TY - JOUR
T1 - Correction of clinical manifestations of canine mucopolysaccharidosis I with neonatal retroviral vector gene therapy
AU - Traas, Anne M.
AU - Wang, Ping
AU - Ma, Xiucui
AU - Tittiger, Mindy
AU - Schaller, Laura
AU - O'donnell, Patricia
AU - Sleeper, Meg M.
AU - Vite, Charles
AU - Herati, Ramin
AU - Aguirre, Gustavo D.
AU - Haskins, Mark
AU - Ponder, Katherine P.
N1 - Funding Information:
We thank Emil Kakkis (Biomarin) for sending us mucopolysaccharidosis I dogs and canine α-l-iduronidase protein, Elizabeth Neufeld (University of California, Los Angeles) for several helpful conversations, Ralph Commons (Michigan State University) for help with pathology, and Clay Semenkovich and Trey Coleman (Washington University) for assistance with real-time PCR. This work was supported by the Ryan Foundation, the National MPS Society, and the National Institutes of Health (DK66448 awarded to K.P.P., EY-13132 awarded to G.D.A., and RR02512 awarded to M.H.). Real-time PCR was supported by the Phenotyping Core of the Diabetes Research and Training Center (DK20579) awarded to Clay Semenkovich.
PY - 2007/8
Y1 - 2007/8
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=34547101208&partnerID=8YFLogxK
U2 - 10.1038/sj.mt.6300201
DO - 10.1038/sj.mt.6300201
M3 - Article
C2 - 17519893
AN - SCOPUS:34547101208
SN - 1525-0016
VL - 15
SP - 1423
EP - 1431
JO - Molecular Therapy
JF - Molecular Therapy
IS - 8
ER -