Repeat dosing of adeno-associated viral vectors

腺相关病毒载体的重复给药

• 批准号: 7669749
• 负责人: William B. Guggino
• 金额: $ 19.39万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7669749
• 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):

我们的实验室小组首次成功地通过AAV 2CFTR将CFTR基因转移到肺上皮细胞 啮齿类动物、非人灵长类动物和人类CF志愿者。我们发现AAV载体具有很好的 作为基因治疗剂的潜力。源于上一预算期间的研究导致首次使用 人类中的rAAV。许多临床前和临床试验表明，AAV载体可以安全地使用。 然而，与我们在灵长类动物中的结果不同，CFTR mRNA的表达在人类中尚未得到证实。 问题研究在非人灵长类动物和人类中，转导需要滴注大滴度的 重组AAV 2.因此，本预算期的目标是评估新的AAV-CFTR血清型 含有更强的CFTR表达启动子。这一努力是成功的，并导致选择 AAV 1 -26- 264 CFTR的启动子。总体目标是 更新的目的是为开发AAV 1-CFTR作为治疗剂提供关键的下一步。的 待测试假设是开发具有CBA启动子的新的AAV 1 -26-264载体血清型 递送到气道的重组基因将是安全的，并导致重组基因表达水平的增加。三 将讨论所有问题。用假型化的AAV 1载体给药是否会导致 从重组载体表达？用假型化的AAV 1载体给药是否会导致 免疫反应？向CF施用的新的更高滴度AAV 1-CFTR载体的气雾剂递送 轻度肺病患者导致广泛的基因转移和CFTR表达？ 相关性（参见说明）：