Determining the Minimally Effective Dose of a Clinical Candidate Adeno-Associated Virus Vector in a Mouse Model of Hemophilia A.
Determining the Minimally Effective Dose of a Clinical Candidate Adeno-Associated Virus Vector in a Mouse Model of Hemophilia A.
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DOI：
10.1089/hum.2021.108
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发表时间：
2022-04
影响因子：
4.2
通讯作者：
Wilson, James M.
中科院分区：
文献类型：
--
作者：
Greig, Jenny A.;Smith, Melanie K.;Nordin, Jayme M. L.;Goode, Tamara;Chroscinski, Edward A.;Buza, Elizabeth L.;Schmidt, Nicole;Kattenhorn, Lisa M.;Wadsworth, Samuel;Wilson, James M.
血友病A是一种出血性疾病，影响1：5,000男性，由人类凝血因子VIII(HFVIII)缺乏引起。在小鼠和猕猴身上的研究被确定为治疗血友病A的临床候选基因治疗载体。在这项研究中，我们试图确定该载体在血友病A小鼠模型中的最小有效剂量(MED)。小鼠通过尾静脉注射4种载体剂量之一(3 × 1011-1 × 1013基因组拷贝[GC]/kg)；另一组接受载体作为对照。每天给药后对动物进行监测。采集血样检测hFVIII活性水平和抗hFVIII抗体。分别于第28、56天处死动物，取组织作组织病理学检查，采血作血清化学面板分析。我们发现，注射任何载体剂量的小鼠与注射赋形剂的小鼠相比，肝脏转氨酶水平没有显著差异(除一组注射3 × 1011GC/kg外)。在第56天，两种载体剂量(1 × 1012和1 × 1013GC/kg)后，总胆红素水平显著高于赋形剂组。我们没有观察到与病媒相关的大体或组织学发现。大多数显微镜检查结果是在赋形剂组中发现的，并被认为是失血的次要表现型，这是该小鼠模型的预期表型。由于我们没有观察到剂量限制的安全标记，我们确定最大耐受剂量大于或等于测试的最高剂量(1 × 1013GC/kg)。由于我们在所有队列注射载体中都检测到hFVIII活性，我们得出结论，MED3 × 1011GC/kg-这是本研究评估的最低剂量。
Hemophilia A, a bleeding disorder, affects 1:5,000 males and is caused by a deficiency of human blood coagulation factor VIII (hFVIII). Studies in mice and macaques identified as a clinical candidate gene therapy vector to treat hemophilia A. In this study, we sought to determine the minimally effective dose (MED) of this vector in a hemophilia A mouse model. Mice received one of four vector doses (3 × 1011–1 × 1013 genome copies [GCs]/kg) via intravenous tail vein injection; one cohort received vehicle as a control. Animals were monitored daily after vector/vehicle administration. Blood samples were collected to evaluate hFVIII activity levels and anti-hFVIII antibodies. Animals were sacrificed and necropsied on days 28 and 56; tissues were harvested for histopathological examination and blood was collected for serum chemistry panel analysis. We found no significant differences in liver transaminase levels in mice administered any vector dose compared to those administered vehicle (except for one group administered 3 × 1011 GC/kg). Total bilirubin levels were significantly elevated compared to the vehicle group following two vector doses at day 56 (1 × 1012 and 1 × 1013 GC/kg). We observed no vector-related gross or histological findings. Most microscopic findings were in the vehicle group and considered secondary to blood loss, an expected phenotype of this mouse model. Since we observed no dose-limiting safety markers, we determined that the maximally tolerated dose was greater than or equal to the highest dose tested (1 × 1013 GC/kg). Since we detected hFVIII activity in all cohorts administered vector, we conclude that the MED is 3 × 1011 GC/kg—the lowest dose evaluated in this study.
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