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One of the risk factors for HF is cardiac hypertrophy (CH), which is frequently accompanied by cardiac fibrosis (CF). CH and CF are controlled by master regulators mTORC1 and TGF\u2010<jats:italic>\u03b2<\/jats:italic>, respectively. Type\u20102\u2010phosphatidylinositol\u20105\u2010phosphate\u20104\u2010kinase\u2010gamma (Pip4k2c) is a known mTORC1 regulator. It is shown that Pip4k2c is significantly downregulated in the hearts of CH and HF patients as compared to non\u2010injured hearts. The role of Pip4k2c in the heart during development and disease is unknown. It is shown that deleting Pip4k2c does not affect normal embryonic cardiac development; however, three weeks after TAC, adult Pip4k2c<jats:sup>\u2212\/\u2212<\/jats:sup> mice has higher rates of CH, CF, and sudden death than wild\u2010type mice. In a gain\u2010of\u2010function study using a TAC mouse model, Pip4k2c is transiently upregulated using a modified mRNA (modRNA) gene delivery platform, which significantly improve heart function, reverse CH and CF, and lead to increased survival. Mechanistically, it is shown that Pip4k2c inhibits TGF<jats:italic>\u03b2<\/jats:italic>1 via its N\u2010terminal motif, Pip5k1<jats:italic>\u03b1<\/jats:italic>, phospho\u2010AKT 1\/2\/3, and phospho\u2010Smad3. In sum, loss\u2010and\u2010gain\u2010of\u2010function studies in a TAC mouse model are used to identify Pip4k2c as a potential therapeutic target for CF, CH, and HF, for which modRNA is a highly translatable gene therapy approach.<\/jats:p>","DOI":"10.1002\/advs.202004661","type":"journal-article","created":{"date-parts":[[2021,3,12]],"date-time":"2021-03-12T03:35:10Z","timestamp":1615520110000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Therapeutic Delivery of Pip4k2c\u2010Modified mRNA Attenuates Cardiac Hypertrophy and Fibrosis in the Failing Heart"],"prefix":"10.1002","volume":"8","author":[{"given":"Ajit","family":"Magadum","sequence":"first","affiliation":[{"name":"Cardiovascular Research Center Icahn School of Medicine at Mount Sinai  New York NY 10029 USA"},{"name":"Department of Genetics and Genomic Sciences Icahn School of Medicine at Mount Sinai  New York NY 10029 USA"},{"name":"Black Family Stem 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