Pre-clinical evaluation of cysteamine bitartrate as a therapeutic agent for mitochondrial respiratory chain disease
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ABSTRACT:
ORGANISM(S): Homo sapiens Caenorhabditis elegans
PROVIDER: GSE119723 | GEO | 2019/03/01
REPOSITORIES: GEO
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Project description:Pre-clinical studies of cysteamine bitartrate demonstrate its narrow therapeutic window, where toxicity at millimolar levels correlates with a marked induction of hydrogen peroxide production. At micromolar range concentrations, cysteamine bitartrate yielded a survival benefit in RC disease subject fibroblasts, and protection from brain death in RC complex IV deficient zebrafish. Mitochondrial oxidative stress and membrane potential were significantly improved by micromolar cysteamine bitartrate in RC complex I disease worms, translating to a modest improvement of animal development and fecundity but not lifespan. Overall, these data suggest that cysteamine bitartrate may hold therapeutic potential but requires careful consideration of safe and effective dose to further evaluate in clinical trials of human subjects with primary mitochondrial disease.
2019-03-01 | GSE119699 | GEO
Project description:Pre-clinical studies of cysteamine bitartrate demonstrate its narrow therapeutic window, where toxicity at millimolar levels correlates with a marked induction of hydrogen peroxide production. At micromolar range concentrations, cysteamine bitartrate yielded a survival benefit in RC disease subject fibroblasts, and protection from brain death in RC complex IV deficient zebrafish. Mitochondrial oxidative stress and membrane potential were significantly improved by micromolar cysteamine bitartrate in RC complex I disease worms, translating to a modest improvement of animal development and fecundity but not lifespan. Overall, these data suggest that cysteamine bitartrate may hold therapeutic potential but requires careful consideration of safe and effective dose to further evaluate in clinical trials of human subjects with primary mitochondrial disease.
2019-03-01 | GSE119696 | GEO
Project description:Cysteamine bitartrate is a US Food and Drug Administration-approved therapy for nephropathic cystinosis also postulated to enhance glutathione biosynthesis. We hypothesized this antioxidant effect may reduce oxidative stress in primary mitochondrial respiratory chain (RC) disease, improving cellular viability and organismal health. Here, we systematically evaluated the therapeutic potential of cysteamine bitartrate in RC disease models spanning three evolutionarily distinct species. These pre-clinical studies demonstrated the narrow therapeutic window of cysteamine bitartrate, with toxicity at millimolar levels directly correlating with marked induction of hydrogen peroxide production. Micromolar range cysteamine bitartrate treatment in Caenorhabditis elegans gas-1(fc21) RC complex I (NDUFS2-/-) disease invertebrate worms significantly improved mitochondrial membrane potential and oxidative stress, with corresponding modest improvement in fecundity but not lifespan. At 10 to 100 μm concentrations, cysteamine bitartrate improved multiple RC complex disease FBXL4 human fibroblast survival, and protected both complex I (rotenone) and complex IV (azide) Danio rerio vertebrate zebrafish disease models from brain death. Mechanistic profiling of cysteamine bitartrate effects showed it increases aspartate levels and flux, without increasing total glutathione levels. Transcriptional normalization of broadly dysregulated intermediary metabolic, glutathione, cell defense, DNA, and immune pathways was greater in RC disease human cells than in C. elegans, with similar rescue in both models of downregulated ribosomal and proteasomal pathway expression. Overall, these data suggest cysteamine bitartrate may hold therapeutic potential in RC disease, although not through obvious modulation of total glutathione levels. Careful consideration is required to determine safe and effective cysteamine bitartrate concentrations to further evaluate in clinical trials of human subjects with primary mitochondrial RC disease.
| S-EPMC6522065 | biostudies-literature
Project description:Pre-clinical evaluation of cysteamine bitartrate as a therapeutic agent for mitochondrial respiratory chain disease
| PRJNA490135 | ENA
Project description:Pre-clinical evaluation of cysteamine bitartrate as a therapeutic agent for mitochondrial respiratory chain disease (human)
| PRJNA490137 | ENA
Project description:Pre-clinical evaluation of cysteamine bitartrate as a therapeutic agent for mitochondrial respiratory chain disease (worm)
| PRJNA490034 | ENA
Project description:Primary mitochondrial respiratory chain (RC) diseases are heterogeneous in etiology and manifestations but collectively impair cellular energy metabolism. To identify a common cellular response to RC disease, systems biology level transcriptome investigations were performed in human RC disease skeletal muscle and fibroblasts. Global transcriptional and post-transcriptional dysregulation in a tissue-specific fashion was identified across diverse RC complex and genetic etiologies. RC disease muscle was characterized by decreased transcription of cytosolic ribosomal proteins to reduce energy-intensive anabolic processes, increased transcription of mitochondrial ribosomal proteins, shortened 5'-UTRs to improve translational efficiency, and stabilization of 3'-UTRs containing AU-rich elements. These same modifications in a reversed direction typified RC disease fibroblasts. RC disease also dysregulated transcriptional networks related to basic nutrient-sensing signaling pathways, which collectively mediate many aspects of tissue-specific cellular responses to primary RC disease. These findings support the utility of a systems biology approach to improve mechanistic understanding of mitochondrial RC disease. To identify a common cellular response to primary RC that might improve mechanistic understanding and lead to targeted therapies for human RC disease, we performed collective transcriptome profiling in skeletal muscle biopsy specimens and fibroblast cell lines (FCLs) of a diverse cohort of human mitochondrial disease subjects relative to controls. Systems biology investigations of common cellular responses to primary RC disease revealed a collective pattern of transcriptional, post-transcriptional and translational dysregulation occurring in a highly tissue-specific fashion. Affymetrix Human Exon 1.0ST microarray analysis was performed on 29 skeletal muscle samples and Fibroblast cell lines from mitochondrial disease patients and age- and gender-matched controls.
