A Novel RNA Therapeutics Platform to Treat Facioscapulohumeral Muscular Dystrophy and other Neuromuscular Disorders

治疗面肩肱型肌营养不良症和其他神经肌肉疾病的新型 RNA 治疗平台

基本信息

批准号：
10155849
负责人：
Anthony D Saleh
金额：
$ 37.05万
依托单位：
MIRECULE, INC.
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-20 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10155849
关键词：
ACTA1 gene Abdomen Address Affect Affinity Animal Model Antibodies Antisense Oligonucleotide Therapy Antisense Oligonucleotides Apoptosis Binding Biodistribution Biological Response Modifier Therapy Blood Cells Chemicals Chemistry Contracts Cytoplasm Data Development Disease Dose Duchenne muscular dystrophy Dyes Elements Endocytosis Engineering Exercise Face Facioscapulohumeral Muscular Dystrophy Genes Half-Life Hand Strength Histopathology Homeobox Human In Vitro Inflammatory Inherited Injections Label Lead Leg Legal patent Libraries Licensing Maximum Tolerated Dose Measures Membrane Metabolic Modeling Monitor Mus Muscle Muscle Cells Muscle function Muscular Dystrophies Mutate Mutation Myoblasts Myopathy Neuromuscular Diseases Oligonucleotides Orphan Outcome Oxidative Stress Pathology Patients Peripheral Blood Mononuclear Cell Phage Display Phase Pre-Clinical Model Process Proteins RNA delivery Rare Diseases Rattus Risk Rodent Running Safety Serum Shoulder Small Business Innovation Research Grant Sum Symptoms Technology Testing Therapeutic Tissues Toxic effect Toxicology Transcript Treatment Efficacy Xenograft procedure antibody conjugate antigen binding arm cellular targeting comparative efficacy cytokine design effective therapy hydrophilicity improved in vivo innovation knock-down lead candidate manufacturing scale-up meetings mouse model muscle degeneration muscular dystrophy mouse model nonhuman primate novel pharmacokinetics and pharmacodynamics receptor receptor mediated endocytosis scale up screening small molecule synergism targeted delivery therapeutic RNA therapeutic development therapeutically effective transcription factor uptake

项目摘要

Abstract: In this Fast Track SBIR application miRecule proposes to develop a muscle-specific platform (Muscle-NAVTM) for the delivery of therapeutic oligonucleotide to treat inherited neuromuscular disorders. Over 50 inherited neuromuscular disorders including myopathies, muscular dystrophies, and metabolic muscle disorders have been identified with a monogenic underpinning, resulting from mutations in a single gene. Oligonucleotide therapeutics offer the potential to correct many of these disorders by specifically targeting the mutated disease- causing gene. A major limiting factor that remains is the ability to deliver effective doses of these large hydrophilic molecules into affected muscle cells. Muscle-NAV will be composed of miRecule’s antibody technology directly conjugated to a therapeutic oligonucleotide. The antibody will be targeted to a muscle expressed receptor that induces uptake via endocytosis upon binding. Once endocytosed our novel protein and conjugation chemistry aids in endosomal escape to the cytoplasm. The third most common inherited muscle disorder is facioscapulohumeral muscular dystrophy (FSHD) an orphan indication in the US, with about 20,000 patients. FSHD results from inherited mutations that lead to inappropriate expression of the double homeobox 4 (DUX4) gene. The aberrant expression of DUX4 is severely toxic to muscle tissues, resulting in oxidative stress and apoptosis of muscle cells degrading muscle function. DUX4 is a transcription factor and is not directly “druggable” by traditional small molecules or biologic therapeutics. Several studies have displayed that antisense oligonucleotide (ASO) therapy has the potential to directly repress DUX4, reversing muscle pathology in pre-clinical models. However, a significant hurdle for the development is an effective means of delivery. To validate our Muscle-NAV platform we propose to deliver our (ASO) targeting DUX4 (miRecule candidate MC-DX4) for the treatment of FSHD. In phase 1 of the fast track SBIR, we will first discover novel antibodies for ten receptors with selective muscle expression through phage display screening (AIM 1). We will demonstrate selective delivery and knockdown in muscle cells in vitro (AIM 2). Then screen five conjugates for muscle specific biodistribution, effective delivery and knockdown in an FSHD mouse model, and safety in mice to select a single lead antibody conjugate for Muscle-NAV (AIM 3). In phase 2 of the fast track SBIR, we will optimize scale-up, process development, and CMC release tests for Muscle-NAV and MC-DX4 (AIM 4). We will use this high-quality agent to characterize PK profiles in Non-Human Primates (NHPs), PK/PD profiles in a mouse model of FSHD, and MTD/ Dosing Range/TK profiles in rats (AIM 5). We will also demonstrate the competitive advantage and long- term therapeutic efficacy of MC-DX4 in two mouse models of FSHD (AIM 6). The completion of these studies will create a compelling data package we will use to market co-development and licensing deals for our Muscle- NAV platform, and enable our pre-IND meeting for MC-DX4 as an effective treatment for FSHD.

