Targeting GPR146 for the Treatment of Homozygous Familial Hypercholesterolemia

项目摘要 水泡治疗公司旨在开发一种治疗纯合子的新疗法并将其商业化 家族性高胆固醇血症(HoFH)。大多数HoFH是由两个等位基因的突变引起的 编码低密度脂蛋白受体(LDLR)的基因。由于他汀类药物和PCSK9的疗效 抗体治疗在很大程度上依赖于功能性低密度脂蛋白受体，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，一种抗体 对于血管生成素样3(Angptl3)的治疗，可用于治疗这种疾病的选择很少。 开发新的靶向疗法以降低低密度脂蛋白胆固醇和低密度脂蛋白的医学需求仍未得到满足 以及HOFH中的脂类。GRP146最近成为一种令人兴奋的潜在的新疗法 霍夫赫的目标。我们的目标是利用我们的专有交付技术开发新的 GPR146治疗HoFH。此第一阶段SBIR项目的总体目标是演示 通过专有的Gectosome递送LwaCas13a/GPR146 crRNA来沉默GPR146是 有效地降低低密度脂蛋白和血脂，在小鼠中具有可接受的安全性，使 HoFH的新疗法。

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.