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

Authors :
Annie Arguello
René Meisner
Elliot R. Thomsen
Hoang N. Nguyen
Ritesh Ravi
Jeffrey Simms
Iris Lo
Jessica Speckart
Julia Holtzman
Thomas M. Gill
Darren Chan
Yuhsiang Cheng
Chi-Lu Chiu
Jason C. Dugas
Meng Fang
Isabel A. Lopez
Hilda Solanoy
Buyankhishig Tsogtbaatar
Yuda Zhu
Akhil Bhalla
Kirk R. Henne
Anastasia G. Henry
Anthony Delucchi
Simona Costanzo
Jeffrey M. Harris
Dolores Diaz
Kimberly Scearce-Levie
Pascal E. Sanchez
Source :
JCI Insight, Vol 6, Iss 19 (2021)
Publication Year :
2021
Publisher :
American Society for Clinical investigation, 2021.

Abstract

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.

Subjects

Subjects :
Neuroscience
Therapeutics
Medicine

Details

Language :
English
ISSN :
23793708
Volume :
6
Issue :
19
Database :
Directory of Open Access Journals
Journal :
JCI Insight
Publication Type :
Academic Journal
Accession number :
edsdoj.7257efca6a4647a28c441e395328432c
Document Type :
article
Full Text :
https://doi.org/10.1172/jci.insight.145445