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<p>Morquio A syndrome is a rare genetic disorder where deficiency in N-acetylgalactosamine-6-sulfate sulfatase (GALNS) enzyme prevents breakdown of glycosaminoglycans (GAGs). Recombinant human GALNS (rhGALNS) is currently administered by intravenous infusion, but the treatment is costly and time-consuming and provides limited efficacy. Patient quality of life could be improved by an injectable sustained rhGALNS release device that would eliminate weekly multi-hour infusions. Polyethylene glycol (PEG) hydrogels can be employed as a hydrophilic, tunable, non-toxic, and biodegradable drug delivery system for the sustained release of rhGALNS, as explored by us previously. Here, we investigated the stability of rhGALNS in various buffers mimicking the in vivo environment that would be encountered by the enzyme, inside of and outside the PEG hydrogels. rhGALNS activity was reduced 85% by reversible inhibition in phosphate-buffered saline (PBS), representing interstitial fluid and plasma. Buffer exchanging into acidic buffer representing the lysosome recovered this loss. However, incubation in PBS for 3&#xa0;days resulted in an irreversible loss of 85%. There were no significant changes in rhGALNS hydrodynamic radius upon activity loss, suggesting structural integrity. Such activity loss makes sustained delivery impractical without additional stabilization, such as confinement within the hydrogel. rhGALNS activity was retained upon encapsulation, and the average specific activity of rhGALNS released from a hydrogel decreased only 20% over 7&#xa0;days. These results show that the activity of rhGALNS was better retained within the hydrogel than in buffer alone, potentially enabling sustained release for rhGALNS or other enzymes unstable in physiological conditions with our hydrogel delivery device.</p> Graphical Abstract <p></p>

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rhGALNS Enzyme Stability in Physiological Buffers: Implications for Sustained Release

  • 期刊论文

  • 发表日期：

    2025年5月24日

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  • Samuel Ruesing,
  • Samuel Stealey,
  • Qi Gan,
  • Linda Winter,
  • Adriana M. Montaño,
  • Silviya P. Zustiak

摘要

Morquio A syndrome is a rare genetic disorder where deficiency in N-acetylgalactosamine-6-sulfate sulfatase (GALNS) enzyme prevents breakdown of glycosaminoglycans (GAGs). Recombinant human GALNS (rhGALNS) is currently administered by intravenous infusion, but the treatment is costly and time-consuming and provides limited efficacy. Patient quality of life could be improved by an injectable sustained rhGALNS release device that would eliminate weekly multi-hour infusions. Polyethylene glycol (PEG) hydrogels can be employed as a hydrophilic, tunable, non-toxic, and biodegradable drug delivery system for the sustained release of rhGALNS, as explored by us previously. Here, we investigated the stability of rhGALNS in various buffers mimicking the in vivo environment that would be encountered by the enzyme, inside of and outside the PEG hydrogels. rhGALNS activity was reduced 85% by reversible inhibition in phosphate-buffered saline (PBS), representing interstitial fluid and plasma. Buffer exchanging into acidic buffer representing the lysosome recovered this loss. However, incubation in PBS for 3 days resulted in an irreversible loss of 85%. There were no significant changes in rhGALNS hydrodynamic radius upon activity loss, suggesting structural integrity. Such activity loss makes sustained delivery impractical without additional stabilization, such as confinement within the hydrogel. rhGALNS activity was retained upon encapsulation, and the average specific activity of rhGALNS released from a hydrogel decreased only 20% over 7 days. These results show that the activity of rhGALNS was better retained within the hydrogel than in buffer alone, potentially enabling sustained release for rhGALNS or other enzymes unstable in physiological conditions with our hydrogel delivery device.

Graphical Abstract