Mucopolysaccharidoses (MPSs) are childhood diseases caused by inherited deficiencies in glycosaminoglycan degradation. Most MPSs involve neurodegeneration, which to date is untreatable. Currently, most therapeutic strategies aim at correcting the primary genetic defect. Among these strategies, gene therapy has shown great potential, although its clinical application is challenging. We have shown previously in an MPS-IIIA mouse model that the molecular tweezer (MT) CLR01, a potent, broad-spectrum anti-amyloid small molecule, inhibits secondary amyloid storage, facilitates amyloid clearance, and protects against neurodegeneration. Here, we demonstrate that combining CLR01 with adeno-associated virus (AAV)-mediated gene therapy, targeting both the primary and secondary pathologic storage in MPS-IIIA mice, results in a synergistic effect that improves multiple therapeutic outcomes compared to each monotherapy. Moreover, we demonstrate that CLR01 is effective therapeutically in mouse models of other forms of neuronopathic MPS, MPS-I, and MPS-IIIC. These strongly support developing MTs as an effective treatment option for neuronopathic MPSs, both on their own and in combination with gene therapy, to improve therapeutic efficacy and translation into clinical application.

中文翻译：

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抗淀粉样蛋白治疗对神经病性粘多糖病广泛有效，并与 MPS-IIIA 的基因治疗协同作用


粘多糖贮积症 （MPS） 是由糖胺聚糖降解的遗传缺陷引起的儿童疾病。大多数 MPS 涉及神经退行性变，迄今为止无法治愈。目前，大多数治疗策略旨在纠正原发性遗传缺陷。在这些策略中，基因治疗显示出巨大的潜力，尽管其临床应用具有挑战性。我们之前在 MPS-IIIA 小鼠模型中已经证明，分子镊子 （MT） CLR01 是一种有效的广谱抗淀粉样蛋白小分子，可抑制次级淀粉样蛋白储存，促进淀粉样蛋白清除，并防止神经退行性变。在这里，我们证明将 CLR01 与腺相关病毒 （AAV） 介导的基因疗法相结合，靶向 MPS-IIIA 小鼠的原发性和继发性病理储存，与每种单一疗法相比，会产生协同效应，改善多种治疗结果。此外，我们证明 CLR01 在其他形式的神经病性 MPS、MPS-I 和 MPS-IIIC 的小鼠模型中具有治疗效果。这些强烈支持将 MTS 开发为神经病性 MPS 的有效治疗选择，无论是单独使用还是与基因治疗联合使用，以提高治疗效果并转化为临床应用。