Early preclinical studies in rodents and other species did not reveal that vector or transgene immunity would present a significant hurdle for sustained gene expression. While there was early evidence of mild immune responses to adeno-associated virus (AAV) in preclinical studies, it was generally believed that these responses were too weak and transient to negatively impact sustained transduction. However, translation of the cumulative success in treating hemophilia B in rodents and dogs with an AAV2-F9 vector to human studies was not as successful. Despite significant progress in recent clinical trials for hemophilia, new immunotoxicities to AAV and transgene are emerging in humans that require better animal models to assess and overcome these responses. The animal models designed to address these immune complications have provided critical information to assess how vector dose, vector capsid processing, vector genome, difference in serotypes, and variations in vector delivery route can impact immunity and to develop approaches for overcoming pre-existing immunity. Additionally, a comprehensive dissection of innate, adaptive, and regulatory responses to AAV vectors in preclinical studies has provided a framework that can be utilized for development of immunomodulatory therapies to overcome or bypass immune responses and for developing strategic approaches toward engineering stealth AAV vectors that can circumvent immunity.

中文翻译：

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在动物模型中针对AAV载体的免疫反应机制。

早期在啮齿动物和其他物种上的临床前研究并未揭示载体或转基因免疫将为持续基因表达提供重大障碍。尽管在临床前研究中已有对腺伴随病毒（AAV）轻度免疫反应的早期证据，但通常认为这些反应太弱和短暂，不会对持续转导产生负面影响。但是，将用AAV2-F9载体在啮齿动物和狗中治疗B型血友病的累积成功转化为人类研究并不成功。尽管在最近的血友病临床试验中取得了重大进展，但人类仍对AAV和转基因产生了新的免疫毒性，需要更好的动物模型来评估和克服这些反应。为解决这些免疫并发症而设计的动物模型已提供了关键信息，以评估载体剂量，载体衣壳加工，载体基因组，血清型差异和载体传递途径的变化如何影响免疫力，并开发出克服现有免疫力的方法。此外，在临床前研究中对AAV载体的先天性，适应性和调节性反应的全面剖析提供了可用于开发免疫调节疗法以克服或绕过免疫反应的框架，以及可用于开发工程隐身AAV载体的战略方法的框架。规避免疫力。载体传递途径的变化会影响免疫力，并开发出克服现有免疫力的方法。此外，在临床前研究中对AAV载体的先天性，适应性和调节性反应的全面剖析提供了可用于开发免疫调节疗法以克服或绕过免疫反应的框架，以及可用于开发工程隐身AAV载体的战略方法的框架。规避免疫力。载体传递途径的变化会影响免疫力，并开发出克服现有免疫力的方法。此外，在临床前研究中对AAV载体的先天性，适应性和调节性反应的全面剖析提供了可用于开发免疫调节疗法以克服或绕过免疫反应的框架，以及可用于开发工程隐身AAV载体的战略方法的框架。规避免疫力。