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Mol Ther ; 27(1): 178-187, 2019 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-30528089

RESUMO

Mucopolysaccharidosis type I (MPS I) is a severe disease due to deficiency of the lysosomal hydrolase α-L-iduronidase (IDUA) and the subsequent accumulation of the glycosaminoglycans (GAG), leading to progressive, systemic disease and a shortened lifespan. Current treatment options consist of hematopoietic stem cell transplantation, which carries significant mortality and morbidity risk, and enzyme replacement therapy, which requires lifelong infusions of replacement enzyme; neither provides adequate therapy, even in combination. A novel in vivo genome-editing approach is described in the murine model of Hurler syndrome. A corrective copy of the IDUA gene is inserted at the albumin locus in hepatocytes, leading to sustained enzyme expression, secretion from the liver into circulation, and subsequent uptake systemically at levels sufficient for correction of metabolic disease (GAG substrate accumulation) and prevention of neurobehavioral deficits in MPS I mice. This study serves as a proof-of-concept for this platform-based approach that should be broadly applicable to the treatment of a wide array of monogenic diseases.


Assuntos
Edição de Genes/métodos , Terapia Genética/métodos , Mucopolissacaridose I/terapia , Nucleases de Dedos de Zinco/metabolismo , Animais , Modelos Animais de Doenças , Terapia de Reposição de Enzimas , Feminino , Glicosaminoglicanos/metabolismo , Iduronidase/metabolismo , Doenças por Armazenamento dos Lisossomos/tratamento farmacológico , Doenças por Armazenamento dos Lisossomos/metabolismo , Doenças por Armazenamento dos Lisossomos/terapia , Masculino , Camundongos , Mucopolissacaridose I/tratamento farmacológico , Mucopolissacaridose I/metabolismo , Nucleases de Dedos de Zinco/genética
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