2013-07-01 | E-GEOD-42986 | biostudies-arrayexpress
Project description:Primary mitochondrial respiratory chain (RC) diseases are heterogeneous in etiology and manifestations but collectively impair cellular energy metabolism. To identify a common cellular response to RC disease, systems biology level transcriptome investigations were performed in human RC disease skeletal muscle and fibroblasts. Global transcriptional and post-transcriptional dysregulation in a tissue-specific fashion was identified across diverse RC complex and genetic etiologies. RC disease muscle was characterized by decreased transcription of cytosolic ribosomal proteins to reduce energy-intensive anabolic processes, increased transcription of mitochondrial ribosomal proteins, shortened 5'-UTRs to improve translational efficiency, and stabilization of 3'-UTRs containing AU-rich elements. These same modifications in a reversed direction typified RC disease fibroblasts. RC disease also dysregulated transcriptional networks related to basic nutrient-sensing signaling pathways, which collectively mediate many aspects of tissue-specific cellular responses to primary RC disease. These findings support the utility of a systems biology approach to improve mechanistic understanding of mitochondrial RC disease. To identify a common cellular response to primary RC that might improve mechanistic understanding and lead to targeted therapies for human RC disease, we performed collective transcriptome profiling in skeletal muscle biopsy specimens and fibroblast cell lines (FCLs) of a diverse cohort of human mitochondrial disease subjects relative to controls. Systems biology investigations of common cellular responses to primary RC disease revealed a collective pattern of transcriptional, post-transcriptional and translational dysregulation occurring in a highly tissue-specific fashion.
2013-07-01 | GSE42986 | GEO
Project description:To determine the extent of respiratory chain abnormalities and investigate the contribution of mtDNA to the loss of respiratory chain complexes (CI-IV) in the substantia nigra (SN) of idiopathic Parkinson disease (IPD) patients at the single-neuron level.Multiple-label immunofluorescence was applied to postmortem sections of 10 IPD patients and 10 controls to quantify the abundance of CI-IV subunits (NDUFB8 or NDUFA13, SDHA, UQCRC2, and COXI) and mitochondrial transcription factors (TFAM and TFB2M) relative to mitochondrial mass (porin and GRP75) in dopaminergic neurons. To assess the involvement of mtDNA in respiratory chain deficiency in IPD, SN neurons, isolated with laser-capture microdissection, were assayed for mtDNA deletions, copy number, and presence of transcription/replication-associated 7S DNA employing a triplex real-time polymerase chain reaction (PCR) assay.Whereas mitochondrial mass was unchanged in single SN neurons from IPD patients, we observed a significant reduction in the abundances of CI and II subunits. At the single-cell level, CI and II deficiencies were correlated in patients. The CI deficiency concomitantly occurred with low abundances of the mtDNA transcription factors TFAM and TFB2M, which also initiate transcription-primed mtDNA replication. Consistent with this, real-time PCR analysis revealed fewer transcription/replication-associated mtDNA molecules and an overall reduction in mtDNA copy number in patients. This effect was more pronounced in single IPD neurons with severe CI deficiency.Respiratory chain dysfunction in IPD neurons not only involves CI, but also extends to CII. These deficiencies are possibly a consequence of the interplay between nDNA and mtDNA-encoded factors mechanistically connected via TFAM.
| S-EPMC4819690 | biostudies-literature
Project description:T-cell acute lymphoblastic lymphoma (T-LBL) is a rare and aggressive blood cancer, most often diagnosed in teenagers and young adults. Patients are usually treated with intensive chemotherapy which causes many side effects and relapse still occurs. Therefore, the search toward less toxic anti-leukemic therapies is ongoing. In line with this, we here focused on targeting a recently described perturbed DNA methylation profile in T-LBL. This aberrantly methylated DNA can serve as a new therapeutic target for DNA hypomethylating epidrugs like decitabine. We evaluated the anti-leukemic properties and downstream effects of decitabine using T-LBL patient derived xenograft (PDX) models. Interestingly, decitabine treatment resulted in prolonged leukemia-free survival in all T-LBL PDX models, which was mediated by i.a. downregulation of the oncogenic MYC pathway. However, some PDX models had more benefit of being treated with decitabine compared to others. Remarkably, differentially methylated CpG islands regions resulted in significantly more differentially expressed genes in open chromatin in the more sensitive group. This resulted in i.a. stronger downregulation of cell cycle genes and upregulation of immune response activating genes. Furthermore, we suggested a gene signature for high decitabine sensitivity. In conclusion, we delivered pre-clinical data of the potential of decitabine to act as a new therapeutic agent in T-LBL.
2023-03-02 | GSE218060 | GEO