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Transcriptomic profile of skeletal muscle in wild-type, GAA knock-out, and AAV treated GAA knock-out mice to understand Pompe disease mechanisms and assess therapeutic efficacy

ABSTRACT: Transcriptomic profile of skeletal muscle in wild-type, GAA knock-out, and AAV treated GAA knock-out mice to understand Pompe disease mechanisms and assess therapeutic efficacy

PROVIDER: PRJNA667501 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR12776600.fastq.gz	Fastqsanger.gz
	SRR12776601.fastq.gz	Fastqsanger.gz
	SRR12776602.fastq.gz	Fastqsanger.gz
	SRR12776603.fastq.gz	Fastqsanger.gz
	SRR12776604.fastq.gz	Fastqsanger.gz

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Transcriptomic profile of skeletal muscle in wild-type, GAA knock-out, and AAV treated GAA knock-out mice to understand Pompe disease mechanisms and assess therapeutic efficacy

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. Gene therapy is a promising approach to treat genetic diseases, and liver-restricted expression of secretable GAA can produce immune tolerance and improve muscle GAA activity. To further understand the molecular mechanisms underlying Pompe disease and impact of gene therapy, we applied RNA sequencing.

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Transcriptome assessment of the Pompe (Gaa-/-) mouse cervical cord confirms widespread neuropathology.

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.

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Project description:Pompe disease is a genetic disorder resulting from a deficiency of lysosomal acid alpha-glucosidase (GAA) that manifests as a clinical spectrum with regard to symptom severity and rate of progression. In this study, we used microarrays to examine gene expression from the muscle of two cohorts of infantile-onset Pompe patients to identify transcriptional differences that may contribute to the disease phenotype. We found strong similarities among the gene expression profiles generated from biceps and quadriceps, and identified a number of signaling pathways altered in both cohorts. We also found that infantile-onset Pompe patient muscle had a gene expression pattern characteristic of immature or regenerating muscle, and exhibited many transcriptional markers of inflammation, despite having few overt signs of inflammatory infiltrate. Further, we identified genes exhibiting correlation between expression at baseline and response to therapy. This combined dataset can serve as a foundation for biological discovery and biomarker development to improve the treatment of Pompe disease.

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Skeletal muscle gene expression in the wild type and the GAA knock-out mice, a model of Pompe disease

Project description:Pompe disease is a Lysosomal glycogen storage disorder due to the deficiency of acid alpha glucosidase. The enzyme degrades glycogen to glucose and its deficiency results in progressive enlargement of glycogen-filled lysosomes in multiple tissues with skeletal and cardiac muscle most severely affected clinically. Clinical spectrum ranges from most severe infantile cardiomegally and skeletal muscle myopathy to milder late onset forms with only skeletal muscle pathology. The currently available enzyme replacement therapy has only limited effect in skeletal muscle. Here we use RNA sequencing of therapy-resistant skeletal muscle (white part of gastrocnemius muscle) to identify the differencies between the diseased and healthy muscle. Total RNA was obtained from gastrocnemius muscle (white part) of acid alpha glucosidase knock-out and wild-type mice.

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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.

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Project description:Pompe disease (PD) is a neuromuscular disorder caused by deficiency of acid-alpha-glucosidase (GAA), leading to motor and respiratory dysfunctions. Available Gaa knock-out (KO) mouse models do not accurately mimic PD, particularly the highly impaired respiratory phenotype. Methods. Here we developed a new mouse model of PD crossing Gaa KO B6;129 with DBA2/J mice. Findings. Male Gaa KODBA2/J presents most of the key features of the human disease, including early lethality, severe respiratory impairment, cardiac hypertrophy and muscle weakness. Transcriptome analyses of Gaa KODBA2/J, compared to the parental Gaa KOB6;129 mice, revealed a profoundly impaired gene signature in the spinal cord and a similarly deregulated gene expression in skeletal muscle. Muscle and spinal cord transcriptome changes in Gaa KODBA2/J, were significantly improved upon gene therapy with AAV vectors expressing a secreted GAA enzyme.

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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.

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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.

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Skeletal muscle gene expression in the wild type and the GAA knock-out mice, a model of Pompe disease

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