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的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 从腺相关病毒（AAV）构建重组病毒载体，所述腺相关病毒（AAV）已被改变以携带从具有巨细胞病毒增强子的杂合鸡β肌动蛋白启动子表达的人α 1-抗胰蛋白酶（hAAT）基因。该构建体已显示在与所提出的人体试验紧密匹配的动物模型中表达hAAT。我们的小组目前正在进行一项I期安全性和剂量探索研究，研究重组腺相关病毒血清型2（rAAV 2）-AAT载体通过肌内（IM）给药α 1-抗胰蛋白酶缺乏症（AATD）患者。 小鼠数据表明，如果将相同的rAAV-AAT基因盒包装在AAV血清型1（假型化）衣壳中，则其将产生高得多的AAT血清水平。 该临床试验是一项开放标签的I期研究，将rAAV 1-CB-hAAT基因载体肌内给予符合入选标准的AAT缺陷型人类受试者。 它将涵盖与当前rAAV 2-AAT研究相同的剂量范围（每例患者约2x 1012至6.9x1013个载体基因组）。 安全性参数将是血清化学和血液学、尿分析、肺功能检测、载体基因组的精液测定、对AAT和AAV的免疫应答以及报告的任何症状的受试者病史的变化的测量。

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.