New Nonsense Suppression Drugs to Treat MPS I

治疗 MPS I 的新型无意义抑制药物

• 批准号: 8842247
• 负责人: David M. Bedwell
• 金额: $ 36.75万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-30 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8842247
• 关键词: Amino Acids; Attenuated; Biological Assay; Blood - brain barrier anatomy; Brain; Catabolism; Clinical; Complement; Cornea; Data; Defect; Dermatan Sulfate; Disease; Disease Progression; Dose; Drug Kinetics; Effectiveness; Embryo; Enzymes; European; Exhibits; Face; Fibroblasts; Frequencies; Genes; Glycosaminoglycan Degradation Pathway; Glycosaminoglycans; Goals; Heart; Heart Valves; Heparitin Sulfate; Human; In Vitro; Intellectual functioning disability; Joints; Knock-in Mouse; L-Iduronidase; Length; Liver; Longevity; Lysosomal Storage Diseases; Mediating; Modeling; Mucopolysaccharidoses; Mucopolysaccharidosis I; Mucopolysaccharidosis I H; Mucopolysaccharidosis I S; Mus; Mutation; Neuraxis; Neurologic; Nonsense Codon; Nonsense Mutation; Patients; Pharmaceutical Preparations; Pharmacodynamics; Phenotype; Proteins; Resistance; Severities; Spleen; Testing; Therapeutic; Tissues; Translations; alternative treatment; base; bone; brain tissue; clinically relevant; enzyme deficiency; hearing impairment; improved; in vivo; mouse model; novel strategies; novel therapeutic intervention; prevent; public health relevance; response; restoration

 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.

 描述（由申请人提供）： 粘多糖样沉积症I-Hurler（MPS I-H）是一种由严重的α-L-艾杜糖醛酸酶缺乏引起的溶酶体贮积病，导致糖胺聚糖（GAG）的溶酶体蓄积。MPS I-H是由无义突变（也称为提前终止密码子或PTC）引起的，约70%的欧洲血统患者。无义抑制疗法是一种通过抑制蛋白质翻译终止来恢复蛋白质功能的治疗疾病的新方法。我们假设无义抑制治疗将减少MPS I-H疾病进展，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。PTC Therapeutics，Inc.已经确定了两种新的无义抑制药物，PTC 415和PTC 418，与他们以前开发的无义抑制药物PTC 124相比，具有更好的大脑暴露。我们假设PTC 415和PTC 418可能比PTC 124更大程度地减缓MPS I-H的进展，特别是在大脑中。具体目标1：检查两种新的无义抑制化合物在Idua-W 402 X小鼠中具有增强的脑分布的有效性。为此，我们将研究PTC 415和PTC 418与PTC 124相比的疗效和剂量反应。我们将首先检查这些药物恢复α-L-艾杜糖醛酸酶活性和减少来自Idua-W 402 X小鼠的永生化小鼠胚胎成纤维细胞（MEF）中GAG蓄积的能力。我们将通过短期体内剂量反应研究补充这些体外研究，以确定最有效地恢复α-L-艾杜糖醛酸酶活性并减少Idua-W 402 X小鼠各种组织（包括脑、心脏、脾脏和肝脏）中GAG蓄积的药物剂量。具体目标二：在Idua-W 402 X小鼠中确定长期给予无义抑制药物是否可维持GAG降低并减缓MPS I-H表型的进展。基于目标1的结果，我们将对Idua-W 402 X小鼠给予PTC 415或PTC 418进行28周研究，然后评价与PTC 124相比，该药物缓解MPS I-H表型进展的能力。这将通过一系列我们最近发现的检测来实现，这些检测可以提供良好的终点来评估长期治疗益处。该长期体内研究的终点将用于：1）确定α-L-艾杜糖醛酸酶活性的部分恢复和GAG储存的减少是否可以在广泛的组织中持续; 2）评价MPS I-H表型的几个进展方面是否在Idua-W 402 X小鼠中得到缓解，特别关注脑、心脏和骨缺损;和3）确定长期给药是否耐受良好。我们预计，如果这些新的无义抑制药物之一在Idua-W 402 X小鼠中有效减缓MPS I-H进展，我们将寻求该药物作为MPS I-H治疗的IND状态。