Therapeutic Delivery of Pip4k2c-Modified mRNA Attenuates Cardiac Hypertrophy and Fibrosis in the Failing Heart

Ajit Magadum, Neha Singh, Ann Anu Kurian, Mohammad Tofael Kabir Sharkar, Nishat Sultana, Elena Chepurko, Keerat Kaur, Magdalena M. Żak, Yoav Hadas, Djamel Lebeche, Susmita Sahoo, Roger Hajjar, Lior Zangi

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

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 TGFβ1 via its N-terminal motif, Pip5k1α, 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.

Original languageEnglish
Article number2004661
JournalAdvanced Science
Volume8
Issue number10
DOIs
StatePublished - 19 May 2021

Keywords

  • fibrosis
  • gene therapy
  • heart failure
  • hypertrophy

Fingerprint

Dive into the research topics of 'Therapeutic Delivery of Pip4k2c-Modified mRNA Attenuates Cardiac Hypertrophy and Fibrosis in the Failing Heart'. Together they form a unique fingerprint.

Cite this