Clinical trial of self complementary AAV8-mediated gene transfer for hemophilia B

自我互补 AAV8 介导的基因转移治疗 B 型血友病的临床试验

基本信息

项目摘要

DESCRIPTION (provided by applicant): We propose an open label, dose-escalation, phase I/II study in which a single dose of the novel self- complementary AAV vector, scAAV2/8 LP1 hFIXco, will be administered into a peripheral vein of adult subjects with severe hemophilia B. Hemophilia B (HB) is an X-linked recessive bleeding disorder that results from a defect in the factor IX (FIX) gene which encodes a serine protease critical for appropriate fibrin clot formation. Clinically the disease is characterized by frequent spontaneous bleeding, most commonly into such sites as joints and soft tissues, but which can also occur in the brain and potentially be life threatening. Our extensive studies in murine models and rhesus macaques have shown that scAAV2/8 LP1 hFIXco vector establishes therapeutic levels of FIX at relatively low doses in these animals, compared to vectors evaluated in previous clinical trials. This study differs from previous HB clinical trials with AAV vectors in three important aspects. Firstly, an AAV8 pseudotyped vector will be used instead of AAV2, primarily because of the substantially lower prevalence of pre-existing immunity to this AAV serotype in humans. The second difference relates to the use of a vector containing a self-complementary genome which, because of its ability to rapidly form stable, transcriptionally active, double stranded linear molecules in target tissues, offers the unique opportunity to mediate efficient therapeutic gene transfer potentially at lower doses of vector. Finally, because the biodistribution of vector is predominantly to the liver regardless of the route of administration, scAAV particles will be administered via a peripheral vein. We propose to test three dose levels: 2x1010, 6x1010 and 2x1011 vector genomes per kilogram body weight. The primary objective of the study is to assess the safety of systemic administration of this vector while the secondary objectives are 1) to determine the dose of vector particles required to achieve stable expression of hFIX at or above 3% of normal; 2) to describe the immune responses to the hFIX transgene product and AAV capsid proteins and 3) to access viral shedding into various body fluids. Recruitment will be limited to adults (greater than or equal to 18 years of age) with a confirmed diagnosis of severe HB resulting from a missense mutation in the hFIX gene. Patients will be observed for at least 42 days following vector administration before enrollment of the next patient. Dose escalation will proceed based on safety (primary) and efficacy (secondary) criteria. Immunosupression will not be given routinely; rather, only if a patient develops acute, significant transaminitis (ALT or bilirubin >10X normal) or persistent (>16 weeks) ALT or bilirubin elevation. The occurrence of any of the following will result in immediate suspension of the trial: 1) The occurrence of Grade IV toxicity in one patient or Grade III toxicity in two patients at a given dose level. 2) The development of neutralizing antibodies to FIX following gene transfer in one subject. 5) Death of a patient at any time point after gene transfer that is possibly, probably, or definitely related to the study agent. The inadequacies of current therapy for hemophilia B have fuelled interest in alternative treatment approaches, including gene transfer. Successful AAV-mediated gene transfer for hemophilia B offers the potential of effective lifetime prevention of bleeding and its complications for patients with this disorder. In addition, the information gained from this study will be important in planning additional future strategies with AAV vectors in which other disorders affecting the liver, such as lysosomal storage and urea cycle disorders, are targeted.
描述(由申请人提供): 我们提出了一项开放标记、剂量递增的I/II期研究,在该研究中,将单剂量的新型自互补AAV载体scAAV2/8 LP1 hFIXco注射到患有严重血友病B的成年受试者的外周静脉中。血友病B(HB)是一种X连锁的隐性出血障碍,由因子IX(FIX)基因缺陷引起,该基因编码一种对适当的纤维蛋白凝块形成至关重要的丝氨酸蛋白酶。临床上,这种疾病的特征是频繁的自发性出血,最常见的是关节和软组织等部位,但也可能发生在大脑中,并有可能危及生命。我们对小鼠模型和恒河猴的广泛研究表明,与先前临床试验中评估的载体相比,scAAV2/8 LP1 hFIXco载体在这些动物中以相对较低的剂量建立了治疗水平的FIX。这项研究与以往使用AAV载体进行的乙肝临床试验有三个重要方面的不同。首先,将使用AAV8伪型载体而不是AAV2,主要是因为人类对这种AAV血清型的原有免疫力大大降低。第二个不同之处在于使用包含自互补基因组的载体,由于其能够在靶组织中快速形成稳定的、转录活性的双链线性分子,因此提供了以较低的载体剂量潜在地介导有效的治疗性基因转移的独特机会。最后,由于载体的生物分布主要是肝脏,无论给药途径如何,scAAV颗粒将通过外周静脉给药。我们建议测试三个剂量水平:每公斤体重2x1010、6x1010和2x1011个载体基因组。该研究的主要目的是评估该载体全身给药的安全性,次要目标是1)确定使hFIX稳定表达达到或超过正常水平3%所需的载体颗粒的剂量;2)描述对hFIX转基因产物和AAV衣壳蛋白的免疫应答;3)获得病毒进入各种体液的机会。招募将仅限于成人(大于或等于18岁),并被确诊为因hFIX基因错义突变而导致的严重乙肝。在登记下一名患者之前,将在病媒接种后对患者进行至少42天的观察。剂量递增将根据安全性(主要)和疗效(次要)标准进行。不会常规给予免疫抑制;相反,只有当患者出现急性、严重的转氨炎(ALT或胆红素>10倍正常)或持续性(>16周)ALT或胆红素升高时才给予免疫抑制。发生下列情况之一将导致试验立即暂停:1)在给定剂量水平上,一名患者出现IV级毒性或两名患者出现III级毒性。2)发展中和抗体,以固定在一个受试者的基因转移。5)患者在基因转移后的任何时间点死亡,这可能、可能或肯定与研究试剂有关。目前治疗血友病B的不足激发了人们对替代治疗方法的兴趣,包括基因转移。成功的AAV介导的血友病B基因转移为血友病患者提供了终生有效预防出血及其并发症的潜力。此外,从这项研究中获得的信息对于规划其他AAV载体的未来策略将是重要的,在AAV载体中,其他影响肝脏的疾病,如溶酶体储存和尿素循环障碍,是有针对性的。

