Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA517737 | ENA |
REPOSITORIES: ENA
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Project description:Biallelic Correction of infantile onset Pompe disease
| PRJNA482478 | ENA
Project description:Pompe disease is caused by autosomal recessive mutations in the GAA gene, which encodes acid alpha-glucosidase. Although enzyme replacement therapy has recently improved patient survival greatly, the results in skeletal muscles and for advanced disease are still not satisfactory. Here, we report the derivation of Pompe disease induced pluripotent stem cells (PomD-iPSCs) and their potential for pathogenesis modeling, drug testing and disease marker identification. PomD-iPSCs maintained pluripotent features, and had low GAA activity and high glycogen content. Cardiomyocyte-like cells (CMLCs) differentiated from PomD-iPSCs recapitulated the hallmark Pompe disease pathophysiological phenotypes, including high levels of glycogen, abundant intracellular LAMP-1- or LC3-positive granules, and multiple ultrastructural aberrances. Drug rescue assessment showed that exposure of PomD-iPSC-derived CMLCs to rhGAA reversed the major pathologic phenotypes. Further, L-carnitine and 3- methyladenine treatment reduced defective cellular respiration and buildup of phagolysosomes, respectively, in the diseased cells. By comparative transcriptome analysis, we identified glycogen metabolism, lysosome and mitochondria related marker genes whose expression robustly correlated with the therapeutic effect of drug treatment in PomD-iPSC-derived CMLCs. Collectively, these results demonstrate that PomD-iPSCs are a promising in vitro disease model for development of novel therapeutic strategies for Pompe disease. Total RNA were isolated from HESC, HF(Pompe disease), PomD-iPSC, HES-CMLC, and PomD-iPS-CMLC. The series included two HESC lines, two HF(Pompe disease) cell lines, four PomD-iPS cell lines, and HES-CMLC were differentiated from one HESC line(HESC2), PomD-iPS-CMLC were differentiated from 3 PomD-iPS cell lines(PomD-iPSC A10, PomD-iPSC A17, PomD-iPSC B03). Each condition was repeated twice and used HESC as control.
2011-02-17 | E-GEOD-27280 | biostudies-arrayexpress
Project description:Pompe disease induced pluripotent stem cells for pathogenesis modeling, drug testing and disease marker identification
| PRJNA137321 | ENA
Project description:Although skeletal muscle cells can be generated from human iPSCs, transgene-free protocols include only limited options for their purification and expansion. In this study we found that FACS-purified myogenic progenitors generated from healthy controls and Pompe disease iPSCs can be robustly expanded as much as 5 x 1011 fold. At all steps during expansion, cells could be cryopreserved or differentiated into myotubes with a high fusion index. In vitro, cells were amenable to maturation into striated and contractile myofibers. Insertion of the acid alpha glucosidase cDNA into the AAVS1 locus in iPSCs using CRISPR/cas9 prevented glycogen accumulation in myotubes generated from a patient with classic infantile Pompe disease. In vivo, the expression of human-specific nuclear and sarcolemmar antigens indicated that myogenic progenitors engraft into murine muscle to form human myofibers. This protocol is useful for modeling of skeletal muscle disorders and for using patient-derived, gene-corrected cells to develop cell-based strategies.
2018-05-03 | GSE111163 | GEO
Project description:Pompe disease is caused by autosomal recessive mutations in the GAA gene, which encodes acid alpha-glucosidase. Although enzyme replacement therapy has recently improved patient survival greatly, the results in skeletal muscles and for advanced disease are still not satisfactory. Here, we report the derivation of Pompe disease induced pluripotent stem cells (PomD-iPSCs) and their potential for pathogenesis modeling, drug testing and disease marker identification. PomD-iPSCs maintained pluripotent features, and had low GAA activity and high glycogen content. Cardiomyocyte-like cells (CMLCs) differentiated from PomD-iPSCs recapitulated the hallmark Pompe disease pathophysiological phenotypes, including high levels of glycogen, abundant intracellular LAMP-1- or LC3-positive granules, and multiple ultrastructural aberrances. Drug rescue assessment showed that exposure of PomD-iPSC-derived CMLCs to rhGAA reversed the major pathologic phenotypes. Further, L-carnitine and 3- methyladenine treatment reduced defective cellular respiration and buildup of phagolysosomes, respectively, in the diseased cells. By comparative transcriptome analysis, we identified glycogen metabolism, lysosome and mitochondria related marker genes whose expression robustly correlated with the therapeutic effect of drug treatment in PomD-iPSC-derived CMLCs. Collectively, these results demonstrate that PomD-iPSCs are a promising in vitro disease model for development of novel therapeutic strategies for Pompe disease.
