Pre-clinical development of SPY-DYS45-55, a CRISPR/Cas9 platform for Duchenne muscular dystrophy

SPY-DYS45-55（一种治疗杜氏肌营养不良症的 CRISPR/Cas9 平台）的临床前开发

• 批准号: 10001742
• 负责人: Courtney Young
• 金额: $ 49.37万
• 依托单位: MYOGENE BIO, LLC
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10001742
• 关键词: Adult; Advanced Development; Alleles; BLT mice; Becker Muscular Dystrophy; CRISPR therapeutics; CRISPR/Cas technology; Capsid; Cessation of life; Child; Clinical; Clinical Data; Code; DNA Sequence Alteration; Data; Dependovirus; Disease; Dose; Duchenne muscular dystrophy; Dystrophin; Eligibility Determination; Exons; Exposure to; Foundations; Frequencies; Gene Delivery; Genes; Goals; Guide RNA; Heart; Human; Immune response; Immunity; Immunosuppression; Individual; Injections; Introns; Knowledge; Lead; Longitudinal Studies; Mendelian disorder; Mus; Muscle; Muscular Atrophy; Mutate; Mutation; Myopathy; Patients; Phase; Phenotype; Procedures; Production; Proteins; Reading Frames; Recombinants; Regimen; Research; Safety; Serotyping; Skeletal Muscle; Specificity; Testing; Therapeutic; Toxic effect; Translating; Treatment Efficacy; Tropism; Virus; Wasting Syndrome; Western Blotting; base; boys; cohort; design; gene therapy; genome sequencing; humanized mouse; immunogenicity; immunoregulation; improved; improved functioning; in vivo; mouse model; mutant; novel; off-target mutation; pre-clinical; preclinical development; preclinical safety; preclinical toxicity; premature; promoter; vector; whole genome

MyoGene Bio is a startup dedicated to developing cutting edge genetic therapies for muscle diseases. In this proposal, the company will advance development of our potential therapeutic, SPY-DYS45-55, a CRISPR/Cas9 gene editing platform for Duchenne muscular dystrophy (DMD) in conjunction with research partners at UCLA. Duchenne is a devastating muscle wasting disorder with no cure that is caused by out-of-frame mutations in the DMD gene. SPY-DYS45-55 removes a mutational hotspot in DMD to restore the reading frame for half of all Duchenne patients by generating an in-frame exon 45-55 deletion. This deletion is associated with a very mild phenotype in human Becker muscular dystrophy patients. Systemic delivery of gene editing platforms to muscle represents a significant challenge. Certain serotypes of recombinant adenoassociated virus (AAV) have tropism to skeletal muscle and heart. However, the immune response to the virus prohibits repeated administration of AAV. Furthermore, pre-existing immunity in some individuals (anticipated to be present in up to 70% of adults), precludes their eligibility to take advantage of this treatment. The goal of this Fast Track proposal is to devise strategies to overcome these challenges. In Phase I, we will determine an optimal immunosuppression regimen that allows redosing of AAV in order to improve the efficacy and applicability of SPY-DYS45-55. In Phase II, we will assess the long-term functional benefit, toxicity, and off-target activity from single or multiple injections of AAV-SPY-DYS45-55 in our novel mouse model containing a mutated human DMD gene. Ultimately, these studies will generate the initial pre-clinical data needed to translate SPY-DYS45-55 to patients with Duchenne muscular dystrophy.

MyoGene Bio 是一家致力于开发尖端肌肉基因疗法的初创公司 疾病。在这项提案中，公司将推进我们潜在治疗药物的开发， SPY-DYS45-55，用于杜氏肌营养不良症 (DMD) 的 CRISPR/Cas9 基因编辑平台 与加州大学洛杉矶分校的研究伙伴合作。 Duchenne 是一种毁灭性的肌肉萎缩 由 DMD 基因异常突变引起的无法治愈的疾病。间谍-DYS45-55 去除 DMD 中的突变热点以恢复一半 Duchenne 的阅读框 通过产生框内外显子 45-55 缺失来治疗患者。这次删除与一个非常相关的 人类贝克尔肌营养不良症患者的轻度表型。基因编辑的系统传递 增强力量的平台是一项重大挑战。重组腺相关蛋白的某些血清型 病毒（AAV）对骨骼肌和心脏有趋向性。然而，免疫 对病毒的反应禁止重复施用 AAV。此外，预先存在的 某些个体的免疫力（预计高达 70% 的成年人中存在），妨碍了他们 有资格利用这种治疗。该快速通道提案的目标是设计 克服这些挑战的策略。在第一阶段，我们将确定一个最佳的 允许重新服用 AAV 的免疫抑制方案，以提高疗效和 SPY-DYS45-55的适用性。在第二阶段，我们将评估长期功能效益， 我们的小说中单次或多次注射 AAV-SPY-DYS45-55 的毒性和脱靶活性 含有突变的人类 DMD 基因的小鼠模型。最终，这些研究将产生 将 SPY-DYS45-55 应用于 Duchenne 肌病患者所需的初始临床前数据 营养不良。