项目成果

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ANDREW M DAVIDOFF其他文献

ANDREW M DAVIDOFF的其他文献

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{{ truncateString('ANDREW M DAVIDOFF', 18)}}的其他基金

Clinical trial of AAV8-mediated FVIII gene transfer for hemophilia A
AAV8 介导的 FVIII 基因转移治疗甲型血友病的临床试验
  • 批准号:
    10304874
  • 财政年份:
    2018
  • 资助金额:
    $ 82.77万
  • 项目类别:
Clinical trial of AAV8-mediated FVIII gene transfer for hemophilia A
AAV8 介导的 FVIII 基因转移治疗甲型血友病的临床试验
  • 批准号:
    10063895
  • 财政年份:
    2018
  • 资助金额:
    $ 82.77万
  • 项目类别:
AAV-Mediated Gene Therapy for Hemophilia
AAV 介导的血友病基因治疗
  • 批准号:
    8287104
  • 财政年份:
    2011
  • 资助金额:
    $ 82.77万
  • 项目类别:
AAV-Mediated Gene Therapy for Hemophilia
AAV 介导的血友病基因治疗
  • 批准号:
    8882512
  • 财政年份:
    2011
  • 资助金额:
    $ 82.77万
  • 项目类别:
AAV-Mediated Gene Therapy for Hemophilia
AAV 介导的血友病基因治疗
  • 批准号:
    8115643
  • 财政年份:
    2011
  • 资助金额:
    $ 82.77万
  • 项目类别:
AAV-Mediated Gene Therapy for Hemophilia
AAV 介导的血友病基因治疗
  • 批准号:
    8501629
  • 财政年份:
    2011
  • 资助金额:
    $ 82.77万
  • 项目类别:
AAV-Mediated Gene Therapy for Hemophilia
AAV 介导的血友病基因治疗
  • 批准号:
    8677943
  • 财政年份:
    2011
  • 资助金额:
    $ 82.77万
  • 项目类别:
ANGIOGENESIS INHIBITORS IN THE MULTIMODAL TREATMENT OF PEDIATRIC SOLID TUMORS
血管生成抑制剂在小儿实体瘤多模式治疗中的应用
  • 批准号:
    8309814
  • 财政年份:
    2011
  • 资助金额:
    $ 82.77万
  • 项目类别:
Strategies to improve the antiglioma action of IFN-?: a role for NF-kB inhibition
改善 IFN-α 抗神经胶质瘤作用的策略:抑制 NF-kB 的作用
  • 批准号:
    8020141
  • 财政年份:
    2009
  • 资助金额:
    $ 82.77万
  • 项目类别:
Clinical trial of self complementary AAV8-mediated gene transfer for hemophilia B
自我互补 AAV8 介导的基因转移治疗 B 型血友病的临床试验
  • 批准号:
    8231434
  • 财政年份:
    2009
  • 资助金额:
    $ 82.77万
  • 项目类别:

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