Towards an improved therapy for MPS disorders

粘多糖病(MPS)是一组相关的11种影响儿童的衰弱遗传疾病。它们是由于一种被称为糖胺多聚糖(GAG)的碳水化合物结构移除所需的酶的减少或完全缺乏造成的。GAG在细胞内的降解发生在称为溶酶体的特定细胞器中，在缺乏适当的酶的情况下，未降解的GAG在细胞内积累。这会导致一系列临床症状和多个组织衰竭。不止一种MPS类型的常见症状包括智力恶化、失明、腹部器官增大和骨骼生长问题，导致身材矮小和骨质丢失。我的实验室对开发MPS的治疗方法有着长期的兴趣，我们的研究导致在2005年对MPS VI进行了酶替代疗法(ERT)的临床应用。虽然为MPS提供了第一个有效的多组织治疗，但我们的研究表明，有几个组织对ERT没有反应。这些是大脑、软骨和角膜，因此接受ERT方案的儿童仍然会患有智力低下、关节炎和失明。为了治疗这些特殊的组织，我们开发了一种新的MPS治疗方法，称为底物剥夺疗法(SDT)。SDT不是将缺失的酶重新添加回来，而是通过减少GAG的产生来起作用，这反过来又减少了细胞中积累的GAG水平。在MPS IIIA小鼠模型中，SDT可以纠正培养中的MPS细胞，并减少几个关键的临床症状。在这项建议中，我们将扩展我们的研究，以评估SDT对脑和骨关节病理的影响。疗效评估将在MPS VII小鼠身上进行，它同时表现出脑部和骨骼疾病，并在专门为这项研究开发的MPS IVA新模型中进行，该模型显示了MPS疾病中独特的关节病理学。

Mucopolysaccharidoses (MPS) are a related group of 11 debilitating genetic disorders affecting children. They result from a reduction or total deficiency of an enzyme required for the removal of carbohydrate structures called glycosaminoglycans (gags). Gag degradation occurs inside the cell in specific organelles termed lysosomes and in the absence of the appropriate enzyme, undegraded gag accumulates in the cell. This leads to a range of clinical symptoms and multiple tissue failure. Symptoms common to more than one MPS type include mental deterioration, blindness, abdominal organ enlargement and bone growth problems leading to short stature and bone loss. My laboratory has had a long-term interest in developing treatment for MPS and our research led to the clinical implementation of enzyme replacement therapy (ERT) for MPS VI in 2005. While providing the first effective, multi-tissue treatment for MPS, our research showed that several tissues were not responsive to ERT. These are the brain, cartilage and cornea, thus children on ERT regimens will still suffer from mental retardation, arthritis and blindness. With the goal of treating these particular tissues we have developed a new approach to MPS therapy called substrate deprivation therapy (SDT). Instead of adding back the missing enzyme, SDT acts by decreasing gag production which in turn reduces the level of accumulated gag in cells. SDT results in the correction of MPS cells in culture and reduces several key clinical symptoms in the mouse model of MPS IIIA. In this proposal we will extend our research to evaluate the effect of SDT on brain and bone-joint pathology. Evaluation of efficacy will take place in the MPS VII mouse which exhibits both brain and bone disease and in a new model of MPS IVA developed specifically for this study which exhibits a joint pathology unique amongst the MPS disorders.