Journal of IiME Volume 1 Issue 2 www.investinme.org Gene therapy for mitochondrial dysfunctions using optimized mRNA transport to the mitochondrial surface (continued) Our position in the international research field Mitochondrial disorders can not be ignored anymore in most medical areas. They include specific and widespread organ involvement, with tissue degeneration or tumor formation. Primary or secondary actors, mitochondrial dysfunctions are also playing a role in the ageing process. Despite the progresses made in the identification of their molecular bases, nearly all remains to be done as regards therapy. Research dealing with mitochondrial physiology and pathology has almost 20 years of history all over the world. We are involved, as many other laboratories, in the challenge to find ways to fight these diseases. However, our main limitation is the absence of animal models required for both the understanding of the molecular mechanisms underlying the diseases and to evaluate therapeutic strategies. This is especially true for diseases due to mtDNA mutations, an American team has recently described a strategy similar to the one we have developed, to induce retinal ganglion cell degeneration in mice 37. Nevertheless, their strategy encounters the limitation of the inefficient mitochondrial import of the protein and will not generate a robust experimental model to evaluate putative treatments. If we succeed in creating a long-term animal model for the mitochondrial ND4 mutation and in confirming that it shares similarities with LHON, it will certainly allow the rapid development of new model systems for studying mtDNA mutations which are to date extremely rare. Most importantly, our protocol of gene replacement therapy for both the rat model and the Harlequin mouse strain will permit the development of clinical trials to treat patients suffering for visual impairment due to mitochondrial dysfunction. These clinical studies will be performed in the Vision Institute, a guarantee of expertise, rigour and thorough. Therefore, we are convinced that we possess a significant advance in comparison to laboratories working in the field worldwide. Bibliography 1. Orrenius S GV, Zhivotovsky. Mitochondrial oxidative stress: implications for cell death. Annu Rev Pharmacol Toxicol. 2007;47:143-183. 2. McFarland R TR, Turnbull DM. Mitochondrial disease-its impact, etiology, and pathology. Curr Top Dev Biol. 2007;77:113-155. 3. Singh KK. Mitochondria damage checkpoint, aging, and cancer. Ann. N. Y. Acad. Sci. 2006;1067:182-190. 4. Schaefer A.M, Taylor R. W., Turnbull D. M., P.F C. The epidemiology of mitochondrial disorders -past, present and future. Biochem. Biophys. Acta 2004;1659:115-120. 5. Shapira AHV. Mitochondrial disease. Lancet 2006;368:70-82. Invest in ME Charity Nr 1114035 (continued on page 28) Page 27/72 Mitochondrial disorders can not be ignored anymore in most medical areas. They include specific and widespread organ involvement, with tissue degeneration or tumor formation. Primary or secondary actors, mitochondrial dysfunctions are also playing a role in the ageing process. Despite the progresses made in the identification of their molecular bases, nearly all remains to be done as regards therapy. 6. Calvo S JM, Xie X, Sheth SA, Chang B, Goldberger OA, Spinazzola A, Zeviani M, Carr SA, Mootha VK. Systematic identification of human mitochondrial disease genes through integrative genomics. Nat. Genet. 2006;38:576-582 7. Taylor SW, Fahy E, Ghosh SS. Global organellar proteomics. Trends in Biotech. 2003;21(2):82-88. 8. Prokisch H AC, Ahting U, Heiss K, Ruepp A, Scharfe C, Meitinger T. MitoP2: the mitochondrial proteome database--now including mouse data. Nucleic Acids Res. 2006;34 (Database issue):D705-711. 9. Perkins GA EM, Fox DA. The structure-function correlates of mammalian rod and cone photoreceptor mitochondria: observations and unanswered questions. Mitochondrion 2004;4:695-703. 10. Feher J KI, Artico M, Cavallotti C, Papale A, Balacco Gabrieli C. Mitochondrial alterations of retinal pigment epithelium in age-related macular degeneration. Neurobiol. Aging 2006;27:983-993. 11. Votruba M. Molecular genetic basis of primary inherited optic neuropathies. Eye 2004;18:1126-1132. 12. Bainbridge J, Tan M, Ali R. Gene therapy progress and prospects: the eye. Gene Ther. 2006;13:1191-1197. 13. Hanein S, Perrault, J., Gerber, S., Tanguy, G., Rozet, J.M. and Kaplan, J. Leber congenital amaurosis: survey of the genetic heterogeneity, refinement of the clinical definition and phenotype-genotype correlations as a strategy for molecular diagnosis. Clinical and molecular survey in LCA. Adv. Exp. Med. Biol. 2006;572:15-20.
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