Paris (France), March 2014 – The EndoStem consortium (www.endostem.eu) a large scale scientific collaboration coordinated by Dr David Sassoon (UPMC/Inserm, Paris, France), and co-financed by the European Commission via the 7th Framework Programme, has generated a number of advances, with continued excitement and advances in the clinical trials for treating muscular dystrophies by targeting endogenous stem cells, while developing future avenues for repair. The impact of the work being performed has great benefit for treating rare muscular disorders, which also extends to the larger number of more common degenerative diseases; diseases which share common mechanisms during tissue damage and repair which could be corrected from the projects insights offering complete functional restoration and a return to a high quality of life. Clinical trials in progress The project participants have carried out preclinical studies on selected compounds with the aim of providing ground for their testing in clinical trials to assess their suitability as therapeutics. Of the various approaches, two have now reached clinical testing. These are the combination of nitric oxide (NO) donating molecules isosorbide dinitrate with the non-steroidal anti-inflammatory drug (NSAIDs) ibuprofen and the histone deacetylase inhibitor Givinostat. The first is pursued with the help of a charity fund, Parent Project Onlus, the second is a joint effort for the preclinical development and biomarkers design, and the clinical development. A third drug, is the antioxidant drug N-acetyl cysteine used as scavenger of reactive oxygen species in the SEPN1-related myopathy. This study has also finalized the preclinical part and a clinical trial is expected to start in a few months time. A fourth compound omigapil, has completed the preclinical and toxicological phase while a fifth compound, a soluble for Cripto is developed to an advanced preclinical development stage. In summary clinical trials using therapeutics of 4 different pharmacological approaches, several clinical trials are scheduled or have already started - Phase IIa Clinical trial Using Nitric Oxide (NO) + NSAID as therapeutic agent - Phase II clinical trial using N-acetyl cysteine (NAC) as a therapeutic agent - Phase 1 pharmacokinetic, tolerability and feasibility study with omigapil in patients with CMD (scheduled to may 2014) - Phase Ib/2a Study of HDACi in Duchenne Muscular Dystrophy (started march 2013) Pre-clinical development Endostem also aims to understand the molecular and cellular mechanisms involved in muscle growth and regeneration. This understanding allows the identification of molecules that can be used to activate muscle regeneration through endogenous stem cell cells mobilization. Several partners have shown the existence of different stem cells lineages that co-exist in skeletal muscle (PICs and FAPs). Most studies show the importance of the signaling and the crosstalk between these lineages. Data indicate that PICs and satellite cells crosstalk through common pathways. The balance between negative factor and positive factors produced by these populations likely plays a crucial role in muscle size regulation. These data, indicate that PICs and FAPs provide a novel source of endogenous, pharmacologically inducible, population of intramuscular cells that can be exploited to regenerate dystrophic muscles and prevent deleterious events, such as fibro-adipose infiltration of muscles that complicate DMD progression. In the aim of identifying new therapeutic targets, 2 miRNAs that have been characterised with functional relevance in skeletal muscle. Both miRNAs are highly upregulated in different muscle disease models thereby representing attractive targets for further investigations. Other targets include the novel form of the HMGB protein which is resistant to oxidation and behaves as a superagonist for cell recruitment while modulating the immune environment. This superagonist has beneficial effects in skeletal muscle regeneration after acute injury by increasing the number of healthy fibres, muscle stem cells and immune regulatory cells, which are essential for muscle repair.
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