Yang Chun, Tian Wenhong, Ma Sisi, Guo Mengmeng, Lin Xiao, Gao Fengying, Dong Xiaoyan, Gao Mingming, Wang Yuhui, Liu George, Xian Xunde
Institute of Cardiovascular Sciences and Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Peking University, Beijing 100191, China.
Beijing FivePlus Molecular Medicine Institute Co. Ltd., Beijing 100176, China.
Mol Ther Methods Clin Dev. 2020 Jul 15;18:692-701. doi: 10.1016/j.omtm.2020.07.011. eCollection 2020 Sep 11.
Apolipoprotein C2 (ApoC2) is a key activator of lipoprotein lipase for plasma triglyceride metabolism. ApoC2-deficient patients present with severe hypertriglyceridemia and recurrent acute pancreatitis, for whom the only effective treatment is the infusion of normal plasma containing ApoC2. However, since ApoC2 has a fast catabolic rate, a repeated infusion is required, which limits its clinical use. To explore a safe and efficient approach for ApoC2 deficiency, we herein established an adeno-associated virus expressing human ApoC2 (AAV-hApoC2) to evaluate the efficacy and safety of gene therapy in ApoC2-deficient hypertriglyceridemic hamsters. Administration of AAV-hApoC2 via jugular or orbital vein in adult and neonatal ApoC2-deficient hamsters, respectively, could prevent the neonatal death and effectively improve severe hypertriglyceridemia of ApoC2-deficient hamsters without side effects in a long-term manner. Our novel findings in the present study demonstrate that AAV-hApoC2-mediated gene therapy will be a promising therapeutic approach for clinical patients with severe hypertriglyceridemia caused by ApoC2 deficiency.
载脂蛋白C2（ApoC2）是血浆甘油三酯代谢中脂蛋白脂肪酶的关键激活剂。ApoC2缺乏的患者表现为严重的高甘油三酯血症和复发性急性胰腺炎，对于他们而言，唯一有效的治疗方法是输注含有ApoC2的正常血浆。然而，由于ApoC2的分解代谢率很快，需要反复输注，这限制了其临床应用。为了探索一种安全有效的治疗ApoC2缺乏的方法，我们在此构建了一种表达人ApoC2的腺相关病毒（AAV-hApoC2），以评估基因治疗对ApoC2缺乏的高甘油三酯血症仓鼠的疗效和安全性。分别通过颈静脉或眶静脉给成年和新生的ApoC2缺乏仓鼠注射AAV-hApoC2，可以预防新生仓鼠死亡，并长期有效改善ApoC2缺乏仓鼠的严重高甘油三酯血症且无副作用。我们在本研究中的新发现表明，AAV-hApoC2介导的基因治疗将是治疗由ApoC2缺乏引起的严重高甘油三酯血症临床患者的一种有前景的治疗方法。
