Intramuscular Administration of AAV1-Lipoprotein LipaseS447X Lowers Triglycerides in Lipoprotein Lipase-Deficient Patients
Intramuscular Administration of AAV1-Lipoprotein LipaseS447X Lowers Triglycerides in Lipoprotein Lipase-Deficient Patients
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DOI：
10.1161/atvbaha.108.175620
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发表时间：
2008-12-01
影响因子：
8.7
通讯作者：
Kuivenhoven, Jan Albert
中科院分区：
文献类型：
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作者：
Stroes, Erik S.;Nierman, Melchior C.;Kuivenhoven, Jan Albert
(甘油三酯)水平，因此使患者容易患上潜在威胁生命的胰腺炎。鉴于缺乏适当的治疗，我们开发了一种基因替代策略来降低这些患者的甘油三酯水平。1本报告总结了首次临床试验(CT-AMT-010-01)的数据，该试验是在LPL缺陷个体肌肉注射病毒载体后进行的。在一项为期3个月的开放标记研究中，将LPLS447X-腺相关病毒亚型1，2载体1，2注射到8名LPL缺陷患者的腿部肌肉中，剂量为每公斤体重11011(N4)或31011(N4)个基因组拷贝(分别为40和60次注射500microL)。主要目的是确定肌肉内应用该载体的有效性和安全性。主要结果是在饮食的基础上将个体空腹血浆甘油三酯降低到等于或小于10 mmoL/L的水平，或者在饮食的基础上实现空腹血浆甘油三酯的降低等于或大于40%。治疗耐受性良好，没有观察到严重的不良事件。12周时，所有患者的甘油三酯水平中位数均较基线降低(P<0.007)，低剂量组和高剂量组的甘油三酯平均降低27%和41%(图c和d)。低剂量组有1例患者和高剂量组有3例患者达到主要疗效终点。在较高剂量的载体注射后26至36周，肌肉匀浆中局部LPL蛋白和活性显著增加。然而，18至31个月后的随访数据显示，与AAV1衣壳蛋白的免疫反应潜在相关的疗效丧失(与基线相比，血浆甘油三酯和甘油三酯)。3观察到抗AAV1衣壳蛋白抗体的形成，但不能产生针对LPL蛋白的抗体反应。
(TG) levels and consequently predisposes patients to potentially life-threatening pancreatitis. In view of the absence of adequate therapy, we developed a gene replacement strategy to lower TG levels in these patients. 1 This report summarizes the data of a first clinical trial (CT-AMT-010-01) in LPL-deficient individuals after intramuscular administration of a viral vector. In a 3-month open-label study, LPLS447X-adenoassociated virus subtype 1 (AAV1) vector1, 2 was injected in the leg musculature of 8 LPL-deficient patients at a dose of 11011 (n4) or 31011 (n4) genome copies per kilogram body weight (40 and 60 injections of 500 microliters, respectively). Primary objectives were to establish efficacy and safety of intramuscular application of this vector. The primary outcome measure was to achieve a reduction in individual median fasting plasma TG to a level equal to or less than 10 mmol/L on top of diet, or to achieve a reduction in median fasting plasma TG equal to or more than 40% on top of diet.The treatment was well tolerated and no serious adverse events were observed. At 12 weeks, all patients presented with a decrease of median TG levels compared to baseline TG (P 0.007 versus baseline; Figure, a and b), corresponding to a mean TG reduction of 27% and 41% in low-and higherdose group, respectively (Figure, c and d). One patient in the low-dose and 3 patients in the high-dose group reached the primary efficacy end point. Twenty-six to 36 weeks after higher vector dose administration, a significant increase in local LPL protein and activity was detected in muscle homogenates. Follow-up data after 18 to 31 months, however, showed a loss of efficacy (plasma TG ns compared to baseline; Figure, c and d) potentially related to an immune response against AAV1-capsid proteins. 3 Whereas antibody formation against AAV1-capsid proteins was observed, no antibody response against LPL protein could be demon-