REPEAT DOSING OF ADENO-ASSOCIATED VIRAL VECTORS

在动物和第一次人类研究中，我们的团队表明 单剂AAV-CFTR可以应用于鼻黏膜上皮，对吗？ 人类肺的下叶和上颌窦，没有任何 不良影响。这些研究和其他几项动物研究 发表在文献中的研究表明，Gen是由AAV载体表达的 导致在各种组织中持续表达。因此，AAV 载体作为治疗剂具有很大的潜力。尽管如此 前景看好的研究，在AAV载体之前必须克服几个障碍 将是有用的治疗剂。这笔赠款将使用以下组合 动物和人体研究，以解决重复的假设 通过气雾剂向呼吸道交付AAV-CFTR载体将是 安全，并导致重组CFTR表达水平增加。 有三个总体问题将得到解决。1.将重复 用AAV载体诱导重组蛋白的表达增加 向量？这个目的是为了确定重复给药的效果。 在兔支气管镜检查模型中AAV载体对转基因表达的影响。 预计这个问题的答案将在 确定载体衣壳蛋白和/或 在反复发作之前，有必要对免疫反应进行干预。 基因的传递将导致基因的成功表达。2.是气雾剂输送吗？ AV-CFTR是支气管镜分娩的实用替代方法吗？它是 在非人类灵长类动物模型中预测到了这个问题的答案 将提供启动研究所需的临床前数据 雾化AAV-CFTR载体在慢性粒细胞白血病患者中的应用3.气溶胶有没有 高滴度AAV-CFTR载体在慢性粒细胞白血病患者中的应用 轻度肺部疾病导致广泛的基因转移和CFTR 表情？还将特别注意是否会重复 AAV-CFTR在人体内的剂量导致AAV-CFTR表达增加 重组载体。预计这个问题的答案将是 构建了一种实用的重组AAV-CFTR递送系统。

In animals and in the first human studies, our group showed that a single dose of AAV-CFTR could be applied to the nasal epithelium, right lower lobe of the human lung, and the maxillary sinus, without any adverse effects. These studies and several other animal studies published in the literature showed that gen expressed from AAV vectors result in persistent expression in a variety of tissues. Thus, AAV vectors have great potential as therapeutic agents. Despite these promising studies, several hurdles must be overcome before AAV vectors will be useful therapeutic agents. This grant will use a combination of animal and human studies to address the hypothesis that repeated delivery of AAV-CFTR vectors via aerosol delivery to the airways will be safe and result in increased levels of recombinant CFTR expression. There are three overall questions that will be addressed. 1. Will repeat dosing with AAV-vectors lead to increased expression of the recombinant vector? This aim is designed to determine the effects of repeated dosing of AAV-vectors on transgene expression, in a rabbit bronchoscopy model. It is anticipated that answers to this question will be critical in determining whether modification of vector capsid proteins and/or interventions in the immune response will be necessary before repeated delivery will lead to successful gene expression. 2. Is aerosol delivery of AV-CFTR a practical alternative to bronchoscopic delivery? It is anticipated that answers to this question in a non-human primate model will provide the pre-clinical data necessary to launch a study of aerosolized AAV-CFTR vector in patients with CF. 3. Does aerosol delivery of higher titer AAV-CFTR vectors administered in CF patients with Mild Lung Disease lead to widespread gene transfer and CFTR expression? Particular attention will also be given to whether repeat dosing for AAV-CFTR in humans leads to increased expression of the recombinant vector. It is expected that answers to this question will lead to a practical delivery system for recombinant AAV-CFTR.