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Expression data from patient iPSC and iPSC-derived cardiomyocytes

ABSTRACT: Dilated cardiomyopathy (DCM) is the leading cause of heart failure and transplantation worldwide. We used iPSCs to model this disease and compared gene expression change before and after gene therapy of cardiomyocytes derived from DCM-specific iPSCs. We used microarrays to detail the global gene expression of patient specific iPSCs, iPSC-derived cardiomyocytes and its response to gene therapy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE35108 | GEO | 2012/02/01

SECONDARY ACCESSION(S): PRJNA150901

REPOSITORIES: GEO

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Expression data from patient iPSC and iPSC-derived cardiomyocytes

Project description:Dilated cardiomyopathy (DCM) is the leading cause of heart failure and transplantation worldwide. We used iPSCs to model this disease and compared gene expression change before and after gene therapy of cardiomyocytes derived from DCM-specific iPSCs. We used microarrays to detail the global gene expression of patient specific iPSCs, iPSC-derived cardiomyocytes and its response to gene therapy. Skin fibroblasts and iPSCs derived from a family exhibiting familial dilated cardiomyopathy and H7 human ESCs were subjected to RNA extraction and hybridization on Affymetrix microarrays.Global gene expression pattern were compared and analyzed. Cardiomyocytes derived from iPSCs generated from this DCM family were treated with or without adenoriral Serca2a and subjected to RNA extraction and hybridization on Affymetrix microarrays. Global gene expression pattern were compared and analyzed.

2012-02-01 | E-GEOD-35108 | biostudies-arrayexpress

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Correction of human phospholamban R14del mutation associated with cardiomyopathy using targeted nucleases and combination therapy [Exome-Seq]

Project description:Phospholamban R14del mutazion (PLN-R14del) has been identified in a large family pedigree in which heterozygous carriers exhibited inherited dilated cardiomyopathy (DCM) and death by middle age. To better understand the causal link between the mutations in PLN and DCM pathology, we derived induced pluripotent stem cells from a DCM patient carrying the PLN R14del mutation. We showed that iPSC-derived cardiomyocytes recapitulated the DCM-specific phenotype and demonstrated that either TALEN-mediated genetic correction or combinatorial gene therapy resulted in phenotypic rescue. Our findings offer novel insights into the pathogenesis caused by mutant PLN and point to the development of potential new therapeutics of pathogenic genetic variants associated with inherited cardiomyopathies. Submitter confirms there are no patient privacy concerns with these data. iPSCs were derived from a female patient carrying a heterozygous mutation (R14del) in the PLN gene. Tree samples were analyzed: R14del-CMs (clone L2), corrected R14del-CMs (clone L2GC1) and corrected R14del-CMs (clone L2GC2)

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Project description:Dilated cardiomyopathy (DCM), a myocardial disorder that can result in progressive heart failure and arrhythmias, is defined by ventricular chamber enlargement and dilatation, and systolic dysfunction. To decipher the basis for the cardiac pathology in titin-mutated patients, we investigated the hypothesis that induced Pluripotent Stem Cell (iPSC)- derived cardiomyocytes (iPSC-CM) generated from patients, recapitulate the disease phenotype.Our findings show that the mutated cardiomyocytes from DCM patients recapitulate abnormalities of the inherited cardiomyopathies.

2019-04-12 | PXD010513 | Pride

Correction of human phospholamban R14del mutation associated with cardiomyopathy using targeted nucleases and combination therapy [RNA-Seq]

2015-02-09 | GSE65761 | GEO

Correction of human phospholamban R14del mutation associated with cardiomyopathy using targeted nucleases and combination therapy [Exome-Seq]

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Project description:Dilated cardiomyopathy (DCM) is characterized by reduced cardiac output, as well as thinning and enlargement of left ventricular chambers. These characteristics eventually lead to heart failure. Current standards of care do not target the underlying molecular mechanisms associated with genetic forms of heart failure, driving a need to develop novel therapeutics for DCM. To identify candidate therapeutics, we developed an in vitro DCM model using induced pluripotent stem cell–derived cardiomyocytes (iPSC-CMs) deficient in BCL2-associated athanogene 3 (BAG3). With these BAG3-deficient iPSC-CMs, we identified cardioprotective drugs with a phenotypic screen and deep learning. Using a library of 5500 bioactive compounds and siRNA validation, we identified that inhibiting histone deacetylase 6 (HDAC6) was cardioprotective at the sarcomere level. We translated this finding to a BAG3 cardiac-knockout (BAG3cKO) mouse model of DCM, showing that inhibiting HDAC6 with two isoform-selective inhibitors (tubastatin A and a novel inhibitor TYA-018) protected heart function. In BAG3cKO and BAG3 E455K mice, HDAC6 inhibitors improved left ventricular ejection fraction and reduced left ventricular diameter at diastole and systole. We also found that HDAC6 inhibitors protected the microtubule network from mechanical damage, increased autophagic flux, decreased apoptosis, and reduced inflammation in the heart. Our results demonstrate the power of combining iPSC-CMs with phenotypic screening and deep learning to accelerate target and drug discovery, and they support the development of novel therapies that address underlying mechanisms associated with heart disease.

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Project description:Noonan syndrome (NS) is a multisystemic developmental disorder characterized by its clinical variability with common symptoms such as typical facial dysmorphism, short stature, developmental delay and intellectual disability as well as congenital heart disease. The disease is causally linked to gain-of-function mutations in a number of genes leading to an increased signal transduction along the RAS-MAP kinase (MAPK) signaling pathway. However, our understanding of the pathophysiological alterations and mechanisms, especially of the associated cardiomyopathy, remains limited and effective therapeutic options are lacking. In this study, we present a family with two siblings displaying an autosomal recessive form of NS with severe hypertrophic cardiomyopathy caused by biallelic mutations within leucine zipper like transcription regulator 1 (LZTR1). Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) of the affected siblings recapitulated the hypertrophic phenotype and uncovered a causal link between LZTR1 dysfunction, RAS accumulation, RAS-MAPK signaling hyperactivity, hypertrophic gene response and cellular hypertrophy. Intronic CRISPR repair in the patients’ iPSCs normalized RAS-MAPK signaling activity and cellular hypertrophy paving the way for personalized medical treatment.

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