Broad objectives and specific aims
The goal of the project is to perturb the microenvironment of dystrophic muscle, rendering it more hospitable for stem cell-mediated therapy.
Background/Rationale
Although stem cell research and related implications have led over the years to a considerable scientific and popular enthusiasm, the important development of regenerative medicine has determined interesting challenges from an ethical and scientific point of view. To date, cell-based therapies stalled by a limited impact of transplanted stem cell on the long term muscle cell replacement. Our working hypothesis is that the hostile dystrophic microenvironment might interfere with and limit the efficacy stem cell-mediated therapy. Thus, the entire path of research is characterized by risks, uncertainties, and problems that require a careful assessment of the foreseeable damages in relation to the expected benefits.
One of the potential candidates that contribute to sustain a hostile microenvironment in dystrophic muscle is Interleukin-6 (IL-6), a molecular marker of M1 macrophages and a critical player in the switch from acute to chronic inflammatory response. Previous work and preliminary results suggest that: i) increased levels of IL-6 exacerbate the pathological phenotype of adult mdx mice, reducing their life span and muscle functional performance; ii) blockade of endogenous IL-6R with neutralizing antibody confer on dystrophic muscles resistance to degeneration.
Description of the project
Based on the preliminary data, we will define whether the therapeutic IL-6 blockade, by the use of IL-6R blocking antibody will improve stem-cell mediated therapy, enhancing the capacity of transplanted stem cells to rescue the dystrophic phenotype.
Anticipated output
The design of a combination of dystrophin and tissue niche therapies might become a potential cornerstone approach for future DMD stem cell therapy.
Lack of a cure drives a necessity for investigation of novel pragmatic therapies to attenuate the multifaceted pathology of DMD. Here we propose to extend and strength previous study, based on the effects of the negative modulation of IL-6 receptor-alpha (IL-6 blockade) on dystrophic phenotype. The anti-inflammatory agents glucocorticoids (GC) are the only available treatment for DMD. However, GC have significant side effects on the course of this fatal disease. Thus, targeting specific mediator of inflammatory response may be more specific, efficacious, and with fewer side effects. Our preliminary data, as well as published evidence, support the hypothesis that a molecule, named interleukin 6 (IL-6), with marked proinflammatory activities, is a pivotal mediator of muscle inflammation in DMD. IL-6 is a pleiotropic cytokine that is produced by different cell types and has the capacity to induce several different intracellular signaling pathways. IL-6 is also locally and transiently produced in response to exercise and injury, and it plays an important role in satellite cell proliferation and muscle growth (Kurek et al. 1996). The complex actions of IL-6 may be linked to the different manners by which this cytokine signals at the plasma membrane and by the different signaling pathways that it can activate (Munoz-Canoves et al. 2013). Based on the activation of either classic or trans-signaling, IL-6 can promote markedly different cellular responses. IL-6 trans-signaling, which requires the soluble IL6R, is pro-inflammatory, whereas classic IL-6 signaling, mediated by membrane-bound receptor, promotes regenerative or anti-inflammatory activities of the cytokine (Rose-John 2012). Proving the role of dystrophic tissue niche on stem cell activity will improve the design of more efficient therapeutic strategies. Thus, if regenerative therapies are to achieve their future potential, an integrated approach is needed to bridge the many gaps in our knowledge in this area of enormous clinical importance. Based on this rationale, any therapeutic strategy aims to restore morpho-functional parameters of dystrophic muscle is unlikely to promote satisfactory results unless the hostile engraftment is modified. We expected that interfering with IL-6 receptor that mediates the transignaling (IL-6RA), create a qualitative environment that makes the dystrophic muscle more resistant to the damage exerted by mechanical contraction. As we stated, our working hypothesis is that the hostile microenvironment impinges the survival and function of rescued dystrophin myofibers. Notably, IL-6 inhibitors are already available and their use have been recently approved in children with systemic juvenile idiopathic arthritis based on a favourable benefit/risk ratio.
Project References
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-Kurek et al 1996. Leukemia inhibitory factor and interleukin-6 are produced by diseased and regenerating skeletal muscle. Muscle Nerve, 19, 1291-1301
-Munoz-Canoves et al 2013. Interleukin-6 myokine signaling in skeletal muscle: a double-edged sword? FEBS J. 280, 4131-4148
-Pelosi et al 2007. Local expression of IGF-1 accelerates muscle regeneration by rapidly modulating inflammatory cytokines and chemokines. FASEB J. 21, 1393-1402
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-Pelosi et al 2015b. Increased levels of interleukin-6 exacerbate the dystrophic phenotype in mdx mice. Hum Mol Genet 24, 6041-6053
-Pelosi et al 2015c. Functional and Morphological Improvement of Dystrophic Muscle by Interleukin 6 Receptor Blockade. EBioMed 2, 285-293
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