IMMUNOLOGY AND BIOLOGY OF PEGYLATED ADENOVIRUS AFTER A SINGLE DOSE

单剂量后聚乙二醇化腺病毒的免疫学和生物学

• 批准号: 7716065
• 负责人: Maria A Croyle
• 金额: $ 0.41万
• 依托单位: TEXAS BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7716065
• 关键词: Adenoviruses; Adverse effects; Animal Model; Animals; Antibodies; Biology; Blood Cell Count; Blood Chemical Analysis; Blood specimen; Capsid Proteins; Clinic; Clinical Treatment; Computer Retrieval of Information on Scientific Projects Database; Data; Development; Dose; Funding; Gene Expression; Gene Transfer; Grant; Health; Hereditary Disease; Immune response; Immunology; Institution; Length; Measurement; Mediating; Organ Harvestings; Papio; Patients; Pattern; Performance; Preparation; Prohibit; Research; Research Personnel; Resources; Rodent Model; Silicon Dioxide; Source; Testing; Toxic effect; United States National Institutes of Health; Viral; Virion; Virus; clinical application; cytokine; day; gene delivery system; gene therapy; helper-dependent adenoviral vector; intravenous injection; nonhuman primate; pre-clinical; response; 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. One of the major challenges in the field of gene therapy is the development of efficient and safe gene delivery systems. Although adenoviruses are one of the most extensively studied viruses currently utilized for gene therapy applications, clinical use of these vectors has been limited due to their ability to elicit a strong immune response. This response can compromise the patient's health, limit the length of transgene expression and prohibit gene expression upon re-administration of the virus. Development of "gutted", or helper-dependent, adenoviral (HD-Ad) vectors by removing all viral sequences has significantly reduced the toxicity associated with the virus, but the host response against capsid proteins can still induce severe side effects soon after administration of doses necessary for clinical treatment. This effect is not seen in rodent models commonly used in pre-clinical testing. These effects are, however, quite profound in non-human primates suggesting that this animal model is more suitable for predicting vector performance in the clinic. In these studies, baboons will be given either a low (5 x 1011 virus particles (vp/kg)) intermediate (3 x 1012 vp/kg) or high does (1 x 1013) of PEGylated adenovirus by intravenous injection. Animals receiving similar doses of unmodified virus from the same preparation will serve as controls. Blood samples will be taken prior to administration of virus and for a period of 4 days after administration for blood cell counts, blood chemistry and cytokine analysis sand measurement of anti-adenovirus antibodies. Animals will be euthanized four days after administration of the virus and all organs harvested for assessment of differences in whole-body distribution patterns between unmodified and PEGylated virus. Results from these studies could have significant impact on the use of adenovirus-mediated gene transfer in the clinic. They will also provide valuable preliminary data for additional pre-clinical testing of other modified viruses for the treatment of genetic disease.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 基因治疗领域的主要挑战之一是开发高效和安全的基因递送系统。 虽然腺病毒是目前用于基因治疗应用的最广泛研究的病毒之一，但由于它们引起强烈免疫应答的能力，这些载体的临床使用受到限制。 这种反应可能损害患者的健康，限制转基因表达的长度，并在重新施用病毒时禁止基因表达。 通过去除所有病毒序列而开发的“去内脏”或辅助病毒依赖性腺病毒（HD-Ad）载体显著降低了与病毒相关的毒性，但在施用临床治疗所需的剂量后不久，宿主对衣壳蛋白的应答仍然会诱导严重的副作用。在临床前试验中常用的啮齿动物模型中未观察到该效应。 然而，这些影响在非人灵长类动物中相当深刻，表明该动物模型更适合于预测临床中的载体性能。 在这些研究中，狒狒将通过静脉注射给予低剂量（5 × 1011病毒颗粒（vp/kg））、中等剂量（3 × 1012 vp/kg）或高剂量（1 × 1013）聚乙二醇化腺病毒。 接受来自相同制剂的相似剂量的未修饰病毒的动物将作为对照。 在病毒给药前和给药后4天内采集血样，用于血细胞计数、血液化学和细胞因子分析以及抗腺病毒抗体测量。 在病毒给药后4天对动物实施安乐死，并收获所有器官以评估未修饰病毒和PEG化病毒之间的全身分布模式差异。 这些研究的结果可能会对临床上使用腺病毒介导的基因转移产生重大影响。 它们还将为治疗遗传疾病的其他改良病毒的临床前试验提供宝贵的初步数据。