Repeat dosing of adeno-associated viral vectors

腺相关病毒载体的重复给药

• 批准号: 8292955
• 负责人: William B. Guggino
• 金额: $ 18.99万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8292955
• 关键词: Address; Aerosols; Budgets; Chickens; Clinical Trials; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Development; Dose; Epithelium; Gene Expression; Gene Transfer; Genes; Goals; Human; Immune response; Instruction; Lead; Lung; Lung diseases; Primates; Recombinants; Rodent; Serotyping; Testing; Therapeutic Agents; adeno-associated viral vector; beta Actin; cystic fibrosis patients; mRNA Expression; nonhuman primate; pre-clinical; promoter; vector; volunteer

Our lab group demonstrated the first successful CFTR gene transfer by AAV2CFTRto pulmonary epithelium of rodents, non-human primates, and human CF volunteers. We showed that AAV vectors have great potential as gene therapeutic agents. Studies originating from a prior budget period lead to the first use of rAAV in humans. Many pre-clinical and clinical trials showed that AAV vectors can be used safely. However, unlike our results in primates, CFTR mRNA expression has not been demonstrated in human studies. In both non-human primates and humans, transduction requires the instillation of large titers of recombinant AAV2. Thus the goal of current budget period was to evaluate new AAV-CFTRserotypes containing more powerful promoters of CFTR expression. This effort was successful and lead to the choice of AAV1-26-264CFTR driven by a powerful chicken beta actin (CBA) promoter. The overall goal the renewal is to provide the critical next steps in developing AAV1 -CFTR as a therapeutic agent. The hypothesis to be tested is that development of a new AAV1-26-264 vector serotype with CBA promoter delivered to the airways will be safe and result in increased levels of recombinant gene expression. Three overall questions will be addressed. Will dosing with a pseudotyped AAV 1 vector leads to increased expression from the recombinant vector? Will dosing with a pseudotyped AAV 1 vector leads to increased immune response? Does aerosol delivery of new higher titer AAV1-CFTRvectors administered to CF patients with Mild Lung Disease lead to widespread gene transfer and CFTR expression? RELEVANCE (See instructions):

我们的实验室组证明了AAV2CFTRTO肺上皮的第一个成功的CFTR基因转移 啮齿动物，非人类灵长类动物和人类CF志愿者。我们表明AAV矢量很棒 作为基因治疗剂的潜力。源自先前预算期的研究导致首次使用 拉夫在人类中。许多临床前和临床试验表明，可以安全地使用AAV矢量。 但是，与我们在灵长类动物中的结果不同，人类尚未证明CFTR mRNA表达 研究。在非人类灵长类动物和人类中，转导需要大量滴度 重组AAV2。因此，当前预算期的目标是评估新的AAV-CFTRSEROTYPES 包含更强大的CFTR表达启动子。这项努力成功并导致选择 由强大的鸡β肌动蛋白（CBA）发起人驱动的AAV1-26-264CFTR。总体目标 更新将提供作为治疗剂开发AAV1 -CFTR的关键下一步。这 要测试的假设是用CBA启动子开发新的AAV1-26-264矢量血清型 传送到气道将是安全的，并导致重组基因表达水平升高。三 总体问题将被解决。将使用假型AAV 1向量给药会导致增加 重组载体的表达？将使用假型AAV 1向量给药会导致增加 免疫反应？送给CF的新型高滴度AAV1-CFTRVECTOR的气溶胶输送是否会输送 轻度肺部疾病的患者会导致广泛的基因转移和CFTR表达？ 相关性（请参阅说明）：