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Rationale and strategies for the development of safe and effective optimized AAV vectors for human gene therapy
Molecular Therapy - Nucleic Acids ( IF 6.5 ) Pub Date : 2023-05-17 , DOI: 10.1016/j.omtn.2023.05.014 Arun Srivastava 1
Molecular Therapy - Nucleic Acids ( IF 6.5 ) Pub Date : 2023-05-17 , DOI: 10.1016/j.omtn.2023.05.014 Arun Srivastava 1
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Recombinant adeno-associated virus (AAV) vectors have been, or are currently in use, in 332 phase I/II/III clinical trials in a number of human diseases, and in some cases, remarkable clinical efficacy has also been achieved. There are now three US Food and Drug Administration (FDA)-approved AAV “drugs,” but it has become increasingly clear that the first generation of AAV vectors are not optimal. In addition, relatively large vector doses are needed to achieve clinical efficacy, which has been shown to provoke host immune responses culminating in serious adverse events and, more recently, in the deaths of 10 patients to date. Thus, there is an urgent need for the development of the next generation of AAV vectors that are (1) safe, (2) effective, and (3) human tropic. This review describes the strategies to potentially overcome each of the limitations of the first generation of AAV vectors and the rationale and approaches for the development of the next generation of AAV serotype vectors. These vectors promise to be efficacious at significant reduced doses, likely to achieve clinical efficacy, thereby increasing the safety as well as reducing vector production costs, ensuring translation to the clinic with higher probability of success, without the need for the use of immune suppression, for gene therapy of a wide variety of diseases in humans.
中文翻译：
开发用于人类基因治疗的安全有效的优化 AAV 载体的基本原理和策略
重组腺相关病毒（AAV）载体已经或正在用于多种人类疾病的332项I/II/III期临床试验，在某些情况下也取得了显着的临床疗效。目前美国食品和药物管理局 (FDA) 批准了三种 AAV“药物”，但越来越明显的是，第一代 AAV 载体并不是最佳的。此外，需要相对较大的载体剂量才能实现临床疗效，这已被证明会激发宿主免疫反应，最终导致严重的不良事件，最近迄今为止已导致 10 名患者死亡。因此，迫切需要开发（1）安全、（2）有效、（3）人类亲和性的下一代 AAV 载体。这篇综述描述了潜在克服第一代 AAV 载体的每个局限性的策略以及开发下一代 AAV 血清型载体的基本原理和方法。这些载体有望在显着降低的剂量下有效，可能达到临床疗效，从而提高安全性并降低载体生产成本，确保以更高的成功概率转化到临床，而无需使用免疫抑制，用于人类多种疾病的基因治疗。
更新日期：2023-05-17
中文翻译：
开发用于人类基因治疗的安全有效的优化 AAV 载体的基本原理和策略
重组腺相关病毒（AAV）载体已经或正在用于多种人类疾病的332项I/II/III期临床试验，在某些情况下也取得了显着的临床疗效。目前美国食品和药物管理局 (FDA) 批准了三种 AAV“药物”，但越来越明显的是，第一代 AAV 载体并不是最佳的。此外，需要相对较大的载体剂量才能实现临床疗效，这已被证明会激发宿主免疫反应，最终导致严重的不良事件，最近迄今为止已导致 10 名患者死亡。因此，迫切需要开发（1）安全、（2）有效、（3）人类亲和性的下一代 AAV 载体。这篇综述描述了潜在克服第一代 AAV 载体的每个局限性的策略以及开发下一代 AAV 血清型载体的基本原理和方法。这些载体有望在显着降低的剂量下有效，可能达到临床疗效，从而提高安全性并降低载体生产成本，确保以更高的成功概率转化到临床，而无需使用免疫抑制，用于人类多种疾病的基因治疗。
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