Preclinical tests for gene therapy of advanced heart failure

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Considerable results was obtained in the first 3 objects, i.e. (1)Preparation of advanced heart failure of human-mimicking type in large animals, (2)Verification of safety and efficacy of gene therapy and (3)Development of reconstructed cell-based therapy. We have identified responsible gene for congenital dilated cardiomyopathy (DCM) as a mutation of δ-sarcoglycan gene (Sakamoto et al., PNAS,1997). Then, we have for the first time succeeded in gene therapy with using stable and long-lasting rAAV vector (Kawada et al, PNAS,2002). Different from other vectors, rAAV was safe and biologically inert. To extend our project for clinical study using apes, we had to consume one and a half year for the permission of the Ministry of Education, Culture, Science and Technology. Our final paradigm that heart failure is proceeded by a common mechanism secondary to dystrophin disruption and increment of sarcolemmal permeability, irrespective of hereditary or acquired origins and acute or chronic processes was common to heart failure in general including human DCM was extremely precious, because these data were not ethically obtained without employing apes (Toyo-oka et al., PNAS,2004). These results would provide a promising fruit to develop for the clinical application, and we do ask future fund.