EndoStem mid-term review: Stimulating Endogenous Stem Cells as a therapy for Degenerative Muscle Disease
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, is making significant advances in the development of novel therapies that target resident stem cells and encourage them to repair damaged tissue in situ, with a specific focus on muscle diseases. Clinical trials portfolio Italfarmaco is initiating a phase Ib/IIA clinical trial using the HDAC inhibitor Givinostat. Already approved by the EMA as an orphan drug to treat systemic juvenile idiopathic arthritis, it is being repositioned to treat Duchenne Muscular dystrophy. It has been shown, by scientists from the consortium, that this same drug can promote regeneration of dystrophic muscles while reducing the formation of fibrotic scars and fat deposition in preclinical animal models. Given the suitability to Givinostat for treatment of paediatric patients, the collaboration is moving forward with the planning of a clinical trial in DMD patients. Santhera is developing a novel formulation of omigapil, a small and repurposed anti-apoptotic molecule, and supporting the planning of a Phase I study that will determine the pharmacokinetic, safety and tolerability profile of omigapil in children. CureCMD, a dedicated patient advocacy group whose mission is to bring research, treatments and, in the future, a cure for Congenital Muscular Dystrophies, also supports the study. IRCCS E. Medea has successfully finalised a phase IIa clinical trial on patients suffering from Duchenne, Becker and Limb Girdle dystrophies using a combination of nitric oxide and ibuprofen last year to establish the profile of safety and tolerability of the drug combination1. The protocol has been sent for auditing to the TreatNMD Therapeutic Advisory Committee (TACT) of the TREAT-NMD EU consortium, and at present further development is being planned with the Parent Project Onlus for commercialisation. Based on the identification of novel biomarkers2, which will give clearer indication of therapeutic success, the Inserm/UPMC sponsored clinical trial for SEPN1-related myopathy using the antioxidant N-acetyl cysteine is having its updated protocol reviewed by the relevant authorities, prior to an anticipated clinical trial start date this year. An important aim of these clinical trials is to correlate the beneficial effects of molecules used and their effect on endogenous stem cells. The consortium has shown that measurements of two specific cytokines, TGF beta and IL-6, may be used as a non-invasive tool to predict of clinical efficacy in terms or regeneration. New biotherapies pre-clinical development Several novel biotherapies are advancing in their validation steps, prior to being considered for submission to the authorities for clinical testing. HMG Biotech is developing a therapeutic based on High-mobility group box 1 (HMGB1), which is a nuclear protein involved in inflammatory responses and tissue repair. An HMGB1 superagonist is under development, and further experiments in a model of muscle damage will determine if it can favour tissue regeneration. However, essential information was still missing: how does HMGB1 recruit stem cells to the damaged tissue? A recent publication coauthored by HMGBiotech scientists3 shows that HMGB1 can form a complex with SDF-1/CXCL12, a chemokine already known to be involved in stem cell recruitment to damaged muscles; the complex acts via CXCR4, a well-known receptor for SDF-1, but is more powerful than SDF-1 alone. The CNR, is developing therapeutics based on the CRIPTO proteins, which enhances skeletal muscle regeneration and satellite cell mobilization. A fragment of Cripto protein (sCripto) is currently being tested as a new therapeutic to improve regeneration that occurs normally and in a mouse model of acute injury. The biodelivery of sCripto is being refined. In order to identify state of the art nucleic acid therapeutics for muscular dysfunction, the impact of miRNA on muscle function and vascular stem cells has been assessed at the University of Frankfurt. Preliminary results indicate that silencing specific miRNA’s with specific antagonists can improve muscle function in models representing the aged scenario, as assessed by non-invasive imaging. Further information on mechanism’s of stem cell control in situ such as the identification of the relationship between the different adult stem cell populations present in muscle, and the method in which stem cells are converted into mobilized stem cells that will activate muscle regeneration matched with the use of pertinent models already present in the partnership are permitting the fast tracking and repositioning of all the therapies in development. One specific area that is being addressed in detail is the impact of the therapies on the scarring (fibrosis) and inflammation process in general: not only will this reveal critical information on mechanism of action of the therapies, but just as importantly, due to the impact of fibrosis and inflammation in the effective regeneration of all damaged tissue (not only muscle), may offer insights into the repositioning of these drugs, in a cost effective way for other degenerative diseases. Quotes "We share and support the commitment of the Endostem Consortium to promote the development of novel therapies in the stem cell field with a specific focus on muscle diseases", said Filippo Buccella - President of Parent Project Onlus, a nonprofit organization focused on Duchenne and Becker Muscular Dystrophy- "to date several new strategies came into clinical trials and additional ones are on the route. This is a great success since it is our opinion that the efficacy of a hypothetical future therapy to cure our sons will be strictly dependent on a multi target approach". Cure CMD's Chairman, Anne Rutkowski, MD, acknowledges the fundamental role Endostem support has played in realizing the Omigapil pK study in congenital muscular dystrophy. "Developing clinical trial opportunities in the rare disease sector, such as CMD, requires a level of intellectual and financial commitment and collaboration by advocacy, the pharmaceutical industry, clinicians and international funding calls. Bringing omigapil forward demonstrates the strength of this network" "At the midterm of the project, the progress being made is exceptional" stated Jonathan Dando PhD (Managing Director, Dando Weiss & Colucci Ltd, responsible for development and exploitation coordination),"the portfolio of clinical and pre clinical projects represent a spectrum of approaches which can be developed to target these rare muscular diseases, and by doing so also provide critical insights into tissue regeneration which can be applied to other degenerative disorders" References 1- Grazia D'Angelo M, Gandossini S, Martinelli Boneschi F, Sciorati C, Bonato S, Brighina E, Pietro Comi G, Turconi AC, Magri F, Stefanoni G, Brunelli S, Baldelli S, Bresolin N, Cattaneo D, Clementi E. Nitric oxide donor and non steroidal anti inflammatory drugs as a therapy for muscular dystrophies: Evidence from a safety study with pilot efficacy measures in adult dystrophic patients. Pharmacol Res. 2012 Apr;65(4):472-9. Link 2- James J. Dowling; Sandrine Arbogast; Junguk Hur; Darcee D. Nelson; Anna McEvoy; Trent Waugh; Isabelle Marty; Joel Lunardi; Susan V. Brooks; John Y. Kuwada; Ana Ferreiro . Oxidative stress and successful antioxidant treatment in models of RYR1-related myopathy. Brain 2012 Apr;135:1115-27. Link 3- Schiraldi M, Raucci A, Muñoz LM, Livoti E, Celona B, Venereau E, Apuzzo T, De Marchis F, Pedotti M, Bachi A, Thelen M, Varani L, Mellado M, Proudfoot A, Bianchi ME, Uguccioni M. HMGB1 promotes recruitment of inflammatory cells to damaged tissues by forming a complex with CXCL12 and signaling via CXCR4. J Exp Med. 2012 Mar 12;209(3):551-63. Link 4- Giampietro C, Taddei A, Corada M, Sarra-Ferraris GM, Alcalay M, Cavallaro U, Orsenigo F, Lampugnani MG, Dejana E. Overlapping and divergent signaling pathways of N-cadherin and VE-cadherin in endothelial cells. Blood. 2012 Mar 1;119(9):2159-70. Link
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