A Novel Preclinical Model of Mucopolysaccharidosis Type II for Developing Human Hematopoietic Stem Cell Gene Therapy

Overview

Journal Gene Ther

Date 2022 Jul 14

PMID 35835952

Authors

Yohta Shimada

Natsumi Ishii

Takashi Higuchi

Motohito Goto

Toya Ohashi

Hiroshi Kobayashi

Affiliations

Soon will be listed here.

Abstract

A hematopoietic stem cell (HSC) gene therapy (GT) using lentiviral vectors has attracted interest as a promising treatment approach for neuropathic lysosomal storage diseases. To proceed with the clinical development of HSC-GT, evaluation of the therapeutic potential of gene-transduced human CD34+ (hCD34+) cells in vivo is one of the key issues before human trials. Here, we established an immunodeficient murine model of mucopolysaccharidosis type II (MPS II), which are transplantable human cells, and demonstrated the application of those mice in evaluating the therapeutic efficacy of gene-modified hCD34+ cells. NOG/MPS II mice, which were generated using CRISPR/Cas9, exhibited a reduction of disease-causing enzyme iduronate-2-sulfatatase (IDS) activity and the accumulation of glycosaminoglycans in their tissues. When we transplanted hCD34+ cells transduced with a lentiviral vector carrying the IDS gene into NOG/MPS II mice, a significant amelioration of biochemical pathophenotypes was observed in the visceral and neuronal tissues of those mice. In addition, grafted cells in the NOG/MPS II mice showed the oligoclonal integration pattern of the vector, but no obvious clonal dominance was detected in the mice. Our findings indicate the promising application of NOG/MPS II mice to preclinical study of HSC-GT for MPS II using human cells.

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