Preclinical gene correction of hemophilia A

A型血友病临床前基因校正

• 批准号: 8136424
• 负责人: HAIG H. KAZAZIAN
• 金额: $ 30.58万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-06 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8136424
• 关键词: 7,7' -dimethoxy-(4,4' -bi-1,3-benzodioxole)-5,5' -dicarboxylic acid dimethyl ester; A Mouse; Adult; Animal Model; Animals; Antibodies; Antibody Formation; B-Lymphocytes; Canis familiaris; Capsid; Clinical Trials; Complementary DNA; Development; Dose; Effectiveness; Gene Delivery; Hemophilia A; Immune response; Infusion procedures; Intravenous; Intravenous infusion procedures; Light; Liver; Mediating; Monitor; Morbidity - disease rate; Plasma; Portal vein structure; Proteins; Risk; Route; Safety; Serotyping; Staging; T-Lymphocyte; Testing; Therapeutic; Transgenes; Viral; Viral Packaging; Virus; Work; adeno-associated viral vector; compare effectiveness; conventional therapy; gene correction; gene therapy; gene therapy clinical trial; high risk; improved; inhibitor/antagonist; neutralizing antibody; novel; pre-clinical; prevent; recombinant antihemophilic factor VIII; response; safety testing; success; transmission process; vector

DESCRIPTION (provided by applicant): This proposal sets the stage for clinical trials of gene therapy for hemophilia A. Here we concentrate on the use of adeno-associated viral (AAV) vectors with new capsid serotypes for liver directed gene therapy in a large animal model, namely, the hemophilia A dog. This work builds upon our previous success in "curing" the hemophilia A mouse using FVIII gene delivery in two new AAV serotypes, AAV8 and AAV9. Our studies in hemophilia A dogs, while more modestly successful, have also been encouraging with both new AAV serotypes. In this application, we evaluate further these AAV serotypes, beginning with delivery of FVIII cDNA in heavy chain and light chain vectors. We test responses at two different doses for both AAV8 and AAV9, and compare intraportal to intravenous routes of vector administration, We then go on to develop an effective, smaller single chain vector that can be produced in high titers, and test this single chain vector using the best combination of serotype, dose, and route of administration. We will also carry out therapy with our best conditions in young dogs, in an effort to initiate treatment before the onset of serious morbidity and also to prevent inhibitor formation to rFVIII used for conventional therapy. Lastly, we will determine whether FVIII can be readministered to dogs using a different serotype vector from the vector used in the original virus infusion. In all of these studies significant efforts will be made to test the safety of the new AAV vectors, concentrating on studies of neutralizing antibodies, development of transaminitis, and germline transmission of virus. At the end of these studies, we expect to have discovered treatment conditions that consistently produce long-term therapeutic levels of FVIII (>10% of normal) in a large animal, the hemophilia A dog. These results should make clinical trials with AAV vectors an appropriate next step.

描述(由申请人提供)：这项建议为血友病A的基因治疗的临床试验奠定了基础。在这里，我们集中在具有新衣壳血清型的腺相关病毒(AAV)载体在大型动物模型(即血友病A犬)中用于肝脏导向基因治疗。这项工作建立在我们之前成功地使用两个新的AAV8和AAV9血清型的FVIII基因传递来治疗血友病A鼠的基础上。我们对血友病A犬的研究虽然比较成功，但两种新的AAV血清型也都令人鼓舞。在这项应用中，我们进一步评估这些AAV血清型，首先在重链和轻链载体中传递FVIII基因。我们测试了AAV8和AAV9在两种不同剂量下的反应，并比较了门脉内和静脉给药的途径，然后我们继续开发了一种有效的、更小的、可以产生高滴度的单链载体，并使用血清型、剂量和给药途径的最佳组合来测试这种单链载体。我们还将在最好的条件下对幼犬进行治疗，以努力在严重发病之前开始治疗，并防止用于常规治疗的rFVIII的抑制剂形成。最后，我们将确定是否可以使用与原始病毒注射中使用的载体不同的血清型载体来重新给狗注射FVIII。在所有这些研究中，将做出重大努力来测试新的AAV载体的安全性，集中在中和抗体、转氨炎的发展和病毒的生殖系传播的研究上。在这些研究结束时，我们期望在大型动物血友病A犬身上发现持续产生长期治疗水平的FVIII(&gt；10%)的治疗条件。这些结果应该会使AAV载体的临床试验成为下一步合适的选择。