Therapeutic Delivery of Pip4k2c‐Modified mRNA Attenuates Cardiac Hypertrophy and Fibrosis in the Failing Heart. Issue 10 (12th March 2021)

• Record Type: Journal Article
• Authors: Magadum, Ajit; Singh, Neha; Kurian, Ann Anu; Sharkar, Mohammad Tofael Kabir; Sultana, Nishat; Chepurko, Elena; Kaur, Keerat; Żak, Magdalena M.; Hadas, Yoav; Lebeche, Djamel; Sahoo, Susmita; Hajjar, Roger; Zangi, Lior
• Is Part Of: Advanced science. Volume 8:Issue 10(2021)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2021-03-12
• Subjects: fibrosis -- gene therapy -- heart failure -- hypertrophy; Science -- Periodicals; 505
• DOI: 10.1002/advs.202004661
• Languages: English
• ISSNs: 2198-3844

Abstract

Abstract: Heart failure (HF) remains a major cause of morbidity and mortality worldwide. 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‐ β, respectively. Type‐2‐phosphatidylinositol‐5‐phosphate‐4‐kinase‐gamma (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‐injured 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 −/− mice has higher rates of CH, CF, and sudden death than wild‐type mice. In a gain‐of‐function 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 β 1 via its N‐terminal motif, Pip5k1 α, phospho‐AKT 1/2/3, and phospho‐Smad3. In sum, loss‐and‐gain‐of‐function 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. Abstract : Heart failure remains a major cause of morbidity and mortality worldwide. One of the risk factors for HF is cardiac hypertrophy (CH), which is frequently accompanied by cardiac fibrosis (CF). Here, gain‐ and loss‐of‐function studies are used to identify the therapeutic role of Pip4k2c in preventing CH and CF via inhibition of mTOR and TGF β 1 pathways, respectively.