European and North American entities support common goal for treating rare degenerative diseases (European Commission FP7 project, Endostem, Sanford Burnham, Parent Project and Fondazione Telethon)
Dr Pier Lorenzo Puri’s group from the Dulbecco Telethon Institute at the Fondazione Santa Lucia in Rome, as part of a large scale FP7 European project aimed to identify stimulating resident stem cells to repair and regenerate damaged tissue has identified a completely novel signalling pathway in stem cells which may lead to advanced therapeutic development for many rare and age related diseases. Published recently in the leading journal Cell Stem Cell (part of Cell family of journals) his team has deciphered one way how cells signal internally so that inflammation events are converted into regenerative signalling, a pathway which if successfully targeted will be a major advance to aiding the body repair itself in the instances of large or hard to treat tissue damage. By identifying, understanding and controlling the precise molecular controls which instruct muscle stem cells to either remain as stem cells or become mature muscle cells new therapeutic avenues have been opened which will offer the possibilty of treatment for many muscle related disorders and will be further explored as part of the Endostem project. In particular, the present work provides important insight into the current controversy regarding the impact of inflammation (and therefore the interventions with antiinflammatory drugs) on the progression of degenerative muscular disorders, such as muscular dystrophy. While anti-inflammatory drugs (steroids) are currently use in the treatment of muscular dystrophy, their overal impact on endogenous, compensatory regeneration remains controversial. Thus, this study indicate the rationale for targeting selective components of the signalling triggered by the specific inflammatory components to promote an expansion of muscle stem cells toward implementing endogenous regeneration. Body of release: Balancing inflammation and the immune response, and correct stimulation of tissue repair after significant tissue damage represent the holy grail of regenerative medicine. It is normal that after tissue damage there is a bodily response which responds as if there has been an attack on the body. This results in the generation of scar tissue and tissue inflammation. While this effect is both shortlived and essential as it does provide a number of factors which can regulate tissue regeneration these events can also prevent resident stem cells (all tissues have their own stem cells nearby) from correctly repairing and regrowing the tissue so that it correctly functions. Specifically these stem cells, which are limited in number can be rapidly induced to become the missing tissue, when in fact what is needed is for the stem cell pool to be sufficiently increased so that there are a large enough number of cells to repair the tissue correctly. Without this, the tissue gaps are filled by scar tissue meaning that it is defective. Dr Puri, in the instance of muscle based stem cells has identified one such specific pathway which does this, linked to the known muscle stem cell gene, Pax 7. By first blocking a known inflammatory molecule that directly influences Pax 7 in both genetic and traumatic defects, Dr Puri demonstrated that these Pax 7 expressing stem cells expanded and then by further genetic analysis identified the precise molecular switch which controls this event. By manipulating this switch in a highly controlled fashion his team were able to prevent inflammation and expand the stem cell pool and then when reverting the switch back to its normal function permit the stem cells to differentiate in greater numbers into the tissue itself. This work belongs to a larger project in Puri’s lab aimed at the identification of the mechanism by which the cues released within the regeneration environment in diseased or injured muscles is converted into the epigenetic modifications that control the expression of those genes that confer on muscle stem cells the ability to proliferate or differentiate into newly formed muscles. Puri’s lab has a longstanding interest in deciphering the molecular and epigenetic basis of endogenous muscle stem cell activity with the ultimate goal of using this information to devise pharmacological approaches to stimulate therapeutic regeneration of diseased muscles. The synergy between Puri’s laboratories in the Dulbecco Telethon Institute at the Fondazione Santa Lucia in Rome and in the Sanford/Burnham Medical Research Institute has previously generated key discoveries that paved the way for the use of epigenetic drugs (such as histone deacetylase inhibitors) for the treatment of muscular dystrophy. Thus, the current work represents one more steps along the scientific journey of Dr Puri groups toward the identification of novel approaches for the pharmacological control of muscle regeneration for the treatment of currently fatal neuromuscular diseases, such as muscular dystrophies. ‘Dr. Puri is a key participant of Endostem, which is an EC funded initiative involving over 15 partners from Europe directing their efforts to bridge the gap between fundamental and preclinical research with the aim to develop pharmacological approaches to mobilizing stem cells within the context of regenerative medicine. His laboratory, which is based both in Italy and in the USA, represents the ever increasing collaborative efforts that extend beyond the standard EC boundaries. This most recent report constitutes a key advance in understanding regeneration in skeletal muscle tissue and has potential impact for patients suffering from muscular dystrophies as well as the loss of muscle tissue that occurs in the elderly.’ Dr David Sassoon (EndoStem Scientific coordinator –UPMC/Inserm) We are proud of this new discovery of dr. Puri because it comes after eight years of continuous support to his scientific career from the Telethon Foundation Italy – says Dr Lucia Monaco - Chief Scientific Officer of Telethon Foundation– and because it represents a breakthrough towards the development of treatments for neuromuscular disorders which are a priority in our mission since Telethon was founded by patients affected by muscular dystrophies in Italy. "These results are really encouraging for the entire Duchenne community - says Filippo Buccella, President of Parent Project Onlus - and we do hope they will partially contribute to heal the wounds for the many broken dreams of our kids and families. Funding basic research is a hard task for a parents because we can't see the light at the end of the tunnel but it is the only thing that can change the outcomes and we believe Dr. Puri's work will pave the way to future treatments." In the context of muscle related diseases such as the muscular dystrophies this work opens new exciting avenues to explore pharmacological development which will enhance the capacity of muscle stem cells to correctly and effectively repair damaged tissues and treat a plethora of both rare genetic and traumatic events which have a high socio economic impact. About Endostem: EndoStem is a partnership of 15 research and clinical teams from globally recognised academic centres, small biotech and large pharmaceutical companies working together to develop new strategies aimed at stimulating stem cells that are resident in damaged tissue to repair it in situ. This approach is recognised as one of the most promising approaches to targeting stem cells for regenerative medicine due to the alignment with existing therapeutic development approaches used by large industry and recent advances in understanding the key barriers for tissue regeneration. Coordinated by Professor David Sassoon, co-financed by the European Commission via the 7th Framework Programme the aims of the project over are: - Implementation of clinical trials, with muscular dystrophies as the primary clinical target using innovative biopharmaceuticals - Development of novel best in class biopharmaceuticals with highly specific and well defined modes of action - Fast track clinical translation based on a constant feedback loop between emerging patient responsiveness to new drugs and the development of the next generation of therapeutics - Better understanding of the key issues preventing effective tissue repair matched with approaches to circumvent them About Fondazione Telethon Fondazione Telethon is one of the biggest biomedical charities in Italy, whose mission is to advance biomedical research towards diagnosis, cure and prevention of genetic diseases. Since 1991, it has invested 323,7 million Euros in research and funded 2,261 research projects on more than 450 human genetic diseases, which range from basic research to clinical trials. In order to favour the career of young talented scientists, Telethon has also conceived a program of personal awards to be granted to independent researchers who wish to pursue topics relevant to human genetic diseases, hosted by suitable Institutions. All the Telethon Scientists are identified as members of the “Dulbecco Telethon Institute” (DTI), so called in honour of Prof. Renato Dulbecco, as he made the first donation to this incentive. For further information, please visit www.telethon.it/english/ About Parent Project Parent Project onlus is a nonprofit organization based in Italy, focused entirely on Duchenne/Becker muscular dystrophy (DMD/BMD) and it is organized and managed by parents of boys who are affected by this genetic disorder. Since 1996 Parent Project Onlus' mission is to identify, support and share promising Duchenne related research. It also works to make state-of-the-art information about treatment and care options available to all members of the Duchenne community and encourages policymakers to afford the same priority to Duchenne as they would to other disorders of similar incidence and prevalence. Parent Project onlus is founding member of the international federation United Parent Projects Muscular Dystrophy, managed by parent project organisations set up in many different countries all over the world. About Sanford Burnham Sanford-Burnham Medical Research Institute is dedicated to discovering the fundamental molecular causes of disease and devising the innovative therapies of tomorrow. Sanford-Burnham, with operations in California and Florida, is one of the fastest-growing research institutes in the country. The Institute ranks among the top independent research institutions nationally for NIH grant funding and among the top organizations worldwide for its research impact. From 1999 – 2009, Sanford-Burnham ranked #1 worldwide among all types of organizations in the fields of biology and biochemistry for the impact of its research publications, defined by citations per publication, according to the Institute for Scientific Information. According to government statistics, Sanford-Burnham ranks #2 nationally among all organizations in capital efficiency of generating patents, defined by the number of patents issued per grant dollars awarded. Sanford-Burnham utilizes a unique, collaborative approach to medical research and has established major research programs in cancer, neurodegeneration, diabetes, and infectious, inflammatory, and childhood diseases. The Institute is especially known for its world-class capabilities in stem cell research and drug discovery technologies. Sanford-Burnham is a nonprofit public benefit corporation. For more information, please visit www.sanfordburnham.org. References: The original of this work has been published in Cell Stem Cell 7, 1-15,October 8, 2010 with the title “TNF/p38 alpha/Polycomb signalling to Pax7 locus in satellite cells links inflammation to the epigenetic control of muscle regeneration”
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