Advancement in early diagnosis and therapeutic intervention for Mucopolysaccharidoses

粘多糖贮积症（MPS）是一种阻止糖胺聚糖（GAG）分解的疾病，导致其蓄积。这种情况会导致出生后的渐进性发育问题，导致过早死亡。总的来说，每30，000名新生儿中约有1名患有MPS。目前没有治愈方法，现有治疗的疗效因诊断延迟和监测不敏感而受损。飞行时间二次离子质谱（ToF-SIMS）与多变量分析（MVA）一起最近已被用于分析GAG，表现出比现有方法高几个数量级的灵敏度。在该项目中，ToF-SIMS将被研究其通过分析患者尿液和血液样本来实现MPS早期诊断的能力，并作为一种工具来帮助开发新的MPS疗法。GAG生物合成酶最近被确定为潜在的MPS疗法。将利用新工具研究这些知之甚少的复合物的相互作用，这些新工具能够使用CRISPR-Cas9基因编辑将亲和力和荧光标记掺入靶向酶。通过研究控制GAG结构和功能的复合物，我们将确定新的治疗靶点。将通过ToF-SIMS分析细胞的GAG谱，并与患者样本中测量的GAG谱进行比较。

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.