Department of Biomedical Engineering, Saint Louis University, 3507 Lindell Blvd, St. Louis, MO, 63103, USA.
Department of Pediatrics, School of Medicine, Saint Louis University, 1100 South Grand Blvd, St. Louis, MO, 63104, USA.
Drug Deliv Transl Res. 2020 Oct;10(5):1341-1352. doi: 10.1007/s13346-020-00714-7.
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.
黏多糖贮积症 IVA(Morquio A 病)是一种由 N-乙酰半乳糖胺-6-硫酸酯酶(GALNS)缺乏引起的遗传性疾病,导致硫酸角质素和软骨素-6-硫酸盐在溶酶体中积累。许多患者在十几岁时就需要依赖轮椅,他们的预期寿命为 20-30 年。目前,酶替代疗法(ERT)是首选的治疗方法。尽管它可以缓解一些症状,但替代 GALNS 酶存在几个挑战,包括在循环中非常快的清除率和在 37°C 时的不稳定性。这些限制影响酶输注的频率和成本,以及到达所有组织的能力。在这项研究中,我们开发了可注射和可生物降解的聚乙二醇(PEG)水凝胶,负载重组人 GALNS(rhGALNS),以提高酶的稳定性和生物利用度,并实现持续释放。我们通过批量释放实验建立了酶的释放曲线,并使用荧光相关光谱法确定了扩散系数。我们观察到 PEG 水凝胶在持续释放 7 天的过程中保持了酶的活性。在水凝胶中,rhGALNS 的扩散速度比在缓冲液中慢近四倍。我们通过测量患者成纤维细胞对水凝胶中释放的酶的摄取,进一步证实了酶在释放时是有活性的。开发的水凝胶递送装置可以克服 rhGALNS 替代的当前限制,提高 Morquio A 患者的生活质量。将 GALNS 酶包封在聚乙二醇水凝胶中可以通过保持其活性来提高 GALNS 的稳定性,并提供至少 7 天的持续释放。
Drug Deliv Transl Res. 2020-10
Pharmaceuticals (Basel). 2023-6-27
Hum Mol Genet. 2008-3-15
Appl Biochem Biotechnol. 2025-5-24
Pharmaceuticals (Basel). 2023-6-27
Biotechnol Bioeng. 2021-12
J Biomed Mater Res A. 2017-9-19
Mater Sci Eng C Mater Biol Appl. 2017-5-15
Soft Matter. 2017-2-22
Mol Genet Metab. 2015-2
Adv Mater. 2014-10
Drugs. 2014-4
PLoS One. 2014-1-21