, which as they move allow air to enter the lungs. Next, Dr. Vianello describes the progress made in recent years thanks to non-invasive mechanical ventilation aids, which have made it possible to greatly improve the life expectancy of dystrophic patients with respiratory insufficiency, even in the most serious cases, such as spinal muscular atrophy.
Photo 4 – Prof. Renzo Orsi
Prof. Renzo Orsi, an economist at the University of Bologna, then takes the floor to explain the mechanisms that lead to some drugs being particularly expensive. Prof. Orsi’s talk focuses on the case of Sofosbuvir (marketed under the name Sovaldi), a new drug used in the treatment of hepatitis C. This drug is extremely effective in eradicating the hepatitis C virus, but has a slight drawback: in the United States, the cost of a four-week course of treatment is $85,000 per patient, while in Italy it is around €30,000. It seems clear that, given the high number of patients suffering from hepatitis C, our National Health Service, which in any case ranks among the best in the world, is unable to provide this therapy to all patients, who would therefore have to pay for it out of their own pockets. The case of Sofosbuvir has sparked controversy in Italy and elsewhere, but why does it cost so much? Prof. Orsi explains that the high cost of drugs depends on how much money is spent during their development phase, which generally lasts 10 to 12 years. In the case of Sofosbuvir, the small pharmaceutical company that developed it and Gilead, the multinational that later purchased it, spent around $60 million between development of the molecule, preclinical and clinical trials. The only way to recoup the costs is to increase the selling price, but this creates the impossibility of access to treatment for many patients and also the risk of the drug remaining unsold. In some countries, Gilead has allowed other companies to produce the drug even though it is still patented, favouring its use, for example in India, where it can be bought for $400 per treatment cycle.
Photo 5 – Dr Massimo Pellegrini
Dr. Massimo Pellegrini, from the University of Modena and Reggio Emilia, who was responsible for organising the clinical trial based on the low-protein diet carried out in 2011, intervenes next to illustrate the main results, published a few weeks earlier in the scientific journal Autophagy. Dr. Pellegrini illustrates how the low-protein diet, followed for a year by 7 patients, proved to be not only safe but also effective in reactivating autophagy, the system whereby muscle cells clean their interiors and eliminate damaged components, a system that is deficient in muscles lacking Collagen VI. Data show that this diet also leads to decreased cell death and improved function of the mitochondria, the organelles responsible for energy production in cells, and which are impaired in Bethlem and Ullrich patients. Dr. Pellegrini went on to describe the characteristics of different types of diets, not only low-protein diets, and those that can be exploited to reactivate autophagy, focusing in particular on foods that contain a higher quantity of spermidine: a substance that, in mice lacking Collagen VI, reactivates autophagy and leads to a series of beneficial effects for the muscles, including a lower rate of cell death and improved mitochondrial function.
Photo 6 – Leonardo Baldinu, Dr Luciano Merlini
Finally, Leonardo Baldinu, President of UILDM (Italian Union for the Fight against Muscular Dystrophies) also intervened, first of all congratulating Cecilia and all the members of col6.it, for having succeeded in forming a small but strong, compact group in constant growth. Further appreciation from Leonardo went to the Group’s commitment in organising these regular meet-ups, useful not only for patients, but also for the doctors and researchers themselves, in order to get to know and understand who is behind their work. While mentioning that col6.it is part of UILDM, Leonardo drew the Group’s attention to what can be done to become an active part of the community. In fact, the condition of dystrophy patients in Italy can be greatly improved by striving for the gradual removal of architectural barriers, and by guaranteeing certain fundamental rights, including education up to university level, the holding of a job and the achievement of a life as independent as possible. It is only by enforcing these rights that the life quality of patients can be significantly improved, enabling them to contribute in parallel to the development of society.
After the lunch break, the video message from Telethon was shown. Anna Ambrosini, head of Telethon’s scientific directorate research programmes, greeted those present and confirmed her solidarity with all members of the col6.it group and Telethon’s support for the doctors and researchers involved in the study of Collagen VI-related diseases. Next, Alessia Daturi, head of the network of the Friends Associations, i.e. those patient associations that support Telethon in the fight against genetic disorders, took the floor. Alessia underlined her willingness to act as a bridge between patients and the Telethon Marathon communication team. She then explained that, for this purpose, volunteers are needed to act as testimonials, who, through both the social media and beyond, could divulge their personal stories and illnesses. Alessia concluded her video message by inviting us to the next Friends Associations conference to be held on 13th and 14th March in Riva del Garda, where more than 180 associations would be meeting with researchers, with the aim of informing patients regarding the progress of research.
At the end of the day, a lively group discussion took place, in which patients put a series of questions to doctors and researchers. Various topics were discussed, including research funding, future clinical trial projects, increasing the group’s visibility and more.
This get-together, like the previous ones, proved to be an excellent forum for the exchange of information, opinions, advice and explanations. We are convinced that the path taken will lead us towards increasingly fruitful group meetings, and will foster the growth and strengthening of the col6.it group.