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：在此 Fast Track SBIR 应用程序中，miRecule 建议开发一个肌肉专用平台 (Muscle-NAVTM) 用于输送治疗性寡核苷酸来治疗 50 多种遗传性神经肌肉疾病。神经肌肉疾病，包括肌病、肌营养不良和代谢性肌肉疾病已被鉴定为单基因基础，由单个基因的突变引起。通过专门针对突变疾病，疗法提供了纠正许多此类疾病的潜力- 仍然存在的一个主要限制因素是提供有效剂量的这些大亲水性物质的能力。 Muscle-NAV 的分子将直接由 MiReule 的抗体技术组成。与治疗性寡核苷酸缀合的抗体将靶向肌肉表达的受体。一旦内吞我们的新型蛋白质和缀合化学，就会通过内吞作用诱导摄取。有助于内体逃逸至细胞质。第三种最常见的遗传性肌肉疾病是面肩肱型肌营养不良症 (FSHD) 在美国，这是一种孤儿适应症，大约有 20,000 名 FSHD 患者是由遗传性突变引起的。双同源框 4 (DUX4) 基因的异常表达 DUX4 的异常表达非常严重。对肌肉组织有毒，导致肌肉细胞氧化应激和凋亡，降低肌肉功能。 DUX4 是一种转录因子，不能通过传统小分子或生物制剂直接“成药” 多项研究表明，反义寡核苷酸（ASO）疗法有潜力直接抑制 DUX4，逆转临床前模型中的肌肉病理学然而，这是一个重大障碍。开发是一种有效的交付方式，为了验证我们的 Muscle-NAV 平台，我们建议交付我们的产品。 (ASO) 靶向 DUX4（miRecule 候选者 MC-DX4）用于治疗 FSHD。在快速通道 SBIR 的第一阶段，我们将首先发现针对十种受体的新型抗体，具有选择性我们将通过噬菌体展示筛选（AIM 1）展示选择性递送和肌肉表达。体外肌肉细胞中的敲低（AIM 2），然后筛选五种缀合物的肌肉特异性生物分布，在 FSHD 小鼠模型中有效递送和敲低，以及在小鼠中选择单一先导抗体的安全性 Muscle-NAV 的共轭 (AIM 3) 在快速通道 SBIR 的第二阶段，我们将优化放大、工艺。 Muscle-NAV 和 MC-DX4 (AIM 4) 的开发和 CMC 发布测试我们将使用这种高质量代理。表征非人类灵长类动物 (NHP) 中的 PK 概况、FSHD 小鼠模型中的 PK/PD 概况，以及大鼠的 MTD/剂量范围/TK 概况（AIM 5）我们还将展示竞争优势和长期优势。 MC-DX4 在两种 FSHD 小鼠模型中的长期治疗效果 (AIM 6) 这些研究的完成。将创建一个引人注目的数据包，我们将用它来营销我们的肌肉的共同开发和许可交易 NAV 平台，并使我们的 MC-DX4 IND 前会议成为 FSHD 的有效治疗方法。