Preclinical Genome Editing for Rare Neurological Diseases

罕见神经系统疾病的临床前基因组编辑

• 批准号: 10668762
• 负责人: Mandana Arbab
• 金额: $ 426.2万
• 依托单位: JACKSON LABORATORY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-16 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10668762
• 关键词: Address; Animal Model; Area; Ataxia; Biodistribution; CRISPR/Cas technology; Cells; Central Nervous System Diseases; Childhood; Clinical; Communication; DNA Double Strand Break; Data; Development; Diagnosis; Diagnostic; Disease; Dose; Drug Kinetics; Drug Packaging; Family; Finding by Cause; Friedreich Ataxia; Future; Genes; Genetic; Genetic Diseases; Genome; Goals; Health Sciences; High-Throughput Nucleotide Sequencing; Huntington Disease; In Vitro; Individual; Investigational Drugs; Investigational New Drug Application; Knowledge; Life; Medical Genetics; Medicine; Modeling; Modification; Monitor; Nervous System; Neurologic; Neurons; Oncogenic; Outcome; Pathway interactions; Patients; Pharmacology Study; Phenotype; Population; Positioning Attribute; Production; Property; Public Health; Rare Diseases; Reproducibility; Research; Research Personnel; Research Project Grants; Resources; Rett Syndrome; Risk; Route; Safety; Scheme; Spinal Muscular Atrophy; Technology; Therapeutic; Therapeutic Index; Tissues; Toxicology; Translating; Translations; Treatment Efficacy; Validation; Variant; base; base editing; base editor; clinical diagnostics; delivery vehicle; effective therapy; exome sequencing; gene replacement; gene therapy; genome editing; human disease; immunogenicity; improved; in vivo; innovation; lead candidate; lead optimization; manufacturability; member; mouse model; multidisciplinary; nervous system disorder; nuclease; pharmacokinetics and pharmacodynamics; postmitotic; pre-Investigational New Drug meeting; pre-clinical; preclinical evaluation; prime editor; programs; rare genetic disorder; repaired; response; success; therapeutic candidate; therapeutic genome editing; tool; translational therapeutics

PROJECT SUMMARY OVERALL While the development of high-throughput sequencing technology and its application to clinical diagnostics has yielded the genetic basis for many rare genetic diseases, the development of effective treatments has not kept pace. Although gene replacement and modulation therapies can be powerful, sometimes even lifesaving treatment options, they come with many risks, such as immunogenicity and oncogenicity. Programmable nucleases such as CRISPR/Cas9 have revolutionized our ability to manipulate the genome, and provide the potential to achieve lasting, precise genome modification for therapeutic benefit. The proposed U19 program seeks to address these challenges through the development, validation and translation of gene editing– based therapeutic solutions for rare neurological genetic diseases. We propose to focus on four neurological conditions that each represent a significant unmet clinical need: Spinal Muscular Atrophy, Friedrich's Ataxia, Huntington's Disease, and Rett Syndrome. Members of our team have developed a suite of base and prime genome editing tools that can install precise alterations without creating a DSB or requiring a donor template. We also have developed validated in vivo mouse models for each of these diseases and bring deep expertise in the IND-enabling preclinical evaluation of gene-editing therapeutics. We propose to merge these considerable assets with disease-specific expertise in each of the four neurological conditions, supported by expertise and resources for scaled production of AAV-based delivery vectors for delivery of precision gene- editing therapies to tissues, and for navigating the regulatory path to IND submission. The proposed U19 team has a track record of individual and collaborative success at every step of the preclinical pipeline pathway and is thus well positioned to achieve our milestones, which include an IND package submitted to FDA for at least one therapy and neurological condition. Our Overall Aims are to: 1) Assemble a multi-disciplinary team with unique strengths and expertise to develop and implement innovative genome editing strategies to address important disease of the CNS, including Spinal Muscular Atrophy, Friedreich's Ataxia, Huntington's Disease, and Rett Syndrome; 2) Optimize lead base editor and prime editor candidates for each disease area, utilizing in vitro platforms and validated animal models; 3) Execute definitive preclinical in vivo pharmacology studies on optimized leads to develop reproducible efficacy data, while monitoring biodistribution, PK/PD, tolerability, and toxicology; and 4) Advance one lead candidate to an allowable investigational new drug (IND) application through coordinated communication with the FDA INTERACT program, the research project team, and the project Cores.

项目概要 虽然高通量测序技术的发展及其在临床诊断中的应用已经成为一个挑战， 虽然为许多罕见的遗传疾病提供了遗传基础，但有效治疗方法的发展并没有保持 步伐。虽然基因替代和调节疗法可能是强大的，有时甚至可以挽救生命 然而，作为治疗选择，它们具有许多风险，例如免疫原性和致癌性。可编程 CRISPR/Cas9等核酸酶已经彻底改变了我们操纵基因组的能力，并提供了 有潜力实现持久、精确的基因组修饰以获得治疗益处。U19计划 旨在通过基因编辑的开发、验证和翻译来应对这些挑战- 为罕见的神经遗传性疾病提供治疗方案。我们建议集中在四个方面 神经系统疾病，每种疾病都代表了显著的未满足的临床需求：脊髓性肌萎缩， 弗里德里希共济失调、亨廷顿病和雷特综合征。我们团队的成员开发了一套 基本和主要的基因组编辑工具，可以安装精确的改变，而无需创建DSB或需要 供体模板。我们还为这些疾病中的每一种开发了经验证的体内小鼠模型， 在IND支持的基因编辑疗法临床前评估方面拥有深厚的专业知识。我们提议合并 这些在四种神经系统疾病中具有疾病特异性专业知识的可观资产， 通过专业知识和资源，规模化生产基于AAV的递送载体，用于递送精确的基因， 编辑治疗组织，并导航监管路径IND提交。U19团队 在临床前管道的每一步都有个人和合作成功的记录， 因此，我们有能力实现我们的里程碑，其中包括提交给FDA的IND包， 一种治疗和神经系统疾病我们的总体目标是：1）组建一个多学科团队， 独特的优势和专业知识，以开发和实施创新的基因组编辑策略， CNS的重要疾病，包括脊髓性肌萎缩、弗里德赖希共济失调、亨廷顿病，以及 Rett综合征; 2）优化每个疾病区域的主要基础编辑器和主要编辑器候选者，利用体外 平台和经验证的动物模型; 3）执行确定的临床前体内药理学研究， 优化电极导线，开发可重现的疗效数据，同时监测生物分布、PK/PD、耐受性和 毒理学;以及4）通过以下方式将一个主要候选药物推进到允许的研究性新药（IND）申请中 协调与FDA INTERACT项目、研究项目团队和项目核心的沟通。