Journal Article

Enzyme replacement therapy in a murine model of Morquio A syndrome

Shunji Tomatsu, Adriana M. Montaño, Amiko Ohashi, Monica A. Gutierrez, Hirotaka Oikawa, Toshihiro Oguma, Vu Chi Dung, Tatsuo Nishioka, Tadao Orii and William S. Sly

in Human Molecular Genetics

Volume 17, issue 6, pages 815-824
Published in print March 2008 | ISSN: 0964-6906
Published online December 2007 | e-ISSN: 1460-2083 | DOI:
Enzyme replacement therapy in a murine model of Morquio A syndrome

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Mucopolysaccharidosis IVA (MPS IVA) is an autosomal recessive disorder caused by a deficiency of N-acetylgalactosamine-6-sulfate sulfatase (GALNS), leading to accumulation of keratan sulfate (KS) and chrondroitin-6-sulfate. The pharmacokinetics and biodistributions were determined for two recombinant human GALNSs produced in CHO cell lines: native GALNS and sulfatase-modifier-factor 1 (SUMF1) modified GALNS. Preclinical studies of enzyme replacement therapy (ERT) by using two GALNS enzymes were performed on MPS IVA mice. The half-lives in blood circulation of two phosphorylated GALNS enzymes were similar (native, 2.4 min; SUMF1, 3.3 min). After intravenous doses of 250 units/g body weight were administered, each enzyme was primarily recovered in liver and spleen, with detectable activity in other tissues including bone and bone marrow. At 4 h post-injection, enzyme activity was retained in the liver, spleen, bone and bone marrow at levels that were 20–850% of enzyme activity in the wild-type mice. After intravenous doses of 250 units/g of native GALNS, and 250, 600 or 1000 units/g of SUMF1-GALNS were administered weekly for 12 weeks, MPS IVA mice showed marked reduction of storage in visceral organs, sinus lining cells in bone marrow, heart valves, ligaments and connective tissues. A dose-dependent clearance of storage material was observed in brain. The blood KS level assayed by tandem mass spectrometry was reduced nearly to normal level. These preclinical studies demonstrate the clearance of tissue and blood KS by administered GALNS, providing the in vivo rationale for the design of ERT trials in MPS IVA.

Journal Article.  6046 words.  Illustrated.

Subjects: Genetics and Genomics

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