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Correction of human phospholamban R14del mutation associated with cardiomyopathy using targeted nucleases and combination therapy

ABSTRACT: This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

ORGANISM(S): Homo sapiens

SUBMITTER: FRANCESCA STILLITANO

PROVIDER: E-GEOD-65763 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Correction of human phospholamban R14del mutation associated with cardiomyopathy using targeted nucleases and combination therapy [RNA-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. iPSCs were derived from a female patient carrying a heterozygous mutation (R14del) in the PLN gene. Tree samples were analyzed: Cardiomyocytes derived from PLN-R41del iPSC cells (R14del-CM); R14del-CMs infected with AAV6-EGFP-miR-PLN and R14del-CMs infected with AAV6-EGFP-miR-luc used as a negative control

2015-02-09 | E-GEOD-65761 | biostudies-arrayexpress

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)

2015-02-09 | E-GEOD-65762 | biostudies-arrayexpress

Correction of human phospholamban R14del mutation associated with cardiomyopathy using targeted nucleases and combination therapy

Project description:This SuperSeries is composed of the SubSeries listed below.

2015-02-09 | GSE65763 | GEO

Correction of human phospholamban R14del mutation associated with cardiomyopathy using targeted nucleases and combination therapy.

Project description:A number of genetic mutations is associated with cardiomyopathies. A mutation in the coding region of the phospholamban (PLN) gene (R14del) is identified in families with hereditary heart failure. Heterozygous patients exhibit left ventricular dilation and ventricular arrhythmias. Here we generate induced pluripotent stem cells (iPSCs) from a patient harbouring the PLN R14del mutation and differentiate them into cardiomyocytes (iPSC-CMs). We find that the PLN R14del mutation induces Ca(2+) handling abnormalities, electrical instability, abnormal cytoplasmic distribution of PLN protein and increases expression of molecular markers of cardiac hypertrophy in iPSC-CMs. Gene correction using transcription activator-like effector nucleases (TALENs) ameliorates the R14del-associated disease phenotypes in iPSC-CMs. In addition, we show that knocking down the endogenous PLN and simultaneously expressing a codon-optimized PLN gene reverses the disease phenotype in vitro. Our findings offer novel strategies for targeting the pathogenic mutations associated with cardiomyopathies.

| S-EPMC4421839 | biostudies-literature

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.

2015-02-09 | GSE65762 | GEO

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

2015-02-09 | GSE65761 | GEO

c-Myb inhibits myoblast fusion

Project description:The study of the effects of modification of c-Myb expression on differenatiation of C2C12 cells

2013-10-21 | E-MTAB-1376 | biostudies-arrayexpress

RNA-Seq of Lgr6 positive and negative cells in mouse mammary gland

Project description:Lgr6-positive cells have been shown to label stem/progenitors cells in several tissues including tongue and skin. However their role in mammary gland has never been investigated. Here we used Lgr6-eGFP-IRES-CreER2 mice to isolate and characterize Lgr6-positive population in mammary gland of 5-week old female mice. Examination of transcriptional differences between Lgr6 positive and negative cells

2016-09-06 | E-GEOD-75648 | biostudies-arrayexpress

Identification of genes differentially expressed in lung cancer cells after the transfection of miR-221 or miR-222.

Project description:To evaluate involvement of miR-221 and miR-222 in lung cancer, we investigated the effects of miR-221 and miR-222 overexpression on six lung cancer cell lines as well as one immortalized normal human bronchial epithelial cell line. Two cell lines, H3255 and H1299 with no replicates were studied. Cells were transfected with miR-221, miR-222, or miR control. Microarray analysis was done to identify genes differentially expressed in lung cancer cells after the transfection of miR-221 or miR-222.

2015-05-22 | E-GEOD-57676 | biostudies-arrayexpress

MiR-34b regulates multiciliogenesis during organ formation in zebrafish

Project description:Multiciliated cells possess multiple motile cilia on the cell surface and are widely distributed throughout the vertebrate body to perform important physiological functions by regulating fluid movement in the intercellular space. However the molecular mechanisms underlying multiciliogenesis are not well understood. Although dysregulation of members of the miR-34 family plays a critical role in the progression of various cancers, the physiological function of miR-34b, especially in regulating multiciliogenesis, is largely unknown. Here we focus on the multiciliated cells in the zebrafish kidney to study whether and how miR-34b regulate multiciliogenesis. We performed genome-wide gene expression profiling of zebrafish kidney multiciliated cells in the absence (miR-34b morpholino) or presence of miR-34b (control morpholino). RNA samples for microarray gene expression profiling were collected at 3 days post fertilization.

2013-06-14 | E-MEXP-3893 | biostudies-arrayexpress

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