Serine biosynthesis as a novel therapeutic target for dilated cardiomyopathy . (22nd June 2022)

• Record Type: Journal Article
• Authors: Perea-Gil, Isaac; Seeger, Timon; Bruyneel, Arne A N; Termglinchan, Vittavat; Monte, Emma; Lim, Esther W; Vadgama, Nirmal; Furihata, Takaaki; Gavidia, Alexandra A; Arthur Ataam, Jennifer; Bharucha, Nike; Martinez-Amador, Noel; Ameen, Mohamed; Nair, Pooja; Serrano, Ricardo; Kaur, Balpreet; Feyen, Dries A M; Diecke, Sebastian; Snyder, Michael P; Metallo, Christian M; Mercola, Mark; Karakikes, Ioannis
• Is Part Of: European heart journal. Volume 43:Number 36(2022)
• Page Start: 3477
• Page End: 3489
• Publication Date: 2022-06-22
• Subjects: Induced pluripotent stem cells -- Cardiomyocytes -- Drug screening -- Dilated cardiomyopathy -- Clinical-trial-in-a-dish -- Precision medicine -- Phenotypic screens; Cardiology -- Periodicals; Heart -- Diseases -- Periodicals; 616.12005
• DOI: 10.1093/eurheartj/ehac305
• Languages: English
• ISSNs: 0195-668X

Abstract

Abstract: Aims: Genetic dilated cardiomyopathy (DCM) is a leading cause of heart failure. Despite significant progress in understanding the genetic aetiologies of DCM, the molecular mechanisms underlying the pathogenesis of familial DCM remain unknown, translating to a lack of disease-specific therapies. The discovery of novel targets for the treatment of DCM was sought using phenotypic sceening assays in induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) that recapitulate the disease phenotypes in vitro . Methods and results: Using patient-specific iPSCs carrying a pathogenic TNNT2 gene mutation (p.R183W) and CRISPR-based genome editing, a faithful DCM model in vitro was developed. An unbiased phenotypic screening in TNNT2 mutant iPSC-derived cardiomyocytes (iPSC-CMs) with small molecule kinase inhibitors (SMKIs) was performed to identify novel therapeutic targets. Two SMKIs, Gö 6976 and SB 203580, were discovered whose combinatorial treatment rescued contractile dysfunction in DCM iPSC-CMs carrying gene mutations of various ontologies ( TNNT2, TTN, LMNA, PLN, TPM1, LAMA2 ). The combinatorial SMKI treatment upregulated the expression of genes that encode serine, glycine, and one-carbon metabolism enzymes and significantly increased the intracellular levels of glucose-derived serine and glycine in DCM iPSC-CMs. Furthermore, the treatment rescued the mitochondrial respiration defects and increased the levels of the tricarboxylic acid cycle metabolites and ATP in DCM iPSC-CMs. Finally, the rescue of the DCM phenotypes was mediated by the activating transcription factor 4 ( ATF4 ) and its downstream effector genes, phosphoglycerate dehydrogenase ( PHGDH ), which encodes a critical enzyme of the serine biosynthesis pathway, and Tribbles 3 (TRIB3), a pseudokinase with pleiotropic cellular functions. Conclusions: A phenotypic screening platform using DCM iPSC-CMs was established for therapeutic target discovery. A combination of SMKIs ameliorated contractile and metabolic dysfunction in DCM iPSC-CMs mediated via the ATF4-dependent serine biosynthesis pathway. Together, these findings suggest that modulation of serine biosynthesis signalling may represent a novel genotype-agnostic therapeutic strategy for genetic DCM. Structured Graphical Abstract: Structured Graphical Abstract Activation of serine biosynthesis pathway with a dual kinase inhibitor treatment rescues DCM contraction deficit. A kinase inhibitor screening was conducted in iPSC-derived cardiomyocytes, and the resulting hits identified were combined into one single treatment, PPi, that improved the contractile response of the cells. Mechanistically, PPi activated the serine biosynthesis pathway, translating in turn into a more efficient mitochondrial respiration and energy production. Finally, PPi rescued DCM phenotype in multiple gene mutations associated to DCM.