Upregulation of Iduronidase Enzyme in MPSI Disease

 描述（由申请人提供） 粘多糖样变性I（MPSI，Hurler-Scheie病）是一种常染色体隐性遗传疾病，其中受影响个体的α-L-艾杜糖醛酸酶（IDUA）耗尽或缺失。这些个体具有有限的处理糖胺聚糖（GAG）的能力，导致溶酶体积聚，导致细胞和器官衰竭，并最终在年轻时死亡。该病的发病率约为1：100，000。同种异体造血干细胞移植（HSCT）和酶替代疗法（ERT）目前是MPSI患者的最佳选择，但HSCT具有显著的患者风险特征，ERT仍然效率低下且成本高昂（每年约40万美元）。仍然显著需要额外的MPSI治疗，以减少外周和脑GAG，并补充ERT。我们进行了高通量筛选以鉴定上调IDUA表达的新化合物。我们发现，通常被认为是安全的（GRAS）化合物（如白藜芦醇，白藜芦醇）的芪家族显着增加IDUA的表达和活性。在本申请中，我们的目标是开发芪相关化合物，以验证其在MPSI模型中的活性，以期最终临床转化。为此，我们将 首先验证我们在化合物家族中的发现，并鉴定和表征具有潜在更好的体外和体内活性的天然产物类似物。我们将在其他患者来源的样本中验证我们的发现，以确定最适合治疗的患者队列，并确定那些没有反应的患者。我们的目的是显示脑渗透剂化合物在体内上调IDUA并改善GAG清除和行为结果（运动、认知能力等）。最后，我们将致力于揭示这些化合物的临床潜力，以便能够转化为MPSI疾病。作为支持这项工作的初步证据，我们鉴定了一种化合物，白藜芦醇，在每天给药一个月后，显示出脑IDUA酶活性的小的但统计学上显著的增加（~25%; p<0.05）， 在野生型小鼠中血浆IDUA酶活性显著增加（>500%; p<0.05）。这些发现将需要在经验证的疾病特异性动物模型中进行复制，特别是W 402 X-syndrome小鼠。该小鼠模型复制了在用于HTS和初步鉴定Piceatannol的患者来源的细胞中发现的突变。W 402 X提前终止密码子突变存在于约40%的MPSI患者中。我们还表明，额外的患者来源的成纤维细胞的白藜芦醇治疗导致IDUA活性增加，表明这些化合物在MPSI患者中的更广泛应用。本申请的基本前提是IDUA酶水平的上调，即使使用由于突变而无效的酶，也将导致外周中GAG水平的有益降低 也可能在大脑中，这可以转化为对患者有临床意义的结果。

 DESCRIPTION (provided by applicant) Mucopolysaccharidosis I (MPSI, Hurler-Scheie Disease) is an autosomal recessive genetic disorder in which the alpha-L-iduronidase (IDUA) enzyme is depleted or absent from the affected individual. Such individuals have a limited capacity to process glycosaminoglycans (GAGs) causing lysosomal buildup leading to cell and organ failure and eventually death at a young age. The prevalence of this disease is approximately 1:100,000. Allogenic hematopoietic stem cell transplant (HSCT) and enzyme replacement therapy (ERT) are currently the best options for MPSI patients, however HSCT carries a significant patient risk profile and ERT remains inefficient and costly (~$400,000 per year). There remains a significant need for additional MPSI treatments, both for reduction of peripheral and also brain GAGs, and to supplement ERT. We engaged in a high throughput screen to identify novel compounds to upregulate IDUA expression. We discovered that stilbene family of generally regarded as safe (GRAS) compounds (e.g. piceatannol, resveratrol) significantly increase in IDUA expression and activity. In this current application, we aim to develop stilbene related compounds to validate their activity in MPSI models, with a view toward eventual clinical translation. To do this we will first validate our findings within the compound family and identify and characterize natural product analogs that have potentially better in vitro and in vivo activity. We will validate our findings in additional patient derived samples, to identify the patient cohorts best suited to treatment, and identify those that do not respond. We aim to show that the brain penetrant compounds upregulate IDUA in vivo and improve both GAG clearance and behavioral outcomes (locomotion, cognitive ability, etc.). Finally, we will work to uncover the clinical potential of te compounds in order to enable translation for MPSI disease. As preliminary evidence to support this work, we identified one compound, piceatannol, that after one month of daily dosing showed a small, but statistically significant increase (~25%; p<0.05) in brain IDUA enzymatic activity and a considerable increase in plasma IDUA enzymatic activity (>500%; p<0.05) in wild type mice. These findings will need to be replicated in validated disease specific animal models, specifically the W402X-synologous mouse. This mouse model replicates the mutations found in the patient derived cells that were used for HTS and initial identification of piceatannol. The W402X premature stop codon mutation is found in some 40% of MPSI patients. We also show that piceatannol treatment of additional patient derived fibroblasts results in increased IDUA activity suggesting broader application of these compounds in MPSI patients. The underlying premise of this application is that upregulation of IDUA enzyme levels, even with enzymes that are inefficient due to mutation, will result in beneficial reduction of GAG levels in the periphery and possibly also in the brain that could translate to clinically meaningful outcomes in patients.