Biodegradable polyethylene glycol hydrogels for sustained release and enhanced stability of rhGALNS enzyme
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ORIGINAL ARTICLE
Biodegradable polyethylene glycol hydrogels for sustained release and enhanced stability of rhGALNS enzyme Era Jain 1 & Michael Flanagan 2 & Saahil Sheth 1 & Shiragi Patel 3 & Qi Gan 2 & Birju Patel 2 & Adriana M. Montaño 2,4 Silviya P. Zustiak 1
&
# Controlled Release Society 2020
Abstract Mucopolysaccharidosis IVA (Morquio A disease) is a genetic disorder caused by deficiency of N-acetylgalactosamine-6-sulfatesulfatase (GALNS), leading to accumulation of keratan sulfate and chondroitin-6-sulfate in lysosomes. Many patients become wheelchair-dependent as teens, and their life span is 20–30 years. Currently, enzyme replacement therapy (ERT) is the treatment of choice. Although it alleviates some symptoms, replacing GALNS enzyme poses several challenges including very fast clearance from circulation and instability at 37 °C. These constraints affect frequency and cost of enzyme infusion and ability to reach all tissues. In this study, we developed injectable and biodegradable polyethylene glycol (PEG) hydrogels, loaded with recombinant human GALNS (rhGALNS) to improve enzyme stability and bioavailability, and to sustain release. We established the enzyme’s release profile via bulk release experiments and determined diffusivity using fluorescence correlation spectroscopy. We observed that PEG hydrogels preserved enzyme activity during sustained release for 7 days. In the hydrogel, rhGALNS diffused almost four times slower than in buffer. We further confirmed that the enzyme was active when released from the hydrogels, by measuring its uptake in patient fibroblasts. The developed hydrogel delivery device could overcome current limits of rhGALNS replacement and improve quality of life for Morquio A patients. Keywords Hydrogel . Polyethylene glycol . GALNS . Enzyme replacement therapy . Morquio A disease . Sustained release . Bioactivity . Enzyme stability
Introduction Mucopolysaccharidosis IVA (MPS IVA, Morquio A) (OMIM# 253000) is a rare progressive genetic disorder. It is Era Jain, Michael Flanagan, Saahil Sheth and Shiragi Patel contributed equally to this work. * Adriana M. Montaño [email protected] * Silviya P. Zustiak [email protected] 1
Department of Biomedical Engineering, Saint Louis University, 3507 Lindell Blvd, St. Louis, MO 63103, USA
2
Department of Pediatrics, School of Medicine, Saint Louis University, 1100 South Grand Blvd, St. Louis, MO 63104, USA
3
School of Medicine, 1402 South Grand Blvd, St. Louis, MO 63104, USA
4
Department of Biochemistry and Molecular Biology, School of Medicine, Saint Louis University, 1100 South Grand Blvd, St. Louis, MO 63104, USA
characterized by the deficiency of the lysosomal enzyme Nacetylgalactosamine-6-sulfate sulfatase (GALNS), which is responsible for breaking down glycosaminoglycans [1, 2]. GALNS deficiency leads to systemic accumulation of keratan sulfate (KS) and chondroitin-6-sulfate in multiple organs [2, 3]. Main symptoms include dysostosis multiplex (short trunk, dwarfism, laxity of joints, hypoplasia of the odo
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