PHASE I TRIAL OF INTRAMUSCULAR INJECTION OF A RECOMBINANT ADENO-ASSOCIATED VIRUS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 用腺相关病毒(AAV)构建了携带人α1-抗胰蛋白酶(Haat)基因的重组病毒载体，该基因由鸡β肌动蛋白启动子和巨细胞病毒增强子杂交而成。这种结构已经被证明在动物模型中表达HAAT，与拟议的人体试验非常接近。我们团队目前正在进行一项重组腺相关病毒血清2型(RAAV2)-AAT载体的I期安全性和剂量发现研究，该载体通过肌肉注射(IM)给阿尔法1抗胰蛋白酶缺陷(AATD)患者。小鼠的数据表明，如果将这个rAAV-AAT基因盒包装在AAV血清1型(假型)衣壳中，它将产生更高的血清AAT水平。这项拟议的临床试验是一项开放标签的第一阶段研究，研究将rAAV1-CB-HAAT基因载体肌肉注射给符合入选标准的AAT缺陷者。它将覆盖与当前rAAV2-AAT研究相同的剂量范围(每个患者大约2x1012到6.9x1013个载体基因组)。安全参数将包括变化的测量、血清化学和血液学、尿液分析、肺功能测试、精液载体基因组分析、对AAT和AAV的免疫反应，以及报告的任何症状的受试者病史。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. A recombinant virus vector was constructed from adeno associated virus (AAV) that has been altered to carry the human alpha 1-antitrypsin (hAAT) gene expressed from a hybrid chicken beta actin promoter with a cytomegalovirus enhancer. This construct has been shown to express hAAT in animal models closely matching the proposed human trial. Our group is currently performing a phase I safety and dose-finding study of a recombinant adeno-associated virus serotype 2 (rAAV2)-AAT vector given by intramuscular (IM) administration to Alpha 1-Antitrypsin Deficient (AATD) patients. Mouse data suggests that this same rAAV-AAT gene cassette will produce much higher serum levels of AAT if it is packaged in an AAV serotype 1 (pseudotyped) capsid. This proposed clinical trial is an open label, phase I study administering rAAV1-CB-hAAT gene vector intramuscularly to AAT deficient human subjects who meet entry criteria. It will cover the same dose range as the current rAAV2-AAT study (approximately 2x1012 to 6.9x1013 vector genomes per patient. Safety parameters will be measurement of changes, in serum chemistries and hematology, urinalysis, pulmonary function testing, semen assay for vector genomes, immunologic response to AAT and AAV, as well as reported subject history of any symptoms.