Enzyme replacement therapy in a murine model of Morquio A syndrome

TLDR

Mucopolysaccharidosis IVA is an autosomal recessive disorder caused by GALNS deficiency, resulting in keratan sulfate and chondroitin‑6‑sulfate accumulation. The study evaluated pharmacokinetics and biodistribution of native and SUMF1‑modified recombinant GALNS produced in CHO cells, administering 250 units g⁻¹ IV and weekly 12‑week dosing, with enzymes mainly localizing to liver, spleen, bone, and bone marrow. The enzymes exhibited similar blood half‑lives, retained 20–850 % of wild‑type activity after 4 h, and weekly dosing reduced storage material in visceral organs, connective tissues, brain, and lowered blood keratan sulfate to near‑normal levels, supporting ERT trials.

Abstract

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.