Correction of clinical manifestations of canine mucopolysaccharidosis I with neonatal retroviral vector gene therapy

Anne M. Traas, Ping Wang, Xiucui Ma, Mindy Tittiger, Laura Schaller, Patricia O'donnell, Meg M. Sleeper, Charles Vite, Ramin Herati, Gustavo D. Aguirre, Mark Haskins, Katherine P. Ponder

Research output: Contribution to journalArticlepeer-review

82 Scopus citations

Abstract

Mucopolysaccharidosis I (MPS I) (Hurler syndrome) is due to deficient α-L-iduronidase (IDUA) activity and is the most common of the MPS disorders. Neonatal MPS I dogs were injected intravenously (IV) with a gamma retroviral vector containing a complete long-terminal repeat (LTR) and an internal human α1-antitrypsin (hAAT) promoter upstream of the canine IDUA complementary DNA (cDNA). This resulted in stable serum IDUA activity of 366 ± 344 units (U)/ml (28-fold normal) for up to 1.8 years, which likely derived primarily from secretion of IDUA by transduced liver cells. Retroviral vector (RV)-treated dogs had >18% of normal IDUA activity in organs and had decreased severity and/or incidence of hernias, chest deformities, joint disease, facial dysmorphia, corneal clouding, valvular heart disease, and aortic dilatation as compared with untreated MPS I dogs. The marked reduction that was observed in lysosomal storage in the brain of RV-treated dogs may have been due in part to expression from the LTR of the vector in cells in the brain. This possibility will be explored in future studies, because the potential for insertional mutagenesis has raised concerns about using vectors with an intact LTR. If proven safe, this gene therapy technique may be utilized in treating children with Hurler syndrome.

Original languageEnglish
Pages (from-to)1423-1431
Number of pages9
JournalMolecular Therapy
Volume15
Issue number8
DOIs
StatePublished - Aug 2007

Fingerprint

Dive into the research topics of 'Correction of clinical manifestations of canine mucopolysaccharidosis I with neonatal retroviral vector gene therapy'. Together they form a unique fingerprint.

Cite this