Development of a Gectosome Therapy for Cardiovascular Diseases

心血管疾病的基因组疗法的开发

• 批准号: 10384422
• 负责人: XUEDONG LIU
• 金额: $ 31.68万
• 依托单位: VESICLE THERAPEUTICS INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10384422
• 关键词: ANGPTL3 gene; Address; Affect; Alleles; Antibody Therapy; Antisense Oligonucleotides; Arterial Fatty Streak; Biological Products; Blood Circulation; C57BL/6 Mouse; Cardiovascular Diseases; Cells; Cholesterol; Clustered Regularly Interspaced Short Palindromic Repeats; Colorado; Complex; Coronary; Coronary Arteriosclerosis; Development; Disease; Dose; Encapsulated; Enzymes; Evaluation; Event; Familial Hypercholesterolemia; Feasibility Studies; Gene Silencing; Genes; Goals; Guide RNA; Health; Hepatocyte; Immunity; Individual; Laboratories; Licensing; Liver; Low Density Lipoprotein Receptor; Low-Density Lipoproteins; Mediating; Medical; Methods; Modality; Monoclonal Antibodies; Mus; Mutation; Patients; Persons; Phase; Phase I Clinical Trials; Production; RNA; RNA Interference; Rare Diseases; Risk; Safety; Small Business Technology Transfer Research; Small Interfering RNA; Specificity; System; Technology; Therapeutic; Therapeutic Agents; Therapeutic Effect; Toxic effect; Translating; Uncertainty; Universities; Vesicle; Work; base; cardiovascular disorder therapy; clinical candidate; clinical translation; drug development; experimental study; in vivo; innovation; innovative technologies; knock-down; novel therapeutics; rare genetic disorder; response; side effect; success; therapeutic target; transcriptome sequencing; treatment response

Project Summary Vesicle Therapeutics Inc aims to develop and commercialize a new therapy for homozygous familial hypercholesterolemia (hoFH). A majority of hoFH is caused by mutations in both alleles of the gene encoding the LDL receptor (LDLR). Since the efficacy of both statins and PCSK9 antibody therapies largely depends on functional LDL receptors, patients with hoFH show limited responses to these existing therapies. There is no cure for hoFH, and few options are available to treat the diseases. Angiopoietin-like 3 (ANGPTL3) has emerged as a possible therapeutic target for hoFH as individuals deficient in ANGPTL3 do not develop coronary atherosclerotic plaque. The RNA targeting CRISPR enzyme LwaCas13 can turn off genes by RNA depletion analogous to RNAi but with very lower rate of off-target gene silencing. The absence of safe delivery methods currently limits the therapeutic potential of LwaCas13. The Liu laboratory at the University of Colorado-Boulder developed an innovative intracellular biologics delivery system called Gectosomes. The overall objective of this phase I STTR project is to demonstrate that silencing of ANGPTL3 by gectosome delivery of LwaCas13a/ANGPTL3 crRNA is efficacious in lowering LDL-C with acceptable safety profile in mice. The proposed strategy combines two innovative technologies for potential clinical translation. The proposed studies are feasible based on our previous success with gectosome delivery of CRISPR RNP that causes inactivation of PCSK9 in mouse liver. ANGPTL3 is primarily expressed in hepatocytes and secreted into the bloodstream. The liver is readily accessible by gectosomes. LwaCas13a-mediated RNA depletion is reversible and may have fewer safety concerns than gene editing. We will determine the efficacy and safety of ANGPTL3 suppression by LwaCas13a in mice and this work is necessary for further studies to advance a potential therapeutic solution for a rare disease.

项目摘要 囊泡Therapeutics Inc的目标是开发和商业化纯合的新疗法 家族性高胆固醇血症（HOFH）。大多数HOFH是由两个等位基因突变引起的 编码LDL受体（LDLR）的基因。由于他汀类药物和PCSK的功效 抗体疗法在很大程度上取决于功能性LDL受体，HOFH患者显示有限 对这些现有疗法的反应。无法治愈HOFH，几乎没有选择 治疗疾病。血管生成素样3（ANGPTL3）已成为可能的治疗 HOFH作为个人缺乏ANGPTL3的目标不发展冠状动脉粥样硬化 牌匾。 RNA靶向CRISPR酶LWACAS13可以通过RNA耗竭关闭基因 类似于RNAi，但脱靶基因沉默的速率较低。缺乏安全 目前，输送方法限制了LWACAS13的治疗潜力。刘的实验室 科罗拉多大学 - 博尔德分校开发了创新的细胞内生物制剂递送系统 称为三十体。 I阶段ISTTR项目的总体目标是证明 通过lwacas13a/angptl3 crrna的刺肠结构递送对angptl3的沉默是有效的 在小鼠中降低具有可接受的安全性的LDL-C。提出的策略结合了两个 潜在临床翻译的创新技术。拟议的研究基于可行的 关于我们以前在gectosoms of crispr rnp的甲状腺体传递中的成功，这会导致失活 小鼠肝脏中的PCSK9。 Angptl3主要在肝细胞中表达，并分泌到 血液。肝脏很容易通过甲型肝脏进入。 LWACAS13A介导的RNA耗竭 可逆，安全问题可能比基因编辑更少。我们将确定 LWACAS13A在小鼠中抑制ANGPTL3的功效和安全性，这项工作是必要的 为了进一步研究，可以推进稀有疾病的潜在治疗溶液。