REPEAT DOSING OF ADENO-ASSOCIATED VIRAL VECTORS

在动物和第一次人类研究中，我们的研究小组表明， 单剂量的AAV-CFTR可以应用于鼻上皮，对 人肺的下叶和上颌窦，没有任何 不良影响这些研究和其他几项动物研究 在文献中发表的结果表明，从AAV载体表达的基因 导致在多种组织中持续表达。因此，AAV 载体具有作为治疗剂的巨大潜力。尽管有这些 有希望的研究，在AAV载体之前必须克服几个障碍 将是有用的治疗剂。该补助金将使用以下组合 动物和人类研究，以解决重复的假设， 通过气雾剂递送至气道的AAV-CFTR载体的递送将是 安全并导致重组CFTR表达水平增加。 将讨论三个总体问题。1.将重复 给药AAV载体导致重组表达增加 向量？该目的旨在确定重复给药的影响 在兔支气管镜检查模型中，AAV载体对转基因表达的影响。 预计对这一问题的回答将是关键， 确定载体衣壳蛋白的修饰和/或 在免疫反应中的干预将是必要的， 递送将导致成功的基因表达。2.是气雾剂输送 AV-CFTR是支气管镜输送的实用替代方案？是 在非人类灵长类动物模型中， 将提供启动研究所需的临床前数据， 雾化AAV-CFTR载体在患有CF的患者中的应用。3.气雾剂是否 在CF患者中施用的更高滴度AAV-CFTR载体的递送 导致广泛的基因转移和CFTR 表情？还将特别注意是否重复 在人类中给予AAV-CFTR导致AAV-CFTR的表达增加， 重组载体预计对这一问题的回答将 从而得到用于重组AAV-CFTR实用递送系统。

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.