The goal of this study is to exploit detailed knowledge of the pathogenesis of myasthenia gravis (MG) to design rational and effective treatments that avoid some of the problems of existing immunosuppressive drugs. One of the major mechanisms of the pathogenesis of MG involves the antibody-accelerated endocytosis of acetylcholine receptors (AChRs). The process of endocytosis represents an important and as yet untested target for therapy. Literature suggests that phospholipid methyltransferase reactions facilitate endocytosis. We have recently found that accelerated endocytosis is markedly decreased in vitro by drugs that inhibit phospholipid methyltransferases. Our overall aim is to apply this therapeutic approach in vivo, using 3-deazaadenosine (3DZA), a potent and nontoxic methyltransferase inhibitor, and to study the mechanisms by which it exerts its beneficial effect. Our long-term objective is to develop this approach for patients with MG. We will test the anti-endocytosis therapeutic approach in two experimental models, passive transfer of MG in the mouse and experimental autoimmune MG in the rat. Although the major effect of 3DZA is to reduce endocytosis, it has additional immunosuppressive and anti-inflammatory properties. The experimental design will enable us to test the efficacy of 3DZA in the therapy of MG and to dissect its mechanism, in particular determining the roles of phospholipid methylation, antibody- mediated endocytosis, complement-dependent mechanisms, and immunosuppression. The potential advantages of this form of therapy include: (1) It targets the site of the abnormality in MG--the AChR--rather than acetylcholinesterase or the immune system as a whole, since its major effect is on endocytosis; (2) It has a powerful effect on AChR turnover in vitro, yet is non-toxic; (3) As disease-modifying therapy, it could be adequate therapy alone, or if used in conjunction with other drugs may decrease the required dose of toxic agents; (4) Since it acts rapidly to inhibit accelerated degradation of AChRs it is expected to produce rapid benefit, unlike other (immunosuppressive) drugs; (5) An extra benefit in MG may be its additional possible immunosuppressive actions; and finally, (6) It is available for human use and is now undergoing Phase II trials. This proposal is prompted by extensive preliminary studies which are predictive of an effective therapy. The development of this strategy for the treatment of MG could be of major benefit not only for this disease but for other receptor disorders.
| Kuncl, Ralph W; Bilak, Masako M; Craig, Susan W et al. (2003) Exocytotic ""constipation"" is a mechanism of tubulin/lysosomal interaction in colchicine myopathy. Exp Cell Res 285:196-207 |
| Kuncl, R W; Drachman, D B; Adams, R et al. (1993) 3-Deazaadenosine: a therapeutic strategy for myasthenia gravis by decreasing the endocytosis of acetylcholine receptors. J Pharmacol Exp Ther 267:582-9 |
| Kuncl, R W; Wittstein, I; Adams, R N et al. (1993) A novel therapy for myasthenia gravis by reducing the endocytosis of acetylcholine receptors. Ann N Y Acad Sci 681:298-302 |
