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• W1578833500 abstract "Stimulating an endogenous regenerative response is a powerful approach for potential treatment of chronic demyelinating diseases such as multiple sclerosis. Recently in Nature, Najm et al., 2015Najm F.J. Madhavan M. Zaremba A. Shick E. Karl R.T. Factor D.C. Miller T.E. Nevin Z.S. Kantor C. Sargent A. et al.Nature. 2015; (in press. Published online April 20, 2015)https://doi.org/10.1038/nature14335Crossref PubMed Scopus (287) Google Scholar identified two clinically relevant, FDA-approved compounds that promote oligodendrocyte progenitor cell differentiation and induce remyelination in demyelinating disease models. Stimulating an endogenous regenerative response is a powerful approach for potential treatment of chronic demyelinating diseases such as multiple sclerosis. Recently in Nature, Najm et al., 2015Najm F.J. Madhavan M. Zaremba A. Shick E. Karl R.T. Factor D.C. Miller T.E. Nevin Z.S. Kantor C. Sargent A. et al.Nature. 2015; (in press. Published online April 20, 2015)https://doi.org/10.1038/nature14335Crossref PubMed Scopus (287) Google Scholar identified two clinically relevant, FDA-approved compounds that promote oligodendrocyte progenitor cell differentiation and induce remyelination in demyelinating disease models. Received wisdom is that the adult mammalian central nervous system (CNS) is not a good regenerator. While undoubtedly true for neurons, which are not widely generated de novo after damage nor readily regenerate damaged axons, the same cannot be said for glia and, in particular, oligodendrocytes. Oligodendrocytes are the myelinating cells of the CNS that protect and promote neuronal function, and loss of these cells, for instance in diseases such as multiple sclerosis (MS), results in demyelination of axons, compromising their activity and survival. Axons require an intact myelin sheath to sustain their integrity, and persistent demyelination leaves them vulnerable to irreversible and cumulative degeneration. The regeneration of lost oligodendrocytes is in many ways a paradigmatic example of regeneration: replacement oligodendrocytes are generated after injury-induced activation, recruitment and differentiation of a widespread population of multipotent adult neural stem cells, commonly referred to as oligodendrocyte progenitor cells (OPCs). These newly generated oligodendrocytes restore the original architecture and function of the damaged tissue (Franklin and Ffrench-Constant, 2008Franklin R.J.M. ffrench-Constant C. Nat. Rev. Neurosci. 2008; 9: 839-855Crossref PubMed Scopus (1100) Google Scholar). This is termed remyelination, and it is a true regenerative process. So, if remyelination works, why then is there an urgent need for remyelination-enhancing therapies and why is a recent study by Najm and colleagues (Najm et al., 2015Najm F.J. Madhavan M. Zaremba A. Shick E. Karl R.T. Factor D.C. Miller T.E. Nevin Z.S. Kantor C. Sargent A. et al.Nature. 2015; (in press. Published online April 20, 2015)https://doi.org/10.1038/nature14335Crossref PubMed Scopus (287) Google Scholar), which reports the identification of two small molecules with such activity, such a significant advance toward meeting this need? The efficiency of remyelination declines progressively with aging (van Wijngaarden and Franklin, 2013van Wijngaarden P. Franklin R.J.M. Development. 2013; 140: 2562-2575Crossref PubMed Scopus (36) Google Scholar). In chronic demyelinating diseases such as MS, the efficiency of remyelination declines to the point where, to all intents and purposes, it fails. Thus, promotion of remyelination, in addition to restoring lost function, should also result in axon preservation. The principal bottleneck in remyelination that occurs with aging is the failure of recruited oligodendrocyte lineage cells to differentiate into new oligodendrocytes, and undifferentiated oligodendrocyte lineage cells are frequently observed in areas of chronic demyelination in MS patients. Previous work using the heterochronic parabiosis model has demonstrated that the effects of aging are reversible, and that when provided with the correct environmental signals, old adult OPCs can remyelinate as efficiently as young adult OPCs (Ruckh et al., 2012Ruckh J.M. Zhao J.W. Shadrach J.L. van Wijngaarden P. Rao T.N. Wagers A.J. Franklin R.J.M. Cell Stem Cell. 2012; 10: 96-103Abstract Full Text Full Text PDF PubMed Scopus (448) Google Scholar). This implies that overcoming the declining efficiency of remyelination with aging can be achieved in principle by pharmacological means rather than by cell therapy, spurring the quest in many laboratories to identity targets that drive OPC differentiation. Tesar and colleagues (Najm et al., 2015Najm F.J. Madhavan M. Zaremba A. Shick E. Karl R.T. Factor D.C. Miller T.E. Nevin Z.S. Kantor C. Sargent A. et al.Nature. 2015; (in press. Published online April 20, 2015)https://doi.org/10.1038/nature14335Crossref PubMed Scopus (287) Google Scholar), using a similar approach to several other recent studies (Deshmukh et al., 2013Deshmukh V.A. Tardif V. Lyssiotis C.A. Green C.C. Kerman B. Kim H.J. Padmanabhan K. Swoboda J.G. Ahmad I. Kondo T. et al.Nature. 