Validation of Recombinant Heparan Sulphate Reagents for CNS Repair.
Validation of Recombinant Heparan Sulphate Reagents for CNS Repair.
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中枢神经系统（CNS）损伤后发生的复杂组织变化需要多靶点治疗方法。存在于我们细胞内部和周围的专门的糖分子，称为硫酸乙酰肝素（HS），调节许多细胞功能，对组织修复很重要。HS含有一种称为硫酸盐的化学基团，根据数量和位置，可以使细胞调节不同的功能。为了利用HS的潜力，我们可以使用肝素模拟物（mHeps）来模拟其功能。mHep是从血液稀释药物肝素（其结构类似于HS）修改而来的。mHep可以化学改变以含有更少或更多的硫酸盐。我们已经表明，具有低水平硫酸盐（低硫酸盐）的mHep有益于CNS修复。然而，mHep是由从猪肠中获得的肝素制成的，其供应可能存在污染或短缺的风险。使用动物源性产品作为未来的治疗方法也存在伦理问题。现在存在衍生自培养细胞的下一代HS模拟物，称为重组HS模拟物（rHS）。rHS还可以促进修复，并且比猪组织衍生的化合物更容易转化为临床。因此，我们验证了这些新的下一代模拟物的修复潜力，并将其与我们的铅低硫酸盐化合物进行了比较。迫切需要靶向中枢神经系统（CNS）疾病/损伤的多细胞病理学的疗法。修饰的非抗凝肝素模拟硫酸乙酰肝素（HS）聚糖家族，并已被提议作为CNS修复的治疗剂，因为它们是许多细胞过程的有效调节剂。我们的体外研究表明，低硫酸化修饰的硫酸乙酰肝素模拟物（LS-mHeps）驱动CNS修复。然而，LS-mHep是从猪肠中纯化的药用肝素衍生而来，供应链存在短缺和污染的风险。或者，可以使用哺乳动物细胞多重基因组工程实现肝素和HS的细胞合成，提供重组HS模拟物（rHS）的替代来源。TEGA Therapeutics（San Diego）已经生产了具有不同硫酸化程度的rHS试剂，我们已经使用模拟CNS损伤的模型验证了它们在体外促进修复的能力，并与之前的先导化合物LS-mHep 7进行了比较。我们已经表明，像LS-mHep 7一样，低硫酸化的rHS化合物促进髓鞘再生并减少星形胶质细胞增生的特征，相反，高硫酸化的rHS驱动神经突生长。因此，细胞产生的肝素模拟物可能为CNS修复提供潜在的临床益处。
The complex tissue changes that occur after central nervous system (CNS) damage/injury require a multi-target treatment approach. Specialised sugar molecules that reside in and around our cells, known as heparan sulphate (HS), regulate numerous cellular functions and are important for tissue repair. HS contains a chemical group called sulphate which, depending on the number and position, can make cells regulate different functions. To harness the potential of HS, we can mimic its function using heparin mimetics (mHeps). mHeps are modified from the blood-thinning drug heparin whose structure resembles HS. mHeps can be chemically altered to contain less or more sulphate. We have shown that mHeps with low levels of sulphate (low-sulphated) are beneficial for CNS repair. However, mHeps are manufactured from heparin obtained from pig intestines, the supply of which can risk contamination or suffer shortages. There are also ethical implications of using animal-derived products as future therapies. Next-generation HS mimics now exist which are derived from cultured cells, termed recombinant HS mimetics (rHS). rHS may also promote repair and would translate to the clinic more readily than pig tissue-derived compounds. We have therefore validated the repair potential of these newer next-generation mimetics and compared them with our lead low-sulphated compound. Therapies that target the multicellular pathology of central nervous system (CNS) disease/injury are urgently required. Modified non-anticoagulant heparins mimic the heparan sulphate (HS) glycan family and have been proposed as therapeutics for CNS repair since they are effective regulators of numerous cellular processes. Our in vitro studies have demonstrated that low-sulphated modified heparan sulphate mimetics (LS-mHeps) drive CNS repair. However, LS-mHeps are derived from pharmaceutical heparin purified from pig intestines, in a supply chain at risk of shortages and contamination. Alternatively, cellular synthesis of heparin and HS can be achieved using mammalian cell multiplex genome engineering, providing an alternative source of recombinant HS mimetics (rHS). TEGA Therapeutics (San Diego) have manufactured rHS reagents with varying degrees of sulphation and we have validated their ability to promote repair in vitro using models that mimic CNS injury, making comparisons to LS-mHep7, a previous lead compound. We have shown that like LS-mHep7, low-sulphated rHS compounds promote remyelination and reduce features of astrocytosis, and in contrast, highly sulphated rHS drive neurite outgrowth. Cellular production of heparin mimetics may, therefore, offer potential clinical benefits for CNS repair.
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影响因子：
5.6
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