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Int J Mol Sci ; 22(20)2021 Oct 10.
Artículo en Inglés | MEDLINE | ID: mdl-34681597

RESUMEN

Enzyme replacement therapy (ERT) improves somatic manifestations in mucopolysaccharidoses (MPS). However, because intravenously administered enzymes cannot cross the blood-brain barrier (BBB), ERT is ineffective against the progressive neurodegeneration and resultant severe central nervous system (CNS) symptoms observed in patients with neuronopathic MPS. Attempts to surmount this problem have been made with intrathecal and intracerebroventricular ERT in order to achieve CNS effects, but the burdens on patients are inimical to long-term administrations. However, since pabinafusp alfa, a human iduronate-2-sulfatase fused with a BBB-crossing anti-transferrin receptor antibody, showed both central and peripheral efficacy in a mouse model, subsequent clinical trials in a total of 62 patients with MPS-II (Hunter syndrome) in Japan and Brazil substantiated this dual efficacy and provided an acceptable safety profile. To date, pabinafusp alfa is the only approved intravenous ERT that is effective against both the somatic and CNS symptoms of patients with MPS-II. This article summarizes the previously obtained preclinical and clinical evidence related to the use of this drug, presents latest data, and discusses the preclinical, translational, and clinical challenges of evaluating, ameliorating, and preventing neurodegeneration in patients with MPS-II.


Asunto(s)
Terapia de Reemplazo Enzimático , Iduronato Sulfatasa/uso terapéutico , Mucopolisacaridosis II/tratamiento farmacológico , Animales , Biomarcadores/líquido cefalorraquídeo , Barrera Hematoencefálica/efectos de los fármacos , Barrera Hematoencefálica/metabolismo , Encéfalo/metabolismo , Ensayos Clínicos como Asunto , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Humanos , Iduronato Sulfatasa/genética , Iduronato Sulfatasa/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Mucopolisacaridosis II/patología , Proteínas Recombinantes/efectos adversos , Proteínas Recombinantes/farmacología , Proteínas Recombinantes/uso terapéutico , Índice de Severidad de la Enfermedad
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