Heart performance declines during aging and contributes to heart failure, the leading cause of combined morbidity and mortality in the United States. The mechanism of altered heart function during aging is not fully understood, although disturbances in myocyte intracellular calcium handling appear directly involved. Progressive, aging-dependent deficits in heart performance are also associated with various genetic diseases of striated muscle. In Duchene Muscular Dystrophy (DMD), the cytoskeletal protein dystrophin is absent and results in mild cardiac abnormalities early in disease progression. However, heart dysfunction in DMD is markedly aggravated by aging such that by the late teen years most patients have clinically relevant cardiomyopathy. Heart failure accounts for at least 10% of the mortality in DMD. There are no clinical treatments available to directly prevent, halt or correct heart failure associated with aging or DMD. This proposal is focused on determining the capability of viral vectors to systematically express potential therapeutic proteins in the old and diseased heart in vivo. The proposal's unifying hypothesis is that genetic modification of cardiac muscle by viral vectors in vivo will prevent or reverse myocardial performance dysfunction in old animals, and in a model of progressive cardiac muscle disease (mdx mice).
The Specific Aims are to test the following hypotheses: 1. Gutted adenoviral gene transfer, and to a lesser extent rAAV (both serotypes 2 and 6) gene transfer, will overcome the decreased efficiency and stability of cardiac gene transfer in old animals obtained with first generation adenoviral vectors in vivo. 2. Gutted adenoviral gene transfer, and to a lesser extent rAAV gene transfer (both serotypes 2 and 6), of intracellular calcium buffers and pumps to the old heart will attain long-term (months) and physiological levels of expression, and reverse the slowed myocardial relaxation characteristic of old animals in vivo. 3. Gutted adenoviral vectors harboring full length dystrophin will lead to efficient gene transfer, expression, and cytoskeletal localization of dystrophin in adult cardiac myocytes from dystrophic (mdx) mice, and restore both myocyte contractile function and heart organ hemodynamics in vivo.
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