Postnatal and Prenatal Therapeutic Base Editing for Metabolic Diseases

代谢性疾病的产后和产前治疗碱基编辑

• 批准号: 10668614
• 负责人: Kiran Musunuru
• 金额: $ 641.57万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10668614
• 关键词: ANGPTL3 gene; Address; Adenine; Anaphylaxis; Animal Model; Animals; Antibodies; Area; Bacteria; Biodistribution; Birth; CRISPR/Cas technology; Clinical Trials; Clustered Regularly Interspaced Short Palindromic Repeats; DNA; Dependovirus; Development; Disease; Dose; Drug Kinetics; Enzymes; Funding; Gene Mutation; Genes; Genetic Diseases; Goals; Guide RNA; Health; Heart; Hematopoietic Stem Cell Transplantation; Hemoglobinopathies; Hepatocyte; Hereditary Disease; Human; Injectable; Intravenous; Joints; Lead; Life; Liver; Lung; Medical; Metabolic; Metabolic Diseases; Modality; Modeling; Morbidity - disease rate; Mucopolysaccharidoses; Mus; Mutation; Neurologic; Nucleotides; Organ; Outcome; Pathogenicity; Patients; Pharmaceutical Preparations; Pharmacology and Toxicology; Phase I/II Clinical Trial; Phenotype; Phenylketonurias; Primates; Process; Publishing; Research Activity; Research Project Grants; Resources; Sheep; Technology; Therapeutic; Time; Tissue Sample; Treatment Efficacy; Tyrosinemias; Variant; Writing; adeno-associated viral vector; animal resource; base editing; base editor; cancer immunotherapy; chimeric antigen receptor T cells; efficacy testing; enzyme replacement therapy; fetal; gene correction; genome editing; human model; humanized mouse; improved; in utero; in vivo; lead optimization; lipid nanoparticle; meetings; mortality; mortality risk; non-compliance; nonhuman primate; novel; novel therapeutics; nuclease; pharmacologic; postnatal; pre-Investigational New Drug meeting; preclinical study; prenatal; prime editing; programs; response; somatic cell gene editing; success; targeted treatment; therapeutic genome editing; timeline; tool; treatment strategy

PROJECT SUMMARY The potential for the development of novel therapeutic modalities has energized the genome editing field since it first emerged in the 1990s and especially since the demonstration of programmable genome editing with CRISPR-Cas9 by multiple groups in 2012. There has been substantial progress with ex vivo therapeutic applications of genome editing in patients in the past few years, most notably with CAR-T immunotherapies for cancer and with durable treatment of hemoglobinopathies. Progress with in vivo therapeutic applications, i.e., somatic cell genome editing, has been slower due to the technical challenges inherent in the delivery of genome- editing tools into the body. As of the time of this writing, there are few published examples of successful genome editing performed in vivo in primates (including humans), with almost all examples involving somatic genome editing in the liver: TTR with Cas9 nuclease delivered by lipid nanoparticles (LNPs), PCSK9 and ANGPTL3 with adenine base editors delivered by LNPs, and PCSK9 with meganucleases delivered by adeno-associated virus (AAV) vectors. The prospects for genome-editing therapies extend to before birth, with in utero genome editing having the potential to treat genetic diseases that result in significant morbidity and mortality before or shortly after birth. Although restricted to small animal models so far, in utero genome editing has proven effective in the liver, lungs, heart, and other organs. Our Overall Program seeks to build on these early successes, pursuing goals that that would be of major impact in advancing the field of therapeutic genome editing. Our three Research Projects seek to develop base-editing therapies targeting the liver in order to treat three rare metabolic genetic diseases: phenylketonuria (PKU), hereditary tyrosinemia type 1 (HT1), and mucopolysaccharidosis type 1 (MPSI). Lead Project 1 will focus on LNP-based postnatal treatment of PKU, with the aim to file an IND application by the end of the five-year funding period and begin a phase 1/2 clinical trial soon afterwards. Project 2 will focus on LNP-based postnatal treatment of HT1, with the aim to file an IND application and begin a clinical trial, and prenatal treatment of HT1, with the aim of performing preclinical studies during the five-year funding period to enable an eventual IND application if the postnatal clinical trial proves successful. Project 3 will focus on AAV-based postnatal and prenatal treatment of MPSI, with similar aims as Project 2. Unique, specialized Resource Cores focused on off-target editing and in utero treatment of small and large animals will be indispensable in achieving these aims.

项目摘要 自从 它首先在1990年代出现，尤其是自与可编程基因组编辑的演示以来 CRISPR-CAS9在2012年由多个小组组成。在体内治疗方面取得了重大进展 在过去的几年中，基因组编辑的应用在患者中，最著名的是CAR-T免疫疗法 癌症和持久的血红蛋白病治疗。体内治疗应用的进展，即 由于基因组传递所固有的技术挑战，体细胞基因组编辑的编辑速度较慢。 编辑工具到体内。截至撰写本文时，很少有成功的基因组的示例 在灵长类动物（包括人类）中进行体内进行的编辑，几乎所有涉及体细胞基因组的例子 肝脏中的编辑：TTR，由脂质纳米颗粒（LNP），PCSK9和ANGPTL3提供的Cas9核酸酶 由LNP交付的腺嘌呤基础编辑器和PCSK9带有巨型核酸的腺苷 病毒（AAV）向量。基因组编辑疗法的前景扩展到出生前，在子宫基因组中 编辑具有治疗遗传疾病的潜力，从而导致或 出生后不久。尽管到目前为止仅限于小型动物模型，但在子宫基因组编辑中已被证明有效 在肝脏，肺，心脏和其他器官中。 我们的整体计划旨在基于这些早期的成功，追求这将带来重大影响的目标 在推进治疗基因组编辑领域。我们的三个研究项目旨在开发基础编辑 针对肝脏的疗法以治疗三种罕见的代谢遗传疾病：苯酮尿症（PKU），， 遗传性酪氨酸1型（HT1）和1型粘二糖化病（MPSI）。领导项目1将重点关注 基于LNP的PKU产后治疗，目的是在五年结束时提交IND申请 资金期并开始进行1/2期临床试验。项目2将重点关注基于LNP的后产后 HT1的处理，目的是提交IND应用并开始临床试验，并在产前治疗 HT1，旨在在五年的资金期间进行临床前研究以实现最终的IND 应用如果产后临床试验证明是成功的。项目3将侧重于基于AAV的产后和 MPSI的产前治疗，其目标与项目2相似。 在实现这些目标方面，不可或缺的小动物对小动物的脱靶编辑和子宫治疗是必不可少的。