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.

项目概要 Vesicle Therapeutics Inc 旨在开发纯合子新疗法并将其商业化 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 PCSK9 的疗效 抗体疗法很大程度上取决于功能性 LDL 受体，hoFH 患者表现有限 对这些现有疗法的反应。 hoFH 无法治愈，可用的选择很少 来治疗疾病。血管生成素样 3 (ANGPTL3) 已成为一种可能的治疗方法 HOFH 的目标，因为 ANGPTL3 缺陷的个体不会发生冠状动脉粥样硬化 牌匾。 RNA靶向CRISPR酶LwaCas13可以通过RNA耗尽来关闭基因 类似于 RNAi，但脱靶基因沉默率非常低。缺乏安全保障 目前的递送方法限制了 LwaCas13 的治疗潜力。刘实验室 科罗拉多大学博尔德分校开发了一种创新的细胞内生物制剂输送系统 称为Gectosomes。 STTR 第一阶段项目的总体目标是证明 通过基因体传递 LwaCas13a/ANGPTL3 crRNA 来沉默 ANGPTL3 在 降低小鼠体内的 LDL-C，安全性可接受。拟议的策略结合了两个 潜在临床转化的创新技术。所提出的研究是可行的 关于我们之前成功地通过基因组传递 CRISPR RNP 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 血流。卵泡体很容易进入肝脏。 LwaCas13a 介导的 RNA 损耗 是可逆的，并且可能比基因编辑有更少的安全问题。我们将确定 LwaCas13a 在小鼠中抑制 ANGPTL3 的有效性和安全性，这项工作是必要的 进行进一步研究以推进罕见疾病的潜在治疗解决方案。