New Nonsense Suppression Drugs to Treat MPS I

 描述(申请人提供)：粘多糖症I-HERLER(MPS I-H)是一种溶酶体储存性疾病，由严重的α-L艾杜糖酸酶缺乏症引起，导致糖胺聚糖(GAG)的溶酶体积聚。在约70%的欧洲血统患者中，MPS I-H是由无义突变(也称为提前终止密码子或PTCs)引起的。无义抑制疗法是一种通过抑制PTCs的翻译终止以恢复功能蛋白来治疗疾病的新方法。我们假设，无意义抑制疗法将减缓MPS I-H疾病的进展，特别是在对当前治疗方法反应不佳的组织中，包括脑、心脏瓣膜、角膜和骨骼。PTC治疗公司已经确定了两种新的无意义抑制药物PTC415和PTC418，与他们之前开发的无意义抑制药物PTC124相比，它们的大脑暴露更好。我们推测，PTC415和PTC418可能比PTC124在更大程度上减缓MPS I-H的进展，特别是在大脑中。为了验证这一假设，我们将追求以下特定目标：特定目标1：检查两种新的无意义抑制化合物在IDUA-W402X小鼠中增强脑分布的有效性。为此，我们将研究PTC415和PTC418与PTC124的疗效和剂量反应。我们将首先检测这些药物在IDUA-W402X小鼠来源的永生化小鼠胚胎成纤维细胞(MEF)中恢复α-L艾杜糖苷酶活性和减少GAG积聚的能力。我们将用体内短期剂量反应研究补充这些体外研究，以确定最有效地恢复IDUA-W402X小鼠各种组织(包括脑、心脏、脾和肝脏)中α-L艾杜糖酸酶活性和减少GAG积聚的药物剂量。具体目标2：确定长期使用无意义抑制药物是否能维持IDUA-W402X小鼠GAG减少和MPS I-H表型进展。基于目标1的结果，我们将给IDUA-W402X小鼠注射PTC415或PTC418进行为期28周的研究，然后评估与PTC124相比，该药物减缓MPS I-H表型进展的能力。这将使用我们最近展示的一系列分析来完成，这些分析可以为评估长期治疗益处提供良好的终点。这项长期的体内研究的终点将用于：1)确定在广泛的组织中是否可以持续部分恢复α-L艾杜糖酸酶活性和减少GAG储存；2)评估MPS I-H表型的几个进行性方面是否在IDUA-W402X小鼠中得到缓解，特别是关注脑、心脏和骨缺陷；以及3)确定长期用药是否耐受。我们预计，如果这些新的无义抑制药物中的一种在减缓IDUA-W402X小鼠的MPS I-H进展方面有效，我们将寻求该药物的IND状态作为MPS I-H的治疗。

 DESCRIPTION (provided by applicant): Mucopolysaccharidosis I-Hurler (MPS I-H) is a lysosomal storage disease caused by severe alpha-L-iduronidase deficiency that results in the lysosomal accumulation of glycosaminoglycans (GAGs). MPS I-H is caused by nonsense mutations (also known as premature termination codons or PTCs) in ~70% of patients of European descent. Nonsense suppression therapy is a novel approach to treat diseases by suppressing translation termination at PTCs in order to restore functional protein. We hypothesize that nonsense suppression therapy will reduce MPS I-H disease progression, particularly in tissues that do not respond well to current therapeutic approaches, including the brain, heart valves, cornea, and bone. PTC Therapeutics, Inc. has identified two new nonsense suppression drugs, PTC415 and PTC418, with better brain exposure compared to their previously developed nonsense suppression drug, PTC124. We hypothesize that PTC415 and PTC418 may moderate progression of MPS I-H to a greater degree than PTC124, particularly in the brain. To test this hypothesis, we will pursue the following Specific Aims: Specific Aim 1: Examine the effectiveness of two new nonsense suppression compounds with enhanced brain distribution in Idua-W402X mice. In this aim, we will investigate the efficacy and dose response of PTC415 and PTC418 compared to PTC124. We will first examine the ability of these drugs to restore alpha-L-iduronidase activity and reduce GAG accumulation in immortalized mouse embryonic fibroblasts (MEFs) derived from Idua-W402X mice. We will complement those in vitro studies with short-term in vivo dose response studies to determine the drug doses that most effectively restore alpha-L-iduronidase activity and reduce GAG accumulation in various tissues (including brain, heart, spleen, and liver) of Idua-W402X mice. Specific Aim 2: Determine whether long-term administration of nonsense suppression drugs can sustain GAG reduction and reduce progression of the MPS I-H phenotype in Idua-W402X mice. Based on the results of Aim 1, we will administer PTC415 or PTC418 to Idua-W402X mice for 28-week studies and then evaluate the ability of the drug to alleviate progression of the MPS I-H phenotype compared to PTC124. This will be accomplished using a battery of assays that we recently showed could provide good endpoints to assess long-term therapeutic benefit. The endpoints of this long-term in vivo study will be used to: 1) determine whether a partial restoration of alpha-L-iduronidase activity and a reduction of GAG storage can be sustained in a broad range of tissues; 2) evaluate whether several progressive aspects of the MPS I-H phenotype are moderated in Idua-W402X mice, with a special focus on brain, heart, and bone defects; and 3) determine whether long-term administration is well tolerated. We anticipate that if one of these new nonsense suppression drugs is effective in moderating MPS I-H progression in Idua-W402X mice, we will pursue IND status for that drug as a treatment for MPS I-H.