抽象的：在这个快速轨道中，SBIR应用程序Mirecule提案以开发肌肉特异性平台（Muscle-Navtm）用于递送治疗性寡核苷酸以治疗遗传的神经肌肉疾病。超过50种继承神经肌肉疾病，包括肌病，肌肉营养不良和代谢肌肉疾病用单基因的基础鉴定出是由单个基因突变引起的。寡核苷酸治疗药通过专门针对突变的疾病来纠正许多这些疾病的潜力引起基因。仍然存在的主要限制因素是能够提供有效剂量的这些大剂量分子成受影响的肌肉细胞。 Muscle-NAV将直接由Mirecule的抗体技术组成共轭到治疗性寡核苷酸。抗体将针对肌肉表达的接收器结合后通过内吞作用诱导摄取。一旦内吞，我们的新型蛋白质和结合化学有助于内体逃避细胞质。第三大常见的遗传性肌肉障碍是Faciosculohumeral肌肉营养不良（FSHD）美国的孤儿指示，约有20,000名患者。 FSHD是由导致的遗传突变引起的双同型4（DUX4）基因的不当表达。 DUX4的异常表达严重对肌肉时机有毒，导致肌肉细胞的氧化应激和凋亡降解肌肉功能。 DUX4是转录因子，不直接由传统的小分子或生物学“吸毒” 疗法。几项研究表明，反义寡核苷酸（ASO）疗法有可能直接抑制DUX4，逆转临床前模型中的肌肉病理学。但是，对于开发是一种有效的交付方式。为了验证我们的肌肉-NAV平台，我们建议提供我们的（ASO）靶向DUX4（mirecule候选MC-DX4）用于治疗FSHD。在快速轨道SBIR的第1阶段中，我们将首先发现具有选择性的十种受体的新型抗体通过噬菌体显示筛查的肌肉表达（AIM 1）。我们将展示选择性交付和肌肉细胞的敲低体外（AIM 2）。然后筛选五个偶联物以特定于肌肉的生物分布，在FSHD鼠标模型中有效递送和敲低，并在小鼠中安全选择单铅抗体共轭肌肉-NAV（AIM 3）。在快速轨道SBIR的第2阶段中，我们将优化扩展，过程肌肉-NAV和MC-DX4的开发和CMC释放测试（AIM 4）。我们将使用这个高质量的代理表征非人类灵长类动物（NHP）中的PK轮廓，FSHD鼠标模型中的PK/PD轮廓大鼠的MTD/剂量范围/ TK轮廓（AIM 5）。我们还将证明竞争优势和长期 MC-DX4在两种小鼠FSHD模型中的术语治疗效率（AIM 6）。这些研究的完成将创建一个引人入胜的数据包，我们将用来为我们的肌肉销售共同开发和许可协议 - NAV平台，并启用我们的MC-DX4预定会议作为FSHD的有效治疗方法。