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Journal of Regenerative Medicine ISSN: 2325-9620

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Commentary, J Regen Med Vol: 2 Issue: 2

Regenerative Potential of Stem Cells for Duchenne Muscular Dystrophy

Dario Siniscalco1,2* and Nataliia Sych3
1Department of Experimental Medicine, Second University of Naples, Italy
2Centre for Autism – La Forza del Silenzio, Caserta, Italy
3Clinical Department, Cell Therapy Center EmCell, Kiev, Ukraine
Corresponding author : Dario Siniscalco, ChemD, PhD
Department of Experimental Medicine, Second University of Naples; via S. Maria di Costantinopoli, 16 - 80138 Napoli, Italy
Tel: +39(0)81-5665880; Fax: +39(0)81-5667503
E-mail: [email protected]
Received: March 08, 2013 Accepted: September 30, 2013 Published: October 05, 2013
Citation: Siniscalco D, Sych N (2013) Regenerative Potential of Stem Cells for Duchenne Muscular Dystrophy. J Regen Med 2:2. doi:10.4172/2325-9620.1000109

Abstract

Regenerative Potential of Stem Cells for Duchenne Muscular Dystrophy

Duchenne muscular dystrophy (DMD) is a childhood, severe, X-chromosome linked neuromuscular disorder, affecting 1:3500 male births. It is characterized by mutations in the dystrophin gene, leading to the alteration of the open reading frame and consequently to the loss of dystrophin protein synthesis. The muscular degeneration of muscle fibres causes progressive damage leading to death. Currently, there is no curative treatment for DMD [4], as this disorder can be considered an untreatable fatal disease. Novel therapeutical approaches have been proposed in the last years. Among them, gene replacement theory has gained substantial attention. Targeted exon-skipping through RNA to exclude specific sites of RNA splicing, or with antisense oligonucleotides can induce the restoring of the open reading frame and the production of a functional, even if smaller, dystrophin protein.

Keywords:

 
Duchenne muscular dystrophy (DMD) is a childhood, severe, X-chromosome linked neuromuscular disorder, affecting 1:3500 male births [1-3]. It is characterized by mutations in the dystrophin gene, leading to the alteration of the open reading frame and consequently to the loss of dystrophin protein synthesis. The muscular degeneration of muscle fibres causes progressive damage leading to death. Currently, there is no curative treatment for DMD [4], as this disorder can be considered an untreatable fatal disease. Novel therapeutical approaches have been proposed in the last years [5]. Among them, gene replacement theory has gained substantial attention. Targeted exon-skipping through RNA to exclude specific sites of RNA splicing, or with antisense oligonucleotides can induce the restoring of the open reading frame and the production of a functional, even if smaller, dystrophin protein [2,6]. However, several efforts must be encompassed for these methods, such as increased exon skipping efficiency, an optimized oligonucleotide sequence, backbone chemistry and additional modifications (i.e. peptideconjugated derivatives, morpholino phosphorodiamidate oligomers and 2’-O-methyl phosphorothioate oligonucleotide) [7]. Currently, there is no approved therapy for the treatment of DMD [8]. Beyond gene replacement strategy, the novel findings in cell therapy and regenerative medicine could offer new treatment modality for incurable human diseases [9-11], including DMD. Cell-based therapy targets muscle regeneration. Several types of cells have been proposed to achieve this goal. Injected myoblast cells are able to develop new muscle fibers, even if several limitations have been proposed, such as poor cell survival and limited migratory ability [12].
Stem cells could help in promoting muscle regeneration through their properties of self-renewal and differentiation [13,14]. Several pre-clinical and/or in vitro studies have shown promising results. In mdx mice, a model of DMD, mesenchymal stem cell (MSC) transplantation was able to restore dystrophin expression in the skeletal muscle up to the 12th week after transplantation [15]. Transducing these stem cells by retrovirus carrying a functional human microdystrophin gene was a successfully strategy. Another experimental study has demonstrated that MSC engraftment in dogs affected by X-linked muscular dystrophy was responsible to develop muscle-like tissue within 8-12 weeks in the absence of immunosuppression and dystrophin gene was up-regulated in the newly formed tissues [16]. Furthermore, in an experimental model of DMD in dogs, adherent stem cells, isolated from healthy dog muscle and injected in dystrophic dogs, were able to promote long-term dystrophin expression, muscle damage course limitation and the regeneration activity [17]. Transplantation of human muscle-derived stem cells to the gastrocnemius muscle of mdx mice increased the levels of muscle regeneration [18].
Interestingly, a combination of human artificial chromosomesmediated gene replacement and transplantation with blood vesselassociated stem cells in mdx mice showed functional amelioration of the dystrophic phenotype [19].
Induced pluripotent stem cells (iPSCs) extracted from healthy mice and transplanted in mdx mice showed promising results [20]. It has been demonstrated that transplantation of iPS-derived myogenic progenitors with conditional expression of Pax7 into dystrophic mice was effective in improved contractility of treated muscles [21] and in restoring dystrophin [22].
Among stem cell types, which could be optimal for treating DMD? Multipotent mesenchymal stem cells are of special interest because of their ability to differentiate in situ to form myogenic cells. Whereas, iPSCs and human amniotic fluid-derived AF-type stem cells hold promise as a potential treatment for DMD [23,24]. In the last years, fetal stem cells have gained many considerations for therapeutic purposes [25]. These stem cells are more specialized than embryonic stem cells, but they do not show the concerns regarding the in vivo teratoma formation and uncontrollable cell proliferation of undifferentiated embryonic stem cells [26], as well as there are no ethical issues [27]. In addition, fetal stem cells exhibit a potent expansion capacity and plasticity [28]. Based on their characteristics: strong immunomodulatory effects, stable phenotype and less senescence, together with the capacity to engraft and home to damaged tissue [29], fetal stem cells are useful candidate for clinical cell-based DMD therapy.
Untreatable diseases could be resolved by cellular therapy [30]. However, full understanding of the exact mechanisms of actions and of the biology of stem cells remains to be elucidated for a better clinical use of these cells.

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