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.

总体项目摘要 而高通量测序技术的发展及其在临床诊断中的应用 产生了许多罕见遗传疾病的遗传基础，有效治疗的发展尚未保持 尽管替代基因和调节疗法可能很强大，有时甚至可以挽救生命 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 诸如CRISPR/CAS9之类的核酸酶已经彻底改变了我们操纵基因组的能力，并提供了 实现持久，精确的基因组修饰以实现治疗益处的潜力。拟议的U19程序 试图通过基因编辑的发展，验证和翻译来应对这些挑战 - 基于稀有神经系统遗传疾病的治疗溶液。我们建议专注于四个 每种神经系统疾病都代表着重要的未满足临床需求：脊柱肌肉萎缩， 弗里德里希的共济失调，亨廷顿氏病和RETT综合征。我们团队的成员已经开发了一套 基础和主要基因组编辑工具，可以安装精确更改而无需创建DSB或需要 捐助者模板。我们还为每种疾病开发了经过验证的体内鼠标模型并带来 基因编辑疗法的临床前评估方面的深厚专业知识。我们建议合并 这些大量资产在四种神经系统疾病中的每一个中都具有特定于疾病的专业知识， 通过专业知识和资源来扩展基于AAV的交付向量，以提供精确基因 对组织进行编辑疗法，并为导航提供IND提交的监管途径。拟议的U19团队 在临床前管道途径的每个步骤中都有个人和协作成功的记录， 因此，在实现我们的里程碑方面的位置很好，其中包括提交给FDA的IND包裹 一种疗法和神经系统状况。我们的总体目的是：1）与 独特的优势和专家，以开发和实施创新的基因组编辑策略来解决 中枢神经系统的重要疾病，包括脊柱肌肉萎缩，弗里德里希的共济失调，亨廷顿氏病和 RETT综合征； 2）使用体外优化每个疾病区域的主要基础编辑器和主要编辑候选者 平台和经过验证的动物模型； 3）执行有关体内药理学的确定性临床前研究 优化的引线可以开发可再现效率数据，同时监视生物分布，PK/PD，耐受性和 毒理学; 4）通过 与FDA Interact计划，研究项目团队和项目核心协调沟通。