Journal
MOLECULAR THERAPY
Volume 15, Issue 8, Pages 1423-1431Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.mt.6300201
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Funding
- NCRR NIH HHS [RR02512] Funding Source: Medline
- NEI NIH HHS [EY-13132] Funding Source: Medline
- NIDDK NIH HHS [DK66448, DK20579] Funding Source: Medline
- NIH HHS [P40 OD010939] Funding Source: Medline
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Mucopolysaccharidosis 1 (MPS 1) (Hurler syndrome) is due to deficient alpha-L-iduronidase (IDUA) activity and is the most common of the MPS disorders. Neonatal MPS 1 dogs were injected intravenously (IV) with a gamma retroviral vector containing a complete long-terminal repeat (LTR) and an internal human alpha(1)-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 1 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.
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