Report of the Patients-Researchers Group meeting, 2 June 2015, Sasso Marconi (BO), Italy
by Prof. Paolo Bonaldo and his team
Dietary modulation and Debio 025: these are the main weapons on which research is focusing today to combat the progression of muscle disorders resulting from genetically based Collagen VI deficiency.
Collagen VI is a component of the adhesive that holds cells in tissues together, the so-called extracellular matrix. It plays a crucial role in providing anchorage and support to cells, especially in the skeletal muscle where it is highly abundant and forms a network around muscle fibres, thus aiding their contraction. The information needed to produce Collagen VI is contained in DNA, and when this information is compromised due to a deleterious mutation, Collagen VI may be missing altogether or altered in such a way that it does not function properly. The lack of functional Collagen VI triggers a series of reactions that induce significant damage within cells. An important goal of research is to clarify the exact sequence of events that lead to this damage, as well as to identify the damaged structures and how they can be regenerated.
An important discovery was made in the laboratories of Prof. Paolo Bonaldo and Prof. Paolo Bernardi in 2003, when it was demonstrated that Collagen VI deficiency damages the energy powerhouses of muscle cells, i.e. the mitochondria. Prof. Bernardi’s group, which specialises in the study of mitochondria, is working on this aspect in order to identify drugs that are able to restore the normal function of the mitochondria, thus improving the function of the entire muscle. Cyclosporin A, tested on laboratory animals by Prof. Bonaldo (mice lacking Collagen VI) and also employed clinically by Dr. Luciano Merlini (in a pilot clinical study on Ullrich and Bethlem patients), has proved highly efficient in restoring damaged mitochondria. However, it is a drug that suppresses the activity of the immune system, and is thus unsuitable for long-term treatment. Interest is therefore now focused on two molecules similar to cyclosporine, which have the added advantage of not suppressing the immune system: NIM811 and Debio 025. Both have passed the tests conducted so far to exclude side effects, and have proven in parallel to be effective in improving the condition of the mitochondria in laboratory animals lacking Collagen VI. Following negotiations with pharmaceutical companies, there is now a possibility that Debio 025 will be made available for the treatment of human muscle diseases related to Collagen VI deficiency. This possibility may be confirmed as soon as the report drawn up at the end of 2014 by researchers in Prof. Bernardi’s group is evaluated by the pharmaceutical company.
But what is the reason for the presence of these altered mitochondria in muscle fibres lacking Collagen VI? In 2010, Prof. Bonaldo’s group provided an answer to this question: there is insufficient cleansing activity within these cells. The process referred to as ‘autophagy’ (from the Greek ‘αυτος’, self, and ‘φαγειν’, eating), whereby the cell removes its own damaged components and recycles the constituents, is blocked in Collagen VI-deficient mice. This blockage causes an accumulation of abnormal mitochondria. It is possible to reactivate it, and studies conducted primarily on laboratory animals have shown that the functionality of Collagen VI-deficient muscles improves significantly in this way. Among the strategies that can be adopted to reactivate autophagy, one of the most suitable for human therapy is a low-protein diet. A number of patients under Dr. Merlini’s supervision therefore underwent a very strict dietary regimen for one year; the results of the study, which are about to be published, have shown that it is possible to reactivate autophagy in this way and that there is also a parallel improvement in muscle function. In the laboratory, meanwhile, studies are in progress to find compounds naturally present in food that can help reactivate autophagy for healing purposes, and a study will soon be published showing that spermidine is effective to this end. Spermidine is present in many foods and is particularly abundant in mushrooms, soya and citrus fruits. A hypoprotein diet that is less restrictive than the one already tested, but enriched in foods containing spermidine, could be easier to follow and not dangerous for paediatric or underweight patients, who must necessarily consume a relatively high daily dose of protein. Diet and spermidine will have to be combined in a balanced way to achieve the desired effect, and finding the most suitable protocol is one of the key objectives of the research.
Our hope is that through these approaches it will be possible to significantly improve the quality of life of patients diagnosed with Collagen VI deficiency. At the same time, research is progressing to clarify in more and more detail what happens when this protein is missing, thus identifying increasingly effective therapies.