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ABSTRACT: Base editing effectively prevents the early-onset hypertrophic cardiomyopathy in Mybpc3 mutant mice

PROVIDER: PRJNA1000763 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR25473200.fastq.gz	Fastqsanger.gz
	SRR25473201.fastq.gz	Fastqsanger.gz
	SRR25473202.fastq.gz	Fastqsanger.gz
	SRR25473203.fastq.gz	Fastqsanger.gz
	SRR25473204.fastq.gz	Fastqsanger.gz

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Base editing effectively prevents the early-onset hypertrophic cardiomyopathy in Mybpc3 mutant mice

Project description:Base editing effectively prevents the early-onset hypertrophic cardiomyopathy in Mybpc3 mutant mice

| PRJNA1001311 | ENA

Base editing effectively prevents the early-onset hypertrophic cardiomyopathy in Mybpc3 mutant mice

Project description:Pathogenic variants in MYBPC3 (myosin-binding protein C3) are the leading cause of genetic hypertrophic cardiomyopathy (HCM). Currently, there is no specific and effective treatment for this disease. Base editing is an emerging modality for treating monogenic diseases; however, its effect on MYBPC3 cardiomyopathy remains unexplored. Mybpc3-R946X/R946X mice developed early-onset left ventricular hypertrophy, systolic dysfunction, ventricular dilatation, and arrythmias. SpRY-ABEmax inefficiently corrected the Mybpc3-R946X mutation. In contrast, SpRY-ABE8e increased the efficiency by 3.6-fold and retained low level off-target editing. In vivo administration of SpRY-ABE8e efficiently corrected Mybpc3-R946X mutation in cardiomyocytes and prevented heart function decline, hypertrophic cardiomyopathy, and ventricular dysfunction. The therapeutic efficacy of SpRY-ABE8e-mediated gene correction surmounted AAV-mediated Mybpc3 gene replacement.Our study unveiled the immense potential of base editing to treat fatal inherited cardiomyopathies and opened a new avenue for the therapeutic managements of inherited cardiac diseases.

2024-04-04 | GSE239872 | GEO

Transcriptome analysis of patient derived induced pluripotent stem cell derived cardiomyocytes with severe, early onset hypertrophic cardiomyopathy due to biallelic MYBPC3 variants c.442G>A and c.506-1G>A

Project description:Induced pluripotent stem cells (iPSCs) were generated from a patient with severe, early onset hypertrophic cardiomyopathy due to pathogenic (c.506-1G>A) and low penetrance pathogenic (c.442G>A) variants in MYBPC3 in trans (i.e. MYBPC3 biallelic patient). Healthy control (WTC11, Coriell repository) iPSCs were used as reference. iPSCs were differentiated into cardiomyocytes for transcriptome analysis and assessment of the c.442G>A variant on MYBPC3 splicing.

2024-08-11 | GSE274124 | GEO

Cardiac Organoids for Modeling Hypertrophic Cardiomyopathy

Project description:BACKGROUND: MYBPC3 is one of the most mutated gene known to cause hypertrophic cardiomyopathy (HCM). However, the molecular mechanisms of how mutations in MYBPC3 lead to the onset and progression of HCM are poorly understood. Thus, advancing in-vitro studies to define these mechanisms of mutations leading to HCM are still warranted. Thus, the primary objective of this study was to investigate the molecular mechanisms underlying the pathogenesis of HCM associated with MYBPC3 mutation utilizing isogenic human-induced pluripotent stem cell (hiPSC)-derived cardiac organoids (hCOs).

2025-01-28 | GSE262876 | GEO

Transcriptomic profileing of iPSC-derived engineered cardiac tissue in which cMyBP-C have been ablated in the heterozygous and homozygous states on an isogenic background

Project description:Truncation mutations in cardiac myosin binding protein C (cMyBP-C), are common causes of hypertrophic cardiomyopathy (HCM). Heterozygous carriers present with classical HCM, while homozygous carriers present with early onset HCM that rapidly progress to heart failure. We used CRISPR-Cas9 to introduce heterozygous (cMyBP-C+/-) and homozygous (cMyBP-C-/-) frame-shift mutations into MYBPC3 in human iPSCs. Cardiomyocytes derived from these isogenic lines were used to generate engineered cardiac tissue constructs (ECTs). RNAseq analysis on 14 day old ECTs revealed enrichment of differentially expressed hypertrophic, sarcomeric, Ca2+-handling and metabolic genes in cMyBP-C+/- and cMyBP-C-/- ECTs.