2013; 502: 327-332Crossref PubMed Scopus (364) Google Scholar, Mei et al., 2014Mei F. Fancy S.P. Shen Y.A. Niu J. Zhao C. Presley B. Miao E. Lee S. Mayoral S.R. Redmond S.A. et al.Nat. Med. 2014; 20: 954-960Crossref PubMed Scopus (363) Google Scholar), performed phenotypic screens using small molecule libraries to reveal compounds that promote oligodendrocyte differentiation. Najm et al. screened a library of bioactive small compounds with a history of safe use in clinical trials, thereby providing immediate translational value, to identify molecules that induce differentiation of mouse epiblast-derived OPCs. This approach identified two FDA-approved drugs, miconazole and clobestasol, the first a topical antifungal agent and the second a potent topical corticosteroid, that are both able to cross the blood-brain barrier. While the initial screen was based on the ability of tested compounds to enhance production of membrane sheet-forming oligodendrocytes in vitro, the two drugs were then tested in what may well become a standard hierarchical series of experimental models of myelination/remyelination of increasing complexity. Both compounds showed activity in ex vivo slice preparations of developmental myelination, toxin-induced demyelination in adult rodent spinal cord, and experimental autoimmune encephalomyelitis (EAE), an immune-mediated model of CNS inflammation believed to most closely model the pathology of MS. Finally, to verify the translational value of data generated from rodents, both drugs were found to induce differentiation of human OPCs derived from hESCs and hiPSCs. Analysis of the OPC signaling pathways likely influenced by these drugs revealed that clobetasol activity is mediated through the glucocorticoid receptor signaling axis, while miconazole functions through MEK-dependent activation of Erk1/2. The use of EAE models for assessing remyelination is not without substantial difficulties. Though proven valuable for understanding the immunopathogenesis of MS, there is the possibility that the therapeutic manipulation being tested may have direct effects on the adaptive immune response on which the EAE model is based. If the intervention were to suppress this response then the degree of demyelination may be reduced, which could be misconstrued as more remyelination. Additionally, if the treatment removes a response inimical to the oligodendrocyte lineage, remyelination could occur at its natural tempo but not necessarily be enhanced (akin to allowing a car to go faster by removing the handbrake rather than pressing the accelerator). Najm and colleagues, attentive to these possibilities, go to some pains to show that their treatments do not influence the adaptive immune response, and therefore that the beneficial effects of miconazole and clobestasol on EAE are likely due to direct enhancement of remyelination. However, only a few of the many versions of the EAE model involve bona fide primary demyelination in which there are intact yet demyelinated axons available for remyelination, which further adds to the possibility of confused interpretation of observations. In light of these reservations, there should always be critical evaluation of the necessity of the EAE model, which was developed to understand CNS autoimmunity, as part of the remyelination validation pipeline to confirm regenerative neurobiology. In the last few years, remyelination biology has moved rapidly to the brink of clinical application. The recognition that approved drugs, including an RXR agonist and muscarinic receptor antagonists (Huang et al., 2011Huang J.K. Jarjour A.A. Nait Oumesmar B. Kerninon C. Williams A. Krezel W. Kagechika H. Bauer J. Zhao C. Baron-Van Evercooren A. et al.Nat. Neurosci. 2011; 14: 45-53Crossref PubMed Scopus (382) Google Scholar, Deshmukh et al., 2013Deshmukh V.A. Tardif V. Lyssiotis C.A. Green C.C. Kerman B. Kim H.J. Padmanabhan K. Swoboda J.G. Ahmad I. Kondo T. et al.Nature. 2013; 502: 327-332Crossref PubMed Scopus (364) Google Scholar Mei et al., 2014Mei F. Fancy S.P. Shen Y.A. Niu J. Zhao C. Presley B. Miao E. Lee S. Mayoral S.R. Redmond S.A. et al.Nat. Med. 2014; 20: 954-960Crossref PubMed Scopus (363) Google Scholar) in addition to the two identified by Najm and colleagues, can enhance remyelination in pre-clinical models makes the prospects of clinical trials a long-sought reality. Indeed, encouraging results of the first of these, a phase 2 trial using antibodies to Lingo-1, have recently been reported at this year’s meeting of the American Academy of Neurology Annual meeting (https://www.aan.com/conferences/2015-annual-meeting/). While a deeper understanding of the biology underlying remyelination and the identification of more potential targets will continue to be important areas of future research, perhaps the most important and urgent challenges that we are now faced with relate to clinical translation. Which patients will benefit most from remyelination therapies, and at what stage of disease should these be administered? What are the most reliable outcome measure of such therapies? How should remyelination therapies be optimally coordinated with immunosupression? These are just some examples of the many questions that need urgent answers. It is a testament to the progress and excitement in the MS regenerative medicine field and the significant strides that studies such as that by Najm and colleagues have made that we are now in a position to be even asking such clinically relevant questions." @default.
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• W1578833500 title "Regenerative Medicines for Remyelination: From Aspiration to Reality" @default.
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