Advancement in early diagnosis and therapeutic intervention for Mucopolysaccharidoses

粘多糖病（MPS）是一种疾病，它阻止糖胺聚糖（GAGs）的分解，导致它们的积累。这种情况会导致出生后的进行性发育问题，导致过早死亡。总的来说，每3万名新生儿中就有1名患有MPS。目前尚无治愈方法，现有治疗方法的疗效因诊断延误和监测不敏感而受到损害。飞行时间二次离子质谱法（ToF-SIMS）和多变量分析（MVA）最近被用于分析gag，显示出比现有方法更高的灵敏度。在这个项目中，ToF-SIMS将研究其通过分析患者尿液和血液样本进行MPS早期诊断的能力，以及作为帮助开发新的MPS治疗方法的工具。GAG生物合成酶最近被确定为潜在的MPS治疗药物。这些知之甚少的复合物的相互作用将利用新的工具进行研究，这些工具能够使用CRISPR-Cas9基因编辑将亲和和荧光标记结合到目标酶上。通过研究控制GAG结构和功能的复合物，我们将发现新的治疗靶点。细胞的GAG特征将通过ToF-SIMS进行分析，并与患者样本中测量的GAG特征进行比较。

Mucopolysaccharidoses (MPS) is a disorder that prevents the breakdown of glycosaminoglycans (GAGs), leading to their accumulation. This condition causes progressive developmental problems after birth that results in premature death. Collectively MPS is observed in about 1 in 30,000 births. There is currently no cure and the efficacy of existing treatments is impaired by delayed diagnosis and insensitive monitoring. Time-of-flight secondary ion mass spectrometry (ToF-SIMS) together with multivariate analysis (MVA) has recently been used to analyse GAGs, demonstrating orders of magnitude greater sensitivity than existing methods. In this project, ToF-SIMS will be investigated for its ability to enable early diagnosis of MPS by analysing patient urine and blood samples and as a tool to aid in the development of new MPS therapies.GAG biosynthetic enzymes have recently been identified as potential MPS therapeutics. The interaction of these poorly understood complexes will be investigated utilising new tools that enable incorporation of affinity and fluorescent labels onto targeted enzymes using CRISPR-Cas9 gene editing. By investigating the complexes that control GAG structure and function we will identify novel therapeutic targets. The GAG profile of the cells will be analysed by ToF-SIMS and compared to the GAG profiles measured in patient samples.