Characterization of a novel mucopolysaccharidosis type II mouse model and recombinant AAV2/8 vector-mediated gene therapy

Molecules and Cells
Sung-Chul JungDong-Kyu Jin

Abstract

Mucopolysaccharidosis type II (MPS II; Hunter syndrome) is an X-linked inherited disorder caused by a deficiency of the enzyme iduronate-2-sulfatase (IDS), which results in the lysosomal accumulation of glycosaminoglycans (GAG) such as dermatan and heparan sulfate. Here, we report the generation of IDS knockout mice, a model of human MPS II, and an analysis of the resulting phenotype. We also evaluated the effect of gene therapy with a pseudotyped, recombinant adeno-associated virus 2/8 vector encoding the human IDS gene (rAAV-hIDS) in IDS-deficient mice. IDS activity and GAG levels were measured in serum and tissues after therapy. Gene therapy completely restored IDS activity in plasma and tissue of the knockout mice. The rescued enzymatic activity completely cleared the accumulated GAGs in all the tissues analyzed. This model can be used to explore the therapeutic potential of IDS replacement and other strategies for the treatment of MPS II. Additionally, AAV2/8 vectors have promising future clinical applications for the treatment of patients with MPS II.

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Citations

Jun 19, 2013·Current Allergy and Asthma Reports·Hayley E TyrerMahmood F Bhutta
Nov 5, 2014·Intractable & Rare Diseases Research·Sung Yoon ChoDong-Kyu Jin
May 27, 2011·Journal of Inherited Metabolic Disease·Ursula MatteRoberto Giugliani
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Jan 24, 2014·Expert Opinion on Drug Delivery·Guilherme BaldoUrsula Matte
Nov 25, 2014·Expert Opinion on Orphan Drugs·Shunji TomatsuTadao Orii
Aug 1, 2012·American Journal of Medical Genetics. Part a·Sung Hwa HongDong-Kyu Jin
Mar 27, 2013·American Journal of Medical Genetics. Part a·Young Bae SohnDong-Kyu Jin
Jun 9, 2016·Human Gene Therapy·Michaël HocquemillerNathalie Cartier
Nov 11, 2016·Journal of Human Genetics·Chihwa KimEui-Cheol Jo
Feb 20, 2020·International Journal of Molecular Sciences·Francesca D'AvanzoRosella Tomanin
Nov 22, 2017·Expert Opinion on Orphan Drugs·Molly StapletonShunji Tomatsu
May 28, 2019·Genetics and Molecular Biology·Edina PolettoGuilherme Baldo
May 1, 2020·Frontiers in Molecular Biosciences·Jacob M FavretDaesung Shin
Jun 3, 2021·International Journal of Molecular Sciences·Paweł Zapolnik, Antoni Pyrkosz
Aug 8, 2021·International Journal of Molecular Sciences·Christiane S HampeR Scott McIvor

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