Targeting GPR146 for the Treatment of Homozygous Familial Hypercholesterolemia

项目摘要 Vesicle Therapeutics Inc旨在开发和商业化一种新的治疗纯合子 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 低密度脂蛋白受体（LDL receptor，LDLR）由于他汀类药物和PCSK 9的疗效 抗体治疗在很大程度上取决于功能性LDL受体，hoFH患者表现出有限的 对现有疗法的反应。除了最近批准的evinacumab， 尽管抗血管生成素样3（ANGPTL 3）的治疗是有效的，但很少有选择可用于治疗这种疾病。 在开发新的靶向疗法以降低LDL-C和LDL-C水平方面，仍存在未满足的医疗需求。 和脂质。GRP 146最近成为一种令人兴奋的和潜在的新治疗药物 hoFH目标。我们的目标是利用我们专有的交付技术， GPR 146治疗hoFH。第一阶段SBIR项目的总体目标是证明 通过LwaCas 13 a/GPR 146 crRNA的专有gectosome递送沉默GPR 146， 在小鼠中有效降低LDL-C和脂质，具有可接受的安全性， 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.