Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0002986 (Fabry)
 5,646 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The history and bases of enzyme replacement therapy are briefly reviewed. The enzyme replacement therapy for Gaucher disease type 1, which has been developed for clinical use and is about to be introduced in our country, was described somewhat in detail under the items of the modification of human placental glucocerebrosidase into the macrophage-terminated enzyme, its clinical usage, effects and their evaluations, adverse effects, and new attempts of its application for Gaucher disease types II and III, now being under clinical trials. Also touched are developments of other enzymes for such lysosomal diseases as Fabry disease, Pompe disease, Hurler syndrome, Hunter disease, and Sly disease.
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PMID:[Enzyme replacement therapy of patients with lysosomal storage disease]. 857 62

Most lysosomal storage diseases (LSDs) are life-threatening genetic diseases. The pathogenesis of these diseases is poorly understood. Induced pluripotent stem (iPS) cell technology offers new opportunities for both mechanistic studies and development of stem cell- based therapies. Here we report the generation of disease-specific iPS cells from mouse models of Fabry disease, globoid cell leukodystrophy (GLD), and mucopolysaccharidosis VII (MPSVII). These mouse model-derived iPS cells showed defects in disease-specific enzyme activities and significant accumulation of substrates for these enzymes. In the lineage-directed differentiation studies, Fabry-iPS and GLD-iPS cells were efficiently differentiated into disease-relevant cell types, such as cardiomyocytes and neural stem cells, which might be useful in mechanistic and therapeutic studies. Notably, MPSVII-iPS cells demonstrated a markedly impaired ability to form embryoid bodies (EBs) in vitro. MPSVII-EBs exibited elevated levels of hyaluronan and its receptor CD44, and markedly reduced expression levels of E-cadherin and cell-proliferating marker. Partial correction of enzyme deficiency in MSPVII-iPS cells led to improved EB formation and reversal of aberrant protein expression. These data indicate a potential mechanism for the partial lethality of MPSVII mice in utero, and suggest a possible abnormality of embryonic development in MPSVII patients. Thus, our study demonstrates the unique promise of iPS cells for studying the pathogenesis and treatment of LSDs.
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PMID:Induced pluripotent stem cells derived from mouse models of lysosomal storage disorders. 2038 25

Lysosomal storage diseases (LSDs) are caused by inborn genetic defects and most affected babies show pathology in the CNS. LSDs are caused by a specific inherited enzyme deficiency that results in accumulation of substrates in the lysosomes, distension of the organelles and subsequent cellular malfunction. Currently, no effective treatment is available for most of the LSDs, because the blood?brain barrier bars entry of enzyme preparations into the brain. Treatment for LSDs can be divided into those address symptoms or those address cause. At present, successful treatments for the LSDs are enzyme replacement therapy (ERT) and cell therapy. ERT is most successful in Gaucher disease and has been approved for Fabry disease, and mucopolysaccharidosis I (MPS I). In addition, ERT for Pompe disease, MPS II, MPS VI and MPS VII has been planned and awaiting approval for treatment. Limitations in ERT include need for life-long treatment, development of antibodies, and inability to cross blood brain barrier (BBB) resulting in failure to halt disease progression in the brain. Transplantation of hematopoietic stem cells (HSCs), bone marrow stem cells (BMSCs) and umbilical cord blood-derived stem cells (UCBSCs) offer effective but limited efficacy for patients suffering from Krabbe disease, MPS VII and adrenal leukodystrophy but in other LSDs they are ineffective. Intracranial/intracerebral transplantation of genetically modified stem cells as enzyme delivery system could bypass the BBB effectively and ensure release of therapeutically beneficial amount of enzymes to affected CNS lesion sites. For this reason, stem cell-based gene therapy is the most effective treatment for LSDs. In mouse models of LSDs, genetically modified neural stem cells encoding enzyme genes effectively decreased lysosomal storage, reduced pathology and extended life span of animals. Cell-based gene therapies for LSDs bridge the application of ERT and gene therapy and are important direction to pursue in the future.
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PMID:Lysosomal storage diseases: Stem cell-based cell- and gene-therapy. 2485 78