Targeting GPR146 for the Treatment of Homozygous Familial Hypercholesterolemia

靶向 GPR146 治疗纯合子家族性高胆固醇血症

基本信息

批准号：
10482589
负责人：
Donna PEAK
金额：
$ 29.8万
依托单位：
VESICLE THERAPEUTICS INC.
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10482589
关键词：
ANGPTL3 gene Address Affect Alleles Antibody Therapy Antisense Oligonucleotides Biological Products C57BL/6 Mouse Cardiovascular Diseases Cells Cholesterol Clustered Regularly Interspaced Short Palindromic Repeats Colorado Complex Coronary Arteriosclerosis Development Disease Dose Encapsulated Enzymes Evaluation Event Familial Hypercholesterolemia Feasibility Studies Gene Silencing Genes Goals Guide RNA Health High Density Lipoprotein Cholesterol Immunity LDL Cholesterol Lipoproteins Laboratories Licensing Lipids Liver Low Density Lipoprotein Receptor Low-Density Lipoproteins Mediating Medical Methods Modality Mus Mutation Patients Persons Phase Production RNA RNA Interference Rare Diseases Risk Safety Small Business Innovation Research Grant Small Interfering RNA Specificity System Technology Therapeutic Therapeutic Effect Toxic effect Translating Uncertainty Universities Vesicle base clinical candidate clinical translation drug development experimental study in vivo innovation innovative technologies knock-down new therapeutic target novel therapeutics rare genetic disorder response success transcriptome sequencing treatment response

项目摘要

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. Other than recently approved evinacumab, an antibody therapy against Angiopoietin-like 3 (ANGPTL3), few options are available to treat this disease. There is still an unmet medical need for developing new targeted therapies to lower both LDL-C and lipids in hoFH. GRP146 has recently emerged as an exciting and potential new therapeutic target for hoFH. Our goal is to leverage our proprietary delivery technology to develop a new GPR146 therapy for hoFH. The overall objective of this Phase I SBIR project is to demonstrate that silencing of GPR146 by proprietary gectosome delivery of LwaCas13a/GPR146 crRNA is efficacious in lowering both LDL-C and lipids with acceptable safety profile in mice, enabling a new therapy for hoFH.

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。除了最近批准的 evinacumab 之外，还有一种抗体针对血管生成素样 3 (ANGPTL3) 的治疗，治疗这种疾病的选择很少。开发新的靶向疗法来降低 LDL-C 的医疗需求仍然未得到满足和 hoFH 中的脂质。 GRP146 最近成为一种令人兴奋且具有潜力的新疗法 hoFH 的目标。我们的目标是利用我们专有的交付技术开发新的 GPR146 治疗 hoFH。第一阶段 SBIR 项目的总体目标是证明通过 LwaCas13a/GPR146 crRNA 的专有基因体递送来沉默 GPR146 有效降低 LDL-C 和血脂，且在小鼠中具有可接受的安全性，从而能够 hoFH 的新疗法。