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Biodegradable polyethylene glycol hydrogels for sustained release and enhanced stability of rhGALNS enzyme

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Abstract

Mucopolysaccharidosis IVA (Morquio A disease) is a genetic disorder caused by deficiency of N-acetylgalactosamine-6-sulfate-sulfatase (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.

Encapsulated GALNS enzyme in a polyethylene glycol hydrogel improves GALNS stability by preserving its activity, and provides sustained release for a period of at least 7 days.

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Acknowledgments

We thank Mike Marcinkowski for editorial assistance and Dr. Nicola Pozzi for access to the FCS instrument used in this study.

Funding

Saint Louis University Department of Pediatrics in association with Cardinal Glennon Foundation provided support. Saahil Sheth was supported by a Barta Graduate Scholarship awarded from Parks College of Engineering, Aviation, and Technology, Saint Louis University.

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Author notes

  1. Era Jain, Michael Flanagan, Saahil Sheth and Shiragi Patel contributed equally to this work.

Authors and Affiliations

  1. Department of Biomedical Engineering, Saint Louis University, 3507 Lindell Blvd, St. Louis, MO, 63103, USA

    Era Jain, Saahil Sheth & Silviya P. Zustiak

  2. Department of Pediatrics, School of Medicine, Saint Louis University, 1100 South Grand Blvd, St. Louis, MO, 63104, USA

    Michael Flanagan, Qi Gan, Birju Patel & Adriana M. Montaño

  3. School of Medicine, 1402 South Grand Blvd, St. Louis, MO, 63104, USA

    Shiragi Patel

  4. Department of Biochemistry and Molecular Biology, School of Medicine, Saint Louis University, 1100 South Grand Blvd, St. Louis, MO, 63104, USA

    Adriana M. Montaño

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  1. Era Jain
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Contributions

A.M.M and S.P.Z. conceived and designed the study; E.J., M.F., S.P., Q.G., S.S., B.P., and A.M.M. performed experiments; A.M.M. and S.P.Z. supervised the study; and A.M.M. and S.P.Z. wrote the manuscript, with input from all authors.

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Correspondence to Adriana M. Montaño or Silviya P. Zustiak.

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Conflict of interest

E.J., A.M.M., and S.P.Z. declare competing financial interests: they have US patent application 16/179,158. The patent covers the underlying concept of the use of hydrogels for lysosomal storage diseases described in the manuscript.

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Jain, E., Flanagan, M., Sheth, S. et al. Biodegradable polyethylene glycol hydrogels for sustained release and enhanced stability of rhGALNS enzyme. Drug Deliv. and Transl. Res. 10, 1341–1352 (2020). https://doi.org/10.1007/s13346-020-00714-7

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