Effect of neonatal administration of a retroviral vector expressing alpha-L-iduronidase upon lysosomal storage in brain and other organs in mucopolysaccharidosis I mice.
Mucopolysaccharidosis I (MPS I) due to deficient alpha-L-iduronidase (IDUA) activity results in accumulation of glycosaminoglycans in many cells. Gene therapy could program cells to secrete IDUA modified with mannose 6-phosphate (M6P), and enzyme could be taken up by other cells via the M6P receptor. We previously reported that newborn MPS I mice that were injected intravenously with 10(9) (high-dose) or 10(8) (low-dose) transducing units/kg of a retroviral vector (RV) expressing canine IDUA achieved stable levels of IDUA activity in serum and had reduced disease in heart, eye, ear, and bone in a dose-dependent fashion. However, the dose required for improvement in manifestations of disease in other organs was not reported. High-dose and low-dose RV mice with an average serum IDUA activity of 1037+/-90 U/ml (471-fold normal) and 43+/-12 U/ml (20-fold normal), respectively, had complete correction of biochemical and pathological evidence of disease in the liver, spleen, kidney, and small intestines. Although mice that received high-dose RV had complete correction of lysosomal storage in thymus, ovary, lung, and testis, correction in these organs was only partial for those that received low-dose RV. Storage in brain was almost completely corrected with high-dose RV, but was not improved with low-dose RV. The correction of disease in brain may be due to diffusion of enzyme from blood. We conclude that high-dose RV prevents biochemical and pathological manifestations of disease in all organs in MPS I mice including brain.
Chung
Sarah
S
Department of Internal Medicine, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA.
Ma
Xiucui
X
Liu
Yuli
Y
Lee
David
D
Tittiger
Mindy
M
Ponder
Katherine P
KP
D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D002540:Cerebral Cortex / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage*; D006025:Glycosaminoglycans / Q000378:metabolism; D007068:Iduronidase / Q000008:administration & dosage* / Q000235:genetics / Q000378:metabolism / Q000493:pharmacokinetics; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008247:Lysosomes / Q000378:metabolism; D008297:Male; D051379:Mice; D008059:Mucopolysaccharidosis I / Q000235:genetics / Q000628:therapy*; D010053:Ovary / Q000378:metabolism / Q000473:pathology; D012190:Retroviridae / Q000235:genetics; D013737:Testis / Q000378:metabolism / Q000473:pathology; D013950:Thymus Gland / Q000378:metabolism / Q000473:pathology; D014018:Tissue Distribution; D001619:beta-N-Acetylhexosaminidases / Q000378:metabolism
D006025:Glycosaminoglycans; D001619:beta-N-Acetylhexosaminidases; D007068:Iduronidase