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

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-, 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 1 via its N-terminal motif, Pip5k1 , 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.

Identification of a chemical probe for lipid kinase phosphatidylinositol-5-phosphate 4-kinase gamma (PI5P4Kγ)

“…With this approach in mind, we noted that several groups had demonstrated that PI5P4Kγ knockout (KO) impacts the activation of p70-S6 kinase (p70-S6K). This is not surprising given the known feedback loop that exists between mTOR and PI5P4Kγ and that p70-S6K has been described as a mTORC1 pathway marker (Mackey et al ., 2014; Magadum et al ., 2021). Western blot analyses from different tissues from WT versus PI5P4Kγ KO ( Pip4k2c -/- ) mice demonstrated differences in phosphorylation of p70-S6K.…”

“…Phosphorylated p70-S6K was significantly higher in PI5P4Kγ KO mice when compared to WT mice and both cohorts had elevated phosho-p70-S6K when compared to animals not subjected to TAC injury. The authors suggest that PI5P4Kγ negatively regulates the mTORC1 pathway in the heart following TAC (Magadum et al ., 2021).…”

“…The function of PI5P4Kγ is not completely characterized and that contributed to its inclusion on the understudied kinase list for the illuminating the druggable genome (IDG) project (Rodgers et al ., 2018; Berginski et al ., 2020). PI5P4Kγ is expressed primarily in the brain, heart, kidney, and testes (Magadum et al ., 2021). Reports suggest roles for PI5P4Kγ in the modulation of vesicle trafficking, cell proliferation, mammalian target of rapamycin (mTOR) signaling, development and maintenance of epithelial cell functional polarity, regulation of autophagy, and eliciting analgesia (Clarke et al ., 2008; Mackey et al ., 2014; Sharma et al ., 2019).…”

“…Accordingly, a human single nucleotide polymorphism (SNP) near PIP4K2C is associated with increased susceptibility to autoimmune diseases (Raychaudhuri et al ., 2008). PIP4K2C is significantly downregulated in the hearts of cardiac hypertrophy and heart failure patients when compared to non-injured hearts (Magadum et al ., 2021). Reduced PIP4K2C mRNA levels have been associated with favorable clinical outcomes of AML patients, suggesting that PI5P4Kγ inhibitors could act as anti-cancer therapeutics (Lima et al ., 2019).…”

Emerging roles of ferroptosis in cardiovascular diseases

“…HF is one of the leading causes of death worldwide, and its prevalence continues to grow [ 81 , 82 ]. Adverse cardiac remodelling characterized by pathological myocardial hypertrophy and myocardial fibrosis caused by various extracellular stimuli will eventually develop into HF [ 83 ].…”