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Atrial-Specific Gene Delivery Using an AAV Vector

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Introduction: Atrial diseases pose a major threaten to human health. Recently Ni L et al established an atrial-specific genetic manipulation system based on AAV (adeno-associated virus) vectors, which facilitates the pathogenesis study of atrial diseases and provides a powerful genetic tool for gene therapy study. The correlated findings were published in the journal of circulation research on Oct 2018.

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The current genetic tool used for atria study is based on an atrial-specific Cre mouse model (sarcolipin-Cre). This genetic tool is beneficial to the study of atrial development and postnatal function. However, as for biomedical and gene therapy study, sarcolipin-Cre-mediated gene manipulation shows many limitations involving labor-intensive and time-consuming. In This study, a promoter sequence of Nppa gene, encoding ANF (atrial natriuretic factor), was packaged into the AAV vectors (AAV-ANF). ANF is a hormone peptide produced and stored in the atria, having a role in the systemic regulation of extracelluar fluid volume and electrolytes. This gene is expressed throughout the whole heart at the early stage, but shows an atrial expression pattern at the postnatal stage.

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Ni L et al constructed two AAV-ANF vectors, AAV-ANF-GFP and AAV-ANF-Cre. They first determined the tissue specificity of AAV-ANF-GFP and found that a dose-dependent GFP expression was specifically restricted to atria compared with other two non-atrial constructs AAV-TNT4-GFP and AAV-enCB-GFP. Then, they investigated the efficiency of AAV-ANF-Cre in Rosa26mT/mG and JPH2 floxed mouse. The results showed an efficient recombination in atrial cardiomyocytes. In addition, an atrial-restricted JPH2 deficiency and abnormal Ca2+ phenotype further supported the high atrial specificity.


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As a whole, this study established an efficient atrial-specific genetic manipulation system (AAV-ANF vectors), showing great insights for mechanistic and gene therapy study on atrial disease.


References
1. Prevalence, incidence and lifetime risk of atrial fibrillation: the Rotterdam study[J]. European Heart Journal
2. American Journal of Physiology - Heart and Circulatory Physiology
3. Atrial-Specific Gene Delivery Using an Adeno-Associated Viral Vector




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