2011-02-17 | GSE27280 | GEO
Project description:The only FDA approved therapy for Pompe is directed at correcting skeletal and cardiac muscle pathology, however, clinical and animal model data show strong histological evidence for a neurological disease component. While neuronal cell death and neuroinflammation are prominent in many lysosomal disorders, these processes have not been evaluated in Pompe disease. There is also no information available regarding the impact of Pompe disease on the fundamental pathways associated with synaptic communication. We used microarrays to gain insight regarding pathogenetic signaling pathways that might contribute to neuropathology in Pompe (Gaa-/-) mice.
2016-10-11 | GSE82081 | GEO
Project description:Pompe disease is a neuromuscular disorder caused by mutations in the gene encoding for the lysosomal enzyme acid α-glucosidase (GAA). GAA converts lysosomal glycogen to glucose, and its deficiency leads to pathologic glycogen accumulation. Enzyme replacement therapy (ERT) is the only available treatment for Pompe disease at the moment with several shortcomings. We have shown that liver expression of secGAA has better therapeutic efficacy than non-engineered GAA after long-term treatment of four months old Gaa-/- mice with low vector doses. Based on those results, we have treated severely affected nine months old Gaa-/- mice with the AAV-secGAA vector and followed the animals for nine months thereafter. At the end of the study, AAV-treated Gaa-/- mice showed complete rescue of the Pompe phenotype. Transcriptomic profiling of skeletal muscle highlighted mitochondrial bioenergetics defects, supported by electron microscopy, western blotting and biochemical findings, which were partially corrected after AAV treatment. Together, these results provide insight into the reversibility of advanced Pompe disease in the Gaa-/- mouse model via liver gene transfer of secGAA.
2021-04-26 | GSE150935 | GEO
Project description:While there are many human skeletal muscle disorders, very few therapies have been developed. It has not been possible to generate large amounts of purified skeletal muscle cells from pluripotent stem cells, and to test therapies quantitatively. We therefore devised conditions for generating and expanding purified human myogenic progenitors from induced pluripotent stem (iPS) cells. The progenitors retained the capacity to differentiate into multinucleated myotubes and showed a normal karyotype throughout the expansion phase. We applied this method to Pompe disease, a metabolic myopathy caused by deficiency of the lysosomal enzyme acid alpha-glucosidase (GAA). In a screen, we identified sequences that suppressed aberrant GAA exon 2 splicing caused by the frequent c.-32-13T>G (IVS1) GAA variant. Antisense oligonucleotides (AONs) that blocked these sequences promoted exon 2 inclusion in patient-derived myotubes. As this raised GAA enzymatic activity above the disease threshold, AON-mediated splicing correction may provide a treatment option for Pompe disease.
2017-04-11 | GSE75713 | GEO
Project description:<p>Diffuse Intrinsic Pontine Glioma (DIPG) is a universally fatal childhood cancer. Here, we performed a chemical screen in patient-derived DIPG cell cultures along with RNAseq expression analysis and integrated computational modeling to identify potentially effective therapeutic strategies. Panobinostat, among the more promising agents identified, demonstrated efficacy in pontine orthotopic xenograft models of both H3K27M and histone WT DIPG. These data suggest the potential utility of specific drug combinations and provides evidence of in vivo treatment efficacy of the multi-histone deacetylase inhibitor panobinostat. We are depositing to dbGaP deep sequencing whole exome data for 22 patient tumor samples and 13 matched normals, along with RNAseq data for 12 patient tumor samples and 6 normal pediatric brain tissue samples. In addition, we are depositing 22 RNAseq samples from DIPG cell lines before and after panobinostat treatment.</p>
| phs000900 | dbGaP
Project description:Pompe disease (glycogen storage disease type II, or acid maltase deficiency) is an autosomal-recessive disorder of metabolism caused by mutations in the lysosomal hydrolase, acid alpha-glucosidase gene (GAA), resulting in progressive muscle atrophy. The current standard of care treatment, enzyme replacement therapy, consists of delivering recombinant human GAA (rhGAA) to reduce muscle glycogen and improve patient quality of life. With the aim of developing in vitro systems to study human disease and test therapies, we applied RNA sequencing to 3D tissue-engineered human skeletal muscle to compare healthy, (infantile onset) Pompe disease, and rhGAA-treated Pompe engineered tissues.
2020-10-06 | GSE159062 | GEO