Improvements in mucopolysaccharidosis I mice after adult retroviral vector-mediated gene therapy with immunomodulation.
Mucopolysaccharidosis I (MPS I) is caused by deficient alpha-L-iduronidase (IDUA) activity and results in the accumulation of glycosaminoglycans and multisystemic disease. Gene therapy could program cells to secrete mannose 6-phosphate-modified IDUA, and enzyme in blood could be taken up by other cells. Neonatal retroviral vector (RV)-mediated gene therapy has been shown to reduce the manifestations of murine MPS I; however, intravenous injection of RV into adults was ineffective owing to a cytotoxic T lymphocyte (CTL) response against transduced cells. In this study, prolonged inhibition of CD28 signaling with CTLA4-Ig, or transient administration of CTLA4-Ig with an anti-CD40 ligand antibody or with an anti-CD4 antibody, resulted in stable expression in most mice that received RV as adults. Mice with stable expression had 81 +/- 41U/ml IDUA activity in serum. This resulted in reductions in bone disease, improvements in hearing and vision, and reductions in biochemical and pathological evidence of lysosomal storage in most organs. Improvements in brain were likely due to diffusion of enzyme from blood. However, aortic disease was refractory to treatment. This demonstrates that most manifestations of MPS I can be prevented using adult gene therapy if an immune response is blocked.
Ma
Xiucui
X
Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Liu
Yuli
Y
Tittiger
Mindy
M
Hennig
Anne
A
Kovacs
Attila
A
Popelka
Sarah
S
Wang
Baomei
B
Herati
Ramin
R
Bigg
Mark
M
Ponder
Katherine P
KP
D000069594:Abatacept; D000818:Animals; D000831:Animals, Newborn; D001842:Bone and Bones / Q000378:metabolism / Q000473:pathology; D001921:Brain / Q000378:metabolism / Q000473:pathology; D018106:CD28 Antigens / Q000235:genetics / Q000378:metabolism; D005434:Flow Cytometry; D015870:Gene Expression / Q000187:drug effects; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D006025:Glycosaminoglycans / Q000378:metabolism; D006309:Hearing; D006801:Humans; D007068:Iduronidase / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D018796:Immunoconjugates / Q000008:administration & dosage / Q000235:genetics / Q000494:pharmacology; D016464:Lysosomal Storage Diseases / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008059:Mucopolysaccharidosis I / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D012190:Retroviridae / Q000235:genetics; D013154:Spleen / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D014785:Vision, Ocular; D001619:beta-N-Acetylhexosaminidases / Q000378:metabolism
D018106:CD28 Antigens; D006025:Glycosaminoglycans; D018796:Immunoconjugates; D000069594:Abatacept; D001619:beta-N-Acetylhexosaminidases; D007068:Iduronidase