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
• 负责人: ANDREW M DAVIDOFF
• 金额: $ 65.25万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-01-05 至 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8231434
• 关键词: 18 year old; Acute; Adult; Adverse event; Affect; Animals; Bilirubin; Biochemistry; Biological Assay; Blood Coagulation Factor; Body Fluids; Body Weight; Brain; Capsid; Capsid Proteins; Cessation of life; Clinical; Clinical Data; Clinical Trials; Coagulation Process; Codon Nucleotides; Defect; Dependovirus; Detection; Development; Diagnosis; Disease; Dose; Dose-Limiting; Enrollment; Enzyme-Linked Immunosorbent Assay; Evaluation; Factor IX; Fibrin; Funding; Future; Gene Transfer; Genes; Genome; Hemophilia B; Hemorrhage; Human; Humoral Immunities; Immune response; Immunity; Incidence; Joints; Kilogram; Kinetics; Laboratories; Life; Link; Liver; Low Prevalence; Macaca mulatta; Measures; Mediating; Missense Mutation; Modeling; Monitor; Mus; Patients; Peripheral; Phase; Phenotype; Prevention; Proteins; Recombinant adeno-associated virus (rAAV); Route; Safety; Seminal fluid; Serine Protease; Serotyping; Serum; Site; Suspension substance; Suspensions; Testing; Therapeutic; Time; Tissues; Toxic effect; Transgenes; Veins; Virus Shedding; adeno-associated viral vector; alternative treatment; base; interest; neutralizing antibody; nonhuman primate; novel; open label; particle; pre-clinical; promoter; soft tissue; targeted delivery; therapeutic gene; urea cycle; vector; vector biodistribution; vector genome

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.

我们提出了一项开放标签的剂量递增I/II期研究，在该研究中，单剂量的新的自身- 互补的AAV载体scAAV2/8 LP1 hFIXco将被注射到成年受试者的外周静脉中 患有严重的血友病B。血友病B(HB)是一种X连锁的隐性出血性疾病，由 因子IX(FIX)基因缺陷，该基因编码一种丝氨酸蛋白酶，对适当的纤维蛋白凝块形成至关重要。 临床上，该病的特征是频繁的自发性出血，最常见的部位是 关节和软组织，但也可能发生在大脑中，并可能危及生命。我们广泛的 对小鼠模型和恒河猴的研究表明，scAAV2/8 LP1 hFIXco载体建立了 与之前评估的载体相比，这些动物中相对较低剂量的FIX的治疗水平 临床试验。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伪类型向量而不是AAV2，这主要是因为 对这种AAV血清型先前存在的免疫在人类中的流行率。第二个区别与使用有关 一种含有自我互补基因组的载体，由于其快速稳定形成的能力， 靶组织中转录活性的双链线性分子提供了独特的机会 以较低剂量的载体潜在地介导有效的治疗性基因转移。最后，因为 载体的生物分布主要分布在肝脏，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：2x1010、6x1010和2x1011 每公斤体重的载体基因组。该研究的主要目的是评估安慰剂的安全性 当次要目标是1)确定载体的剂量时，系统地给药该载体 需要达到hFIX稳定表达的颗粒达到或超过正常的3%；2)描述免疫 对hFIX转基因产物和AAV衣壳蛋白的反应以及3)将病毒脱落到不同的 体液。招募将仅限于成年人(大于或等于18岁)，并确认 HFIX基因错义突变所致重型乙肝的诊断。病人将在医院接受观察 在下一名患者登记之前，至少在病媒接种后42天。剂量升级将继续进行 基于安全性(主要)和有效性(次要)标准。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(丙氨酸氨基转移酶或胆红素10倍正常)或持续性时 (&gt；16周)ALT或胆红素升高。如果发生下列情况之一，将立即导致 暂停试验：1)一名患者出现IV级毒性或两名患者出现III级毒性 在给定的剂量水平下。2)发展中和抗体以固定基因转移后的一种 主题。5)患者在基因转移后的任何时间点死亡，这可能、很可能或肯定是相关的 给学习代理。目前治疗血友病B的不足之处激起了人们对替代疗法的兴趣 治疗方法，包括基因转移。AAV介导的基因转移成功 对于血友病B提供了有效的终身预防出血的潜力和它的 这种疾病患者的并发症。此外，从这一事件中获得的信息 研究对于规划其他使用AAV载体的未来策略将是重要的 其他影响肝脏的疾病，如溶酶体储存和尿素循环障碍， 都是有针对性的。