Acidic amino acid tag enhances response to enzyme replacement in mucopolysaccharidosis type VII mice.
We have tested an acidic oligopeptide-based targeting system for delivery of enzymes to tissues, especially bone and brain, in a murine mucopolysaccharidosis type VII (MPS VII) model. This strategy is based upon tagging a short peptide consisting of acidic amino acids (AAA) to N terminus of human beta-glucuronidase (GUS). The pharmacokinetics, biodistribution, and the pathological effect on MPS VII mouse after 12 weekly infusions were determined for recombinant human untagged and tagged GUS. The tagged GUS was taken up by MPS VII fibroblasts in a mannose 6-phosphate receptor-dependent manner. Intravenously injected AAA-tagged enzyme had five times more prolonged blood clearance compared with the untagged enzyme. The tagged enzyme was delivered effectively to bone, bone marrow, and brain in MPS VII mice and was effective in reversing the storage pathology. The storage in osteoblasts was cleared similarly with both enzyme types. However, cartilage showed a little response to any of the enzymes. The tagged enzyme reduced storage in cortical neurons, hippocampus, and glia cells. A highly sensitive method of tandem mass spectrometry on serum indicated that the concentration of serum dermatan sulfate and heparan sulfate in mice treated with the tagged enzyme decreased more than the untagged enzyme. These preclinical studies suggest that this AAA-based targeting system may enhance enzyme-replacement therapy.
Montaño
Adriana M
AM
Department of Pediatrics, Saint Louis University, 1100 South Grand Boulevard, St. Louis, MO 63104, USA.
Oikawa
Hirotaka
H
Tomatsu
Shunji
S
Nishioka
Tatsuo
T
Vogler
Carole
C
Gutierrez
Monica A
MA
Oguma
Toshihiro
T
Tan
Yun
Y
Grubb
Jeffrey H
JH
Dung
Vu Chi
VC
Ohashi
Amiko
A
Miyamoto
Ken-ichi
K
Orii
Tadao
T
Yoneda
Yukio
Y
Sly
William S
WS
D024342:Amino Acids, Acidic / Q000235:genetics / Q000627:therapeutic use*; D000818:Animals; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D004195:Disease Models, Animal; D018390:Gene Targeting; D005966:Glucuronidase / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008247:Lysosomes / Q000201:enzymology; D051379:Mice; D008822:Mice, Transgenic; D016538:Mucopolysaccharidosis VII / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D010455:Peptides / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use
D024342:Amino Acids, Acidic; D010455:Peptides; D011993:Recombinant Fusion Proteins; D005966:Glucuronidase