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.

总体项目总结 而高通量测序技术的发展及其在临床诊断中的应用 许多罕见的遗传性疾病产生了遗传基础，有效的治疗方法的发展一直没有跟上 佩斯。尽管基因替代和调节疗法可能是有效的，有时甚至可以挽救生命 尽管有多种治疗方法可供选择，但它们会带来许多风险，例如免疫原性和致瘤性。可编程的 像CRISPR/Cas9这样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 有可能实现持久、精确的基因组修改，从而获得治疗效益。建议的U19计划 寻求通过基因编辑的开发、验证和翻译来应对这些挑战- 基于罕见神经遗传病的治疗解决方案。我们建议重点关注四个方面 每一种神经疾病都代表着一种重要的未得到满足的临床需求：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 基本和主要基因组编辑工具，可以安装精确的更改，而无需创建DSB或需要 供体模板。我们还为每种疾病开发了经过验证的活体小鼠模型，并带来了 在基因编辑疗法的IND-Enabling临床前评估方面拥有深厚的专业知识。我们建议合并 这些相当大的资产在四种神经疾病中的每一种都具有疾病特有的专业知识，支持 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基因- 编辑组织疗法，并导航管理路径以提交IND。提议的U19团队 在临床前管道途径的每一步都有个人和合作成功的记录， 因此能够很好地实现我们的里程碑，其中包括至少提交给FDA的IND包 一种是治疗和神经疾病。我们的总体目标是：1)组建一支多学科团队， 开发和实施创新的基因组编辑策略的独特优势和专业知识，以解决 中枢神经系统的重要疾病，包括脊髓肌肉萎缩、Friedreich‘s共济失调、亨廷顿氏病和 Rett综合征；2)优化每个疾病区域的主要碱基编辑和主要编辑候选，利用体外 平台和有效的动物模型；3)执行明确的临床前活体药理学研究 优化导致开发可重现的疗效数据，同时监控生物分布、PK/PD、耐受性和 毒理学；以及4)通过以下方式使一名主要候选者获得允许的研究性新药(IND)申请 与FDA InterAct项目、研究项目团队和项目核心进行协调沟通。