Gene therapy for myositis
The inflammatory myopathies, polymyositis (PM), dermatomyositis (DM) and inclusion body myositis (IBM), lead to moderate to severe muscle weakness and are characterised by the presence of endomysial inflammation. Each entity has unique clinical, immunopathological and histological characteristics which are associated with different responses to therapies and prognosis. In DM and PM, first-line treatment options include oral corticosteroids, other immunosuppressant drugs, and intravenous immunoglobulins. Patients with IBM, by contrast, usually show a poor or no response to immunomodulatory treatments. Patients with IBM and non-responding patients with PM and DM are candidates for alternative treatment options and experimental therapies including gene therapy. The genetic treatment of inflammatory muscle disorders could involve at least two different strategies: first, to ectopically express local immune modulatory, notably immunosuppressive molecules which would limit inflammation and autoimmunity more effectively than systemic immunosuppressive treatment; second, strategies to promote the repair or allow for the replacement of damaged muscle might be envisaged. Immunosuppressive molecules might include HLA-G, a non-classical major histocompatibility (MHC) Class I molecule, or other cell surface molecules which negatively modulate immune effector cell function. Muscle regeneration might be promoted by myotrophic factors including utrophin or insulin-like growth factors. In addition, cell-based therapies using stem cells or myoblasts might have a therapeutic potential in neuromuscular disorders.
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- 10.Boonstra A, Asselin-Paturel C, Gilliet M, Crain C, Trinchieri G, Liu YJ, O’Garra A (2003) Flexibility of mouse classical and plasmacytoid-derived dendritic cells in directing T helper type 1 and 2 cell development: dependency on antigen dose and differential toll-like receptor ligation. J Exp Med 197: 101–109.CrossRefPubMedGoogle Scholar
- 18.Wiendl H, Mitsdoerffer M, Hofmeister V, Wischhusen J, Weiss EH, Dichgans J, Lochmuller H, Hohlfeld R, Melms A, Weller M (2003) The non-classical MHC molecule HLA-G protects human muscle cells from immune-mediated lysis: implications for myoblast transplantation and gene therapy. Brain 126: 176–185.CrossRefPubMedGoogle Scholar
- 46.Périé S, Mamchaoui K, Mouly V, Blot S, Bouazza B, Thornell LE, St Guily JL, Butler-Browne G (2006) Premature proliferative arrest of cricopharyngeal myoblasts in oculo-pharyngeal muscular dystrophy: Therapeutic perspectives of autologous myoblast transplantation. Neuromuscul Disord 16: 770–781.CrossRefPubMedGoogle Scholar
- 50.Eisenberg I, Avidan N, Potikha T, Hochner H, Chen M, Olender T, Barash M, Shemesh M, Sadeh M, Grabov-Nardini G et al. (2001) The UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase gene is mutated in recessive hereditary inclusion body myopathy. Nat Genet 29: 83–87.CrossRefPubMedGoogle Scholar
- 51.Salama I, Hinderlich S, Shlomai Z, Eisenberg I, Krause S, Yarema K, Argov Z, Lochmuller H, Reutter W, Dabby R et al. (2005) No overall hyposialylation in hereditary inclusion body myopathy myoblasts carrying the homozygous M712T GNE mutation. Biochem Biophys Res Commun 328: 221–226.CrossRefPubMedGoogle Scholar