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1.
Proc Natl Acad Sci U S A ; 111(41): 14870-5, 2014 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-25267636

RESUMO

Mucopolysaccharidosis type IIIB (MPS IIIB, Sanfilippo syndrome type B) is a lysosomal storage disease characterized by profound intellectual disability, dementia, and a lifespan of about two decades. The cause is mutation in the gene encoding α-N-acetylglucosaminidase (NAGLU), deficiency of NAGLU, and accumulation of heparan sulfate. Impediments to enzyme replacement therapy are the absence of mannose 6-phosphate on recombinant human NAGLU and the blood-brain barrier. To overcome the first impediment, a fusion protein of recombinant NAGLU and a fragment of insulin-like growth factor II (IGFII) was prepared for endocytosis by the mannose 6-phosphate/IGFII receptor. To bypass the blood-brain barrier, the fusion protein ("enzyme") in artificial cerebrospinal fluid ("vehicle") was administered intracerebroventricularly to the brain of adult MPS IIIB mice, four times over 2 wk. The brains were analyzed 1-28 d later and compared with brains of MPS IIIB mice that received vehicle alone or control (heterozygous) mice that received vehicle. There was marked uptake of the administered enzyme in many parts of the brain, where it persisted with a half-life of approximately 10 d. Heparan sulfate, and especially disease-specific heparan sulfate, was reduced to control level. A number of secondary accumulations in neurons [ß-hexosaminidase, LAMP1(lysosome-associated membrane protein 1), SCMAS (subunit c of mitochondrial ATP synthase), glypican 5, ß-amyloid, P-tau] were reduced almost to control level. CD68, a microglial protein, was reduced halfway. A large amount of enzyme also appeared in liver cells, where it reduced heparan sulfate and ß-hexosaminidase accumulation to control levels. These results suggest the feasibility of enzyme replacement therapy for MPS IIIB.


Assuntos
Acetilglucosaminidase/uso terapêutico , Encéfalo/metabolismo , Sistemas de Liberação de Medicamentos , Fator de Crescimento Insulin-Like II/uso terapêutico , Mucopolissacaridose III/tratamento farmacológico , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/uso terapêutico , Animais , Biomarcadores/metabolismo , Encéfalo/patologia , Células CHO , Células Cultivadas , Cricetinae , Cricetulus , Endocitose , Fibroblastos/metabolismo , Fibroblastos/patologia , Heparitina Sulfato/metabolismo , Humanos , Injeções Intraventriculares , Fígado/metabolismo , Proteínas de Membrana Lisossomal/metabolismo , Camundongos , Mucopolissacaridose III/patologia , Neurônios/metabolismo , Neurônios/patologia , Ligação Proteica , beta-N-Acetil-Hexosaminidases/metabolismo
2.
Drug Deliv Transl Res ; 10(2): 425-439, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31942701

RESUMO

BMN 250 is being developed as enzyme replacement therapy for Sanfilippo type B, a primarily neurological rare disease, in which patients have deficient lysosomal alpha-N-acetylglucosaminidase (NAGLU) enzyme activity. BMN 250 is taken up in target cells by the cation-independent mannose 6-phosphate receptor (CI-MPR, insulin-like growth factor 2 receptor), which then facilitates transit to the lysosome. BMN 250 is dosed directly into the central nervous system via the intracerebroventricular (ICV) route, and the objective of this work was to compare systemic intravenous (IV) and ICV delivery of BMN 250 to confirm the value of ICV dosing. We first assess the ability of enzyme to cross a potentially compromised blood-brain barrier in the Naglu-/- mouse model and then assess the potential for CI-MPR to be employed for receptor-mediated transport across the blood-brain barrier. In wild-type and Naglu-/- mice, CI-MPR expression in brain vasculature is high during the neonatal period but virtually absent by adolescence. In contrast, CI-MPR remains expressed through adolescence in non-affected non-human primate and human brain vasculature. Combined results from IV administration of BMN 250 in Naglu-/- mice and IV and ICV administration in healthy juvenile non-human primates suggest a limitation to therapeutic benefit from IV administration because enzyme distribution is restricted to brain vascular endothelial cells: enzyme does not reach target neuronal cells following IV administration, and pharmacological response following IV administration is likely restricted to clearance of substrate in endothelial cells. In contrast, ICV administration enables central nervous system enzyme replacement with biodistribution to target cells.


Assuntos
Acetilglucosaminidase/administração & dosagem , Acetilglucosaminidase/genética , Barreira Hematoencefálica/química , Fator de Crescimento Insulin-Like II/administração & dosagem , Mucopolissacaridose III/tratamento farmacológico , Receptor IGF Tipo 2/metabolismo , Proteínas Recombinantes de Fusão/administração & dosagem , Acetilglucosaminidase/uso terapêutico , Administração Intravenosa , Animais , Modelos Animais de Doenças , Terapia de Reposição de Enzimas , Feminino , Infusões Intraventriculares , Fator de Crescimento Insulin-Like II/uso terapêutico , Masculino , Camundongos , Camundongos Transgênicos , Mucopolissacaridose III/genética , Primatas , Proteínas Recombinantes de Fusão/uso terapêutico , Pesquisa Translacional Biomédica
3.
Mol Ther Methods Clin Dev ; 6: 43-53, 2017 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-28664165

RESUMO

Sanfilippo syndrome type B (mucopolysaccharidosis IIIB), caused by inherited deficiency of α-N-acetylglucosaminidase (NAGLU), required for lysosomal degradation of heparan sulfate (HS), is a pediatric neurodegenerative disorder with no approved treatment. Intracerebroventricular (ICV) delivery of a modified recombinant NAGLU, consisting of human NAGLU fused with insulin-like growth factor 2 (IGF2) for enhanced lysosomal targeting, was previously shown to result in marked enzyme uptake and clearance of HS storage in the Naglu-/- mouse brain. To further evaluate regional, cell type-specific, and dose-dependent biodistribution of NAGLU-IGF2 (BMN 250) and its effects on biochemical and histological pathology, Naglu-/- mice were treated with 1-100 µg ICV doses (four times over 2 weeks). 1 day after the last dose, BMN 250 (100 µg doses) resulted in above-normal NAGLU activity levels, broad biodistribution, and uptake in all cell types, with NAGLU predominantly localized to neurons in the Naglu-/- mouse brain. This led to complete clearance of disease-specific HS and reduction of secondary lysosomal defects and neuropathology across various brain regions lasting for at least 28 days after the last dose. The substantial brain uptake of NAGLU attainable by this highest ICV dosage was required for nearly complete attenuation of disease-driven storage accumulations and neuropathology throughout the Naglu-/- mouse brain.

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