Familial hypercholesterolemia (FH) is a genetic hyperlipidemia characterized by elevated concentrations of plasma LDL cholesterol. Statins are not always effective for the treatment of FH patients; unresponsive patients have poor prognosis and rely on LDL apheresis. In the past, we developed safe and effective gene therapy strategies for the expression of anti-atherogenic proteins using PEGylated helper-dependent adenoviral (HD-Ad) vectors. We recently developed a HD-Ad vector for the expression of the soluble form of the extracellular portion of the human LDL receptor (LDLR) fused with a rabbit transferrin dimer (LDLR-TF). We evaluated the efficacy of the LDLR-TF chimeric protein in CHOLDLA7, a cell line lacking LDLR expression, restoring the ability to uptake LDL. Subsequently, we administered intravenously 1 × 10E13 vp/kg of this vector in LDLR-deficient mice and observed amelioration of lipid profile and reduction of aortic atherosclerosis. Finally, we studied LDL distribution after HD-Ad vector-mediated expression of LDLR-TF in LDLR-deficient mice and found LDL accumulation in liver, and in heart and intestine. These results support the possibility of lowering LDL-C levels and reducing aortic atherosclerosis using a secreted therapeutic transgene; the present strategy potentially can be modified and adapted to non-systemic gene transfer with expression of the secreted chimeric protein in muscle or other tissues. Intramuscular or local administration strategies could improve the safety profile of this strategy and facilitate applicability.

家族性高胆固醇血症（FH）是一种遗传性高脂血症，其特征在于血浆LDL胆固醇的浓度升高。他汀类药物并不总是对FH患者有效。无反应的患者预后较差，依赖LDL血液分离术。过去，我们开发了使用聚乙二醇化的辅助依赖性腺病毒（HD-Ad）载体表达抗动脉粥样硬化蛋白的安全有效的基因治疗策略。我们最近开发了一种HD-Ad载体，用于表达与兔转铁蛋白二聚体（LDLR-TF）融合的人LDL受体（LDLR）细胞外部分的可溶形式。我们评估了CHOLDLA7（一种缺乏LDLR表达的细胞系）中LDLR-TF嵌合蛋白的功效，恢复了摄取LDL的能力。随后，我们在LDLR缺陷的小鼠中静脉内注射1×10E13 vp / kg的该载体，观察到脂质分布的改善和主动脉粥样硬化的减轻。最后，我们研究了HD-Ad载体介导的LDLR缺陷小鼠中LDLR-TF表达后的LDL分布，发现LDL在肝脏，心脏和肠中蓄积。这些结果支持使用分泌的治疗性转基因降低LDL-C水平并减少主动脉粥样硬化的可能性。通过在肌肉或其他组织中表达所表达的嵌合蛋白，可以潜在地修改本策略并将其适应于非系统性基因转移。肌内或局部给药策略可改善该策略的安全性并促进适用性。