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most significant opportunity presented by the MSUD mouse models is to test novel treatments such as gene [38-41] and cell based therapies (e.g., hepatocytes [42,43] or embryonic stem cells [44]). Relevant to gene therapy, recent problems with gene therapy in humans highlight the importance and critical need of animal models of genetic diseases for preclinical studies. The testing of gene and cell based therapies on appropriate animal model systems provides a preliminary method of establishing not only the efficacy, but also short- and long-term safety. Success with animal studies is expected to advance such therapeutic approaches and could pave the way for studies in humans. In addition to testing various treatments, these models should also be very useful for investigating the underlying pathophysiologic consequences of the disease. Such studies are very difficult/impossible to do in human patients for obvious ethical reasons, and often must rely on autopsy tissue. Additionally, the intermediate MSUD model may also be useful for studies to test the effect of thiamin. A thiamin-responsive form of MSUD has been described [1]. The phenotype of these patients is heterogeneous and treatment with a wide range of thiamin doses has produced limited success [1]. Recent cell culture studies with MSUD cells have suggested that the thiamin-responsive phenotype is dependent upon the presence of at least one E2 expressing allele [45,46]. In light of these newer findings, our intermediate MSUD mouse provides a model to test the effect of thiamin with respect to BCKDH activity and blood amino acid levels at the level of the whole animal. Because of recent interest in structural analysis of multienzyme complexes [35,36,45,46], the intermediate MSUD model may provide a valuable resource for studies of structural biology. Lastly, the information and knowledge gained from studies with the MSUD models described here will also be applicable and transferable to other mitochondrial disorders due to defects in multisubunit enzymes."}

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{"project":"craft-ca-core-dev","denotations":[{"id":"T19647","span":{"begin":1597,"end":1602},"obj":"UBERON:0000178"},{"id":"T19646","span":{"begin":1554,"end":1561},"obj":"CHEBI:26948"},{"id":"T19645","span":{"begin":1509,"end":1514},"obj":"NCBITaxon:10088"},{"id":"T19644","span":{"begin":1437,"end":1443},"obj":"SO:0001023"},{"id":"T19643","span":{"begin":1426,"end":1436},"obj":"GO:0010467"},{"id":"T19642","span":{"begin":1423,"end":1425},"obj":"PR:000006300"},{"id":"T19641","span":{"begin":1347,"end":1354},"obj":"CHEBI:26948"},{"id":"T19640","span":{"begin":1231,"end":1238},"obj":"CHEBI:26948"},{"id":"T19639","span":{"begin":1091,"end":1098},"obj":"CHEBI:26948"},{"id":"T19638","span":{"begin":1080,"end":1087},"obj":"CHEBI:26948"},{"id":"T19637","span":{"begin":977,"end":983},"obj":"UBERON:0000479"},{"id":"T19636","span":{"begin":902,"end":907},"obj":"NCBITaxon:9606"},{"id":"T19635","span":{"begin":680,"end":686},"obj":"NCBITaxon:9606"},{"id":"T19634","span":{"begin":576,"end":582},"obj":"NCBITaxon:33208"},{"id":"T19633","span":{"begin":435,"end":441},"obj":"NCBITaxon:33208"},{"id":"T19632","span":{"begin":390,"end":394},"obj":"SO:0000704"},{"id":"T19631","span":{"begin":333,"end":340},"obj":"SO:0000704"},{"id":"T19630","span":{"begin":316,"end":322},"obj":"NCBITaxon:33208"},{"id":"T19629","span":{"begin":263,"end":269},"obj":"NCBITaxon:9606"},{"id":"T19628","span":{"begin":247,"end":251},"obj":"SO:0000704"},{"id":"T19627","span":{"begin":212,"end":216},"obj":"SO:0000704"},{"id":"T19626","span":{"begin":172,"end":192},"obj":"CL:0002322"},{"id":"T19625","span":{"begin":172,"end":181},"obj":"UBERON:0000922"},{"id":"T19624","span":{"begin":149,"end":160},"obj":"CL:0000182"},{"id":"T19623","span":{"begin":104,"end":108},"obj":"SO:0000704"},{"id":"T19622","span":{"begin":55,"end":60},"obj":"NCBITaxon:10088"},{"id":"T19650","span":{"begin":1984,"end":1997},"obj":"GO:0005739"},{"id":"T19649","span":{"begin":1720,"end":1729},"obj":"GO:0032991"},{"id":"T19648","span":{"begin":1647,"end":1653},"obj":"NCBITaxon:33208"}],"text":"The most significant opportunity presented by the MSUD mouse models is to test novel treatments such as gene [38-41] and cell based therapies (e.g., hepatocytes [42,43] or embryonic stem cells [44]). Relevant to gene therapy, recent problems with gene therapy in humans highlight the importance and critical need of animal models of genetic diseases for preclinical studies. The testing of gene and cell based therapies on appropriate animal model systems provides a preliminary method of establishing not only the efficacy, but also short- and long-term safety. Success with animal studies is expected to advance such therapeutic approaches and could pave the way for studies in humans. In addition to testing various treatments, these models should also be very useful for investigating the underlying pathophysiologic consequences of the disease. Such studies are very difficult/impossible to do in human patients for obvious ethical reasons, and often must rely on autopsy tissue. Additionally, the intermediate MSUD model may also be useful for studies to test the effect of thiamin. A thiamin-responsive form of MSUD has been described [1]. The phenotype of these patients is heterogeneous and treatment with a wide range of thiamin doses has produced limited success [1]. Recent cell culture studies with MSUD cells have suggested that the thiamin-responsive phenotype is dependent upon the presence of at least one E2 expressing allele [45,46]. In light of these newer findings, our intermediate MSUD mouse provides a model to test the effect of thiamin with respect to BCKDH activity and blood amino acid levels at the level of the whole animal. Because of recent interest in structural analysis of multienzyme complexes [35,36,45,46], the intermediate MSUD model may provide a valuable resource for studies of structural biology. Lastly, the information and knowledge gained from studies with the MSUD models described here will also be applicable and transferable to other mitochondrial disorders due to defects in multisubunit enzymes."}