Iduronate-2-sulfatase transport vehicle rescues behavioral and skeletal phenotypes in a mouse model of Hunter syndrome

被引：15

作者：

Arguello, Annie ^{[1
]}

Meisner, Rene ^{[1
]}

Thomsen, Elliot R. ^{[1
]}

Nguyen, Hoang N. ^{[1
]}

Ravi, Ritesh ^{[1
]}

Simms, Jeffrey ^{[2
]}

Lo, Iris ^{[2
]}

Speckart, Jessica ^{[2
]}

Holtzman, Julia ^{[2
]}

Gill, Thomas M. ^{[2
]}

Chan, Darren ^{[1
]}

Cheng, Yuhsiang ^{[1
]}

Chiu, Chi-Lu ^{[1
]}

Dugas, Jason C. ^{[1
]}

Fang, Meng ^{[1
]}

Lopez, Isabel A. ^{[1
]}

Solanoy, Hilda ^{[1
]}

Tsogtbaatar, Buyankhishig ^{[1
]}

Zhu, Yuda ^{[1
]}

Bhalla, Akhil ^{[1
]}

Henne, Kirk R. ^{[1
]}

Henry, Anastasia G. ^{[1
]}

Delucchi, Anthony ^{[1
]}

Costanzo, Simona ^{[1
]}

Harris, Jeffrey M. ^{[1
]}

Diaz, Dolores ^{[1
]}

Scearce-Levie, Kimberly ^{[1
]}

Sanchez, Pascal E. ^{[1
]}

机构：

[1] Denali Therapeut Inc, San Francisco, CA 94080 USA

[2] Gladstone Inst Neurol Dis, Behav Core, San Francisco, CA USA

来源：

JCI INSIGHT | 2021年 / 6卷 / 19期

关键词：

ENZYME REPLACEMENT THERAPY; II PATIENTS; MUCOPOLYSACCHARIDOSES; NEURODEGENERATION; MANIFESTATIONS; IDURSULFASE; DISEASE; SULFATE;

D O I：

10.1172/jci.insight.145445

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

Mucopolysaccharidosis type II (MPS II) is a lysosomal storage disorder caused by deficiency of the iduronate-2-sulfatase (IDS) enzyme, resulting in cellular accumulation of glycosaminoglycans (GAGs) throughout the body. Treatment of MPS II remains a considerable challenge as current enzyme replacement therapies do not adequately control many aspects of the disease, including skeletal and neurological manifestations. We developed an IDS transport vehicle (ETV:IDS) that is engineered to bind to the transferrin receptor; this design facilitates receptor-mediated transcytosis of IDS across the blood-brain barrier and improves its distribution into the brain while maintaining distribution to peripheral tissues. Here we show that chronic systemic administration of ETV:IDS in a mouse model of MPS II reduced levels of peripheral and central nervous system GAGs, microgliosis, and neurofilament light chain, a biomarker of neuronal injury. Additionally, ETV:IDS rescued auricular and skeletal abnormalities when introduced in adult MPS II mice. These effects were accompanied by improvements in several neurobehavioral domains, including motor skills, sensorimotor gating, and learning and memory. Together, these results highlight the therapeutic potential of ETV:IDS for treating peripheral and central abnormalities in MPS II. DNL310, an investigational ETV:IDS molecule, is currently in clinical trials as a potential treatment for patients with MPS II.

引用

页数：17

共 43 条

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