Noncoding RNA based strategies to treat doxorubicin induced cardiotoxicity

• Applicant: Shashi Kumar Gupta, Ph.D.
• Subject Area: Cardiology, Angiology
• Term: from 2015 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 282185944

Doxorubicin, a commonly used anthracycline for chemotherapy, has shown a dose dependent cardiotoxicity in patients leading to heart failure. There is no promising treatment strategy available to reduce doxorubicin associated cardiotoxicity as efforts have been hampered by lower anti-tumour effects and chances of secondary malignancies. Thus, there is an urgent need for development of therapies, which reduce cardiotoxicity without compromising anti-tumour effects for healthy living of cancer survivors. MicroRNAs are short non coding RNA molecules which had demonstrated therapeutic potential in various disease conditions. However, microRNA based therapies have never been used to reduce doxorubicin associated cardiotoxicity. We have previously shown that the miR-212/132 family regulates cardiac hypertrophy and autophagy. Furthermore, our preliminary results indicate that miR-212/132 family can inhibit atrophy and autophagy stimulated by doxorubicin in vitro in cardiomyocytes. Therefore, we aim to overexpress miR-212/132 to decrease cardiotoxicity induced by doxorubicin by utilizing AAV9 based viral delivery strategy. In the proposed project, we will employ a clinically relevant mouse model of doxorubicin mediated cardiotoxicity and will overexpress the miR-212/132 family in vivo by AAV9 to improve cardiac function and avoid induced atrophy. A detailed analysis will be performed to uncover the mechanism behind the protective effect of miR-212/132 family. The findings from rodent models will also be translated to iPS derived human cardiomyocytes. The proposed study may lead to the successful development of therapy in a field compromised due to unavailability of proper treatment.

• DFG Programme: Research Grants