2023-02-23 | GSE224129 | GEO

Heat Shock Proteins and Small Nucleolar RNAs are Dysregulated in a Drosophila Model for Feline Hypertrophic Cardiomyopathy

Project description:We report the application of RNA-sequencing technology for high-throughput profiling of Drosophila that express clinical variants of feline-MyBPC3 associated with Hypertrophic Cardiomyopathy (HCM).

2020-12-04 | GSE141574 | GEO

Efficient in vivo genome editing prevents hypertrophic cardiomyopathy in mice

Project description:Efficient in vivo genome editing prevents hypertrophic cardiomyopathy in mice

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Base Editing Correction of a Hypertrophic Cardiomyopathy-Causing MYH7 Mutation in Human Cardiomyocytes and Humanized Mice

Project description:The most common form of genetic heart disease is hypertrophic cardiomyopathy (HCM), which is caused by mutations in cardiac sarcomeric genes and leads to abnormal heart muscle thickening. Complications of HCM include heart failure, arrhythmia, and sudden cardiac death. The dominant-negative c.1208 G>A (p.R403Q) mutation in b-myosin (MYH7) is a common and well-studied mutation that leads to increased cardiac contractility and HCM onset. Here we identify an adenine base editor (ABE) and single-guide RNA system that can efficiently correct this human pathogenic mutation with minimal off-target and bystander editing. We show that delivery of base editing components rescues pathological manifestations of HCM in iPSC-cardiomyocytes derived from HCM patients and in a humanized mouse model of HCM. Our findings demonstrate the use of base editing to treat inherited cardiac diseases and prompt the further development of ABE-based therapies to correct a variety of monogenic mutations causing cardiac disease.

2022-10-25 | GSE201755 | GEO

Irf7 orchestrates the immunological reaction in cardiomyocytes upon Adar1 deletion

Project description:Adenosine deaminases acting on RNA (Adar1 and Adar2) catalyze I-to-A RNA editing, a post-transcriptional mechanism involved in multiple cellular functions. The role of Adar1-dependent RNA editing in cardiomyocytes (CMs) remains unclear. Here we show that conditional deletion of Adar1 in CMs results in myocarditis progressively evolving into dilated cardiomyopathy and heart failure at only 6 months of age. Adar1 depletion drives activation of interferon signaling genes (ISGs) in the absence of apoptosis and cytokine activation, and reduces the hypertrophic response of CMs upon pressure overload. Interestingly, ablation of the cytosolic sensor MDA5 prevents cardiac ISG activation and delays disease onset, but does not rescue the long-term lethal phenotype elicited by conditional deletion of Adar1. Retention of a single catalytically inactive Adar1 allele in CMs, in combination with MDA5 depletion, however, completely restores the cardiac function and prevents heart failure. Finally, ablation of interferon regulatory factor 7 (Irf7) attenuates the phenotype of Adar1-deficient CMs to a similar extent as MDA5 depletion, highlighting Irf7 as the main regulator of the immune response triggered by lack of Adar1 in CMs.

2022-08-24 | PXD024974 | Pride

Gene expression patterns in cMyBP-CΔC10mut HCM mice and cMyBP-C(t/t) DCM mice

Project description:A 25-base pair deletion in the cardiac myosin binding protein-C (cMyBP-C) gene (MYBPC3), proposed to skip exon 33, modifies the C10 domain (cMyBP-CΔC10mut) and is associated with hypertrophic cardiomyopathy (HCM) and heart failure, affecting approximately 100 million South Asians. However, the molecular mechanisms underlying the pathogenicity of cMyBP-CΔC10mut in vivo are unknown. To determine whether expression of cMyBP-CΔC10mut is sufficient to cause HCM and contractile dysfunction in vivo, we generated transgenic (TG) mice having cardiac-specific protein expression of cMyBP-CΔC10mut at approximately half the level of endogenous cMyBP-C. At 12 weeks of age, significant hypertrophy was observed in TG mice expressing cMyBP-CΔC10mut. Also RNA Sequencing revealed that genes related to muscle contraction and proteosome biological process are dysregulated. Similarly,to determine whether myocardial inflammation is associated with cardiac dysfunction in dilated cardiomyopathy (DCM) caused by MYBPC3 mutation, we used the well-characterized cMyBP-C(t/t) mouse model of DCM at 3months of age.RNA-seq analysis revealed the upregulation of inflammatory pathways in the DCM hearts.

2024-03-22 | GSE262253 | GEO

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