Therapeutic neonatal hepatic gene therapy in mucopolysaccharidosis VII dogs.
Dogs with mucopolysaccharidosis VII (MPS VII) were injected intravenously at 2-3 days of age with a retroviral vector (RV) expressing canine beta-glucuronidase (cGUSB). Five animals received RV alone, and two dogs received hepatocyte growth factor (HGF) before RV in an attempt to increase transduction efficiency. Transduced hepatocytes expanded clonally during normal liver growth and secreted enzyme with mannose 6-phosphate. Serum GUSB activity was stable for up to 14 months at normal levels for the RV-treated dogs, and for 17 months at 67-fold normal for the HGF/RV-treated dog. GUSB activity in other organs was 1.5-60% of normal at 6 months for two RV-treated dogs, which was likely because of uptake of enzyme from blood by the mannose 6-phosphate receptor. The body weights of untreated MPS VII dogs are 50% of normal at 6 months. MPS VII dogs cannot walk or stand after 6 months, and progressively develop eye and heart disease. RV- and HGF/RV-treated MPS VII dogs achieved 87% and 84% of normal body weight, respectively. Treated animals could run at all times of evaluation for 6-17 months because of improvements in bone and joint abnormalities, and had little or no corneal clouding and no mitral valve thickening. Despite higher GUSB expression, the clinical improvements in the HGF/RV-treated dog were similar to those in the RV-treated animals. This is the first successful application of gene therapy in preventing the clinical manifestations of a lysosomal storage disease in a large animal.
Ponder
Katherine Parker
KP
Departments of Internal Medicine and Biochemistry and Molecular Biophysics, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA.
Melniczek
John R
JR
Xu
Lingfei
L
Weil
Margaret A
MA
O'Malley
Thomas M
TM
O'Donnell
Patricia A
PA
Knox
Van W
VW
Aguirre
Gustavo D
GD
Mazrier
Hamutal
H
Ellinwood
N Matthew
NM
Sleeper
Meg
M
Maguire
Albert M
AM
Volk
Susan W
SW
Mango
Robert L
RL
Zweigle
Jean
J
Wolfe
John H
JH
Haskins
Mark E
ME
D000818:Animals; D000831:Animals, Newborn; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D004285:Dogs; D005123:Eye / Q000473:pathology; D005260:Female; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D006801:Humans; D008297:Male; D008943:Mitral Valve / Q000473:pathology; D016538:Mucopolysaccharidosis VII / Q000196:embryology* / Q000628:therapy*; D011401:Promoter Regions, Genetic; D017527:Receptor, IGF Type 2 / Q000378:metabolism; D013997:Time Factors; D014018:Tissue Distribution; D000515:alpha 1-Antitrypsin / Q000235:genetics
D017527:Receptor, IGF Type 2; D000515:alpha 1-Antitrypsin; D017228:Hepatocyte Growth Factor