DELIVERY OF HD-AD VECTORS TO PRIMATE LUNG

将 HD-AD 载体递送至灵长类动物肺部

• 批准号: 7957892
• 负责人: Philip Ng
• 金额: $ 8.23万
• 依托单位: TEXAS BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-06 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7957892
• 关键词: Acetic Acids; Adenovirus Vector; Animals; Autopsy; Blood Tests; Bronchoscopes; Cells; Chemical Agents; Chest; Complex; Computer Retrieval of Information on Scientific Projects Database; Dose; Egtazic Acid; Funding; Gene Delivery; Genes; Grant; Human; Inflammation; Inflammatory Response; Institution; Liver; Location; Lung; Methods; Mus; Organ; Papio; Primates; Procedures; Proteins; Recovery; Research; Research Personnel; Resources; Source; Surface; Time; United States National Institutes of Health; Upper Respiratory Infections; Viral Vector; Virus; alpha-Fetoproteins; beta-Galactosidase; flexibility; gene delivery system; lymph nodes; pre-clinical; research study; transgene expression; vector

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. In this study, baboons will be treated with a new form of gene delivery system in an attempt to produce new gene products in the cells of the airways. The gene delivery vehicle is a modified virus vector expressing common protein marker genes (beta-galactosidase (Bgal) or the baboon alpha fetoprotein (AFB) gene). Adenovirus vectors are modified versions of a common virus usually responsible for upper respiratory infections in humans. The new vector to be used in these trials has been delivered to the livers and lungs of mice, and to the livers of some primates, with very promising results. Expression of the newly introduced genes has lasted for much longer periods of time in studies with the previous vectors, and the inflammatory response has been greatly reduced. We will begin to study the use of these new vectors in the lungs, which are very complex and immunologically active organs. Animals will first be treated with a chemical agent called EGTA (n-tetra acetic acid), which relaxes in the cells of the airway surface to help them take up the virus, and then with a viral vector, which will be delivered directly to the airways using a flexible fiberoptic bronchoscope. After recovery, the animals will undergo serial chest radiographs and several blood tests, but there will be no further invasive procedures until sacrifice. The animals will be necropsied so that the location and degree of transgene expression in the lungs can be evaluated. We will also examine the animals carefully for evidence of inflammation in the lungs and regional lymph nodes, and for expression of the transgene in locations other than the lung. The use of the Bgal vector will allow us to examine the distribution of transgene expression with the greatest accuracy. AFB expressing vector will be a better indicator of vector-associated inflammation or duration of expression, and will allow us to track the true extent of vector-associated inflammation. These experiments will help determine the appropriate doses, timing and delivery methods for further preclinical and human trials of pulmonary gene delivery using these agents.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 在这项研究中，将使用一种新形式的基因递送系统处理狒狒，以试图在气道细胞中产生新的基因产物。 基因递送载体是一种表达常见蛋白质标记基因（β-半乳糖苷酶（BGAL）或狒狒α胎儿蛋白（AFB）基因）的改性病毒载体。 腺病毒载体是通常导致人类上呼吸道感染的常见病毒的修饰版本。 这些试验中要使用的新载体已交付给小鼠的肝脏和肺，以及一些灵长类动物的肝脏，结果非常有前途。 在与先前的载体的研究中，新引入的基因的表达持续了很长时间，并且炎症反应大大降低。我们将开始研究这些新向量在肺中的使用，这些向肺部非常复杂且具有免疫学上的器官。 动物将首先用称为EGTA（N-tetra乙酸）的化学剂处理，该化学剂在气道表面的细胞中放松，以帮助它们吸收病毒，然后再用病毒载体，该病毒载体将使用柔性纤维支气管镜直接传递到气道。 恢复后，动物将经历连续的胸部X光片和几次血液检查，但是在牺牲之前，将没有进一步的侵入性手术。 这些动物将被刺穿，以便可以评估转基因表达的位置和程度。 我们还将仔细检查动物是否有肺和区域淋巴结炎症的证据，并在肺以外的其他位置表达转基因。 BGAL载体的使用将使我们能够以最高的精度检查转基因表达的分布。 AFB表达载体将是载体相关炎症或表达持续时间的更好指标，并使我们能够跟踪与载体相关的炎症的真实程度。 这些实验将有助于确定使用这些药物进一步临床前和人类试验的临床前和人类试验的适当剂量，时机和递送方法。