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Iduronate-2-sulfatase transport vehicle rescues behavioral and skeletal phenotypes in a mouse model of Hunter syndrome
Annie Arguello, … , Kimberly Scearce-Levie, Pascal E. Sanchez
Annie Arguello, … , Kimberly Scearce-Levie, Pascal E. Sanchez
Published October 8, 2021
Citation Information: JCI Insight. 2021;6(19):e145445. https://doi.org/10.1172/jci.insight.145445.
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Research Article Neuroscience Therapeutics

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

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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.

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

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Figure 1

ETV:IDS reduces peripheral and CNS GAGs, microgliosis, and neurofilament light chain levels.

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ETV:IDS reduces peripheral and CNS GAGs, microgliosis, and neurofilament...
(A) ETV:IDS is a fusion of IDS to the transport vehicle, a TfR-binding Fc fragment. Ids-KO TfRmu/hu mice (n = 20), 4.5 months old, were administered 17 weekly doses of 3 mg/kg ETV:IDS via IP injection. Vehicle-treated TfRmu/hu (n = 22) and Ids-KO TfRmu/hu mice (n = 19) served as the nondisease and disease comparator groups, respectively. All behavioral assays were run from week 11 to week 15 of dosing, and mice were sacrificed at 9 months of age, 7 days following the last dose. GAG levels were measured in the (B) liver, (C) brain, and (D) CSF. (E) CD68 was assessed using coronal brain sections immunostained with antibodies against CD68 and imaged using a wide-field fluorescence slide scanner. Quantification of CD68 staining in the hippocampus was calculated based on the total area of detected CD68-positive cells in the region of interest (ROI) divided by the total area in the ROI. Graphs display superimposed summary statistics from 4–5 animals (solid shapes) consisting of 2–3 sections from each animal (open shapes). Each animal is coded by different shapes. The 4–5 means were then used to calculate the mean ± SEM: 1-way ANOVA with Tukey’s multiple-comparison test. Neurofilament light chain (Nf-L) levels were evaluated in the (F) serum and (G) CSF. Graphs display mean ± SEM: 1-way ANOVA with Tukey’s multiple-comparison test; *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001.

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