Phenotypic Correction of Murine Mucopolysaccharidosis Type II by Engraftment of Ex Vivo Lentiviral Vector-Transduced Hematopoietic Stem and Progenitor Cells

Miles C. Smith, Lalitha R. Belur, Andrea D. Karlen, Olivia Erlanson, Kelly M. Podetz-Pedersen, Jessica McKenzie, Jenn Detellis, Khatuna Gagnidze, Geoffrey Parsons, Nicholas Robinson, Shelby Labarre, Saumil Shah, Justin Furcich, Troy C. Lund, Hsing Chen Tsai, R. Scott McIvor, Melissa Bonner

Research output: Contribution to journalArticlepeer-review

6 Scopus citations


Mucopolysaccharidosis type II (MPS II, Hunter syndrome) is an X-linked recessive lysosomal disease caused by deficiency of iduronate-2-sulfatase (IDS). The absence of IDS results in the accumulation of the glycosaminoglycans (GAGs) heparan sulfate and dermatan sulfate. Currently, the only approved treatment option for MPS II is enzyme replacement therapy (ERT), Elaprase. However, ERT is demanding for the patient and does not ameliorate neurological manifestations of the disease. Using an IDS-deficient mouse model that phenocopies the human disease, we evaluated hematopoietic stem and progenitor cells (HSPCs) transduced with a lentiviral vector (LVV) carrying a codon-optimized human IDS coding sequence regulated by a ubiquitous MNDU3 promoter (MNDU3-IDS). Mice treated with MNDU3-IDS LVV-transduced cells showed supraphysiological levels of IDS enzyme activity in plasma, peripheral blood mononuclear cells, and in most analyzed tissues. These enzyme levels were sufficient to normalize GAG storage in analyzed tissues. Importantly, IDS levels in the brains of MNDU3-IDS-engrafted animals were restored to 10-20% than that of wild-type mice, sufficient to normalize GAG content and prevent emergence of cognitive deficit as evaluated by neurobehavioral testing. These results demonstrate the potential effectiveness of ex vivo MNDU3-IDS LVV-transduced HSPCs for treatment of MPS II.

Original languageEnglish (US)
Pages (from-to)1279-1292
Number of pages14
JournalHuman gene therapy
Issue number23-24
StatePublished - Dec 1 2022

Bibliographical note

Funding Information:
The work detailed in this article was sponsored by bluebird bio, Inc. J.M., J.D., K.G., G.P., N.R., S.L., S.S., H.-C.T., and M.B. are all current or former employees of bluebird bio, Inc. The remaining authors declare no competing interests.

Publisher Copyright:
© Miles C. Smith et al., 2022. Published by Mary Ann Liebert, Inc. 2022.


  • glycosaminoglycan
  • hematopoietic stem cell
  • iduronate-2-sulfatase
  • lentiviral vector
  • mucopolysaccharidosis type II

PubMed: MeSH publication types

  • Journal Article
  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural


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