绕过B细胞反应以允许AAV载体的重投。

IF 3.9 3区 医学 Q2 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Human gene therapy Pub Date : 2024-07-01 Epub Date: 2023-12-06 DOI:10.1089/hum.2023.162
Hildegund C J Ertl
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引用次数: 0

摘要

腺相关病毒(AAV)介导的基因治疗在过去几十年中取得了重大进展。然而,免疫系统带来的挑战依然存在。用于某些疾病的非常高剂量的AAV载体已导致严重不良事件(SAE)甚至死亡,这表明可以安全注射到患者体内的AAV矢量剂量是有限的,并且对于某些适应症,AAV矢量的剂量低于治疗剂量。目前使用的免疫抑制药物并没有预防严重急性呼吸系统综合征,这表明,谨慎的治疗方法可能是反复转移中等剂量的患者,而不是单次注射高剂量的AAV载体。前一种方法已被避免,因为AAV载体会引发中和抗体,从而阻止血清学交叉反应载体的成功再应用。因此,需要开发阻断B细胞对腺相关病毒(AAV)载体反应的免疫抑制方案或去除AAV中和抗体的治疗方法,以允许从AAV载体的毒性单剂量注射转向更温和和安全剂量的重复治疗。预防或阻断抗体反应还可以使转基因产物表达下降的患者重做,或将AAV介导的基因有效转移到已有中和抗体的患者体内。
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Circumventing B Cell Responses to Allow for Redosing of Adeno-Associated Virus Vectors.

Adeno-associated virus (AAV)-mediated gene therapy has made significant progress in the last few decades. Nevertheless, challenges imposed by the immune system remain. The very high doses of AAV vectors used for some disorders have resulted in serious adverse events (SAEs) or even deaths, demonstrating that AAV vector doses that can safely be injected into patients are limited and for some indications below the therapeutic dose. Currently used immunosuppressive drugs have not prevented the SAEs, indicating that it may be prudent to treat patients with repeated transfer of moderate doses rather than a single injection of high doses of AAV vectors. The former approach has been avoided as AAV vectors elicit neutralizing antibodies that prevent successful reapplication of serologically crossreactive vectors. Immunosuppressive regimens that block B cell responses to AAV vectors or treatments that remove AAV neutralizing antibodies thus need to be developed to allow for a shift from toxic single-dose injections of AAV vectors to repeated treatments with more moderate and safe doses. Preventing or blocking antibody responses would also allow for redosing of patients with declining transgene product expression, or for effective AAV-mediated gene transfer into patients with the pre-existing neutralizing antibodies.

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来源期刊
Human gene therapy
Human gene therapy 医学-生物工程与应用微生物
CiteScore
6.50
自引率
4.80%
发文量
131
审稿时长
4-8 weeks
期刊介绍: Human Gene Therapy is the premier, multidisciplinary journal covering all aspects of gene therapy. The Journal publishes in-depth coverage of DNA, RNA, and cell therapies by delivering the latest breakthroughs in research and technologies. Human Gene Therapy provides a central forum for scientific and clinical information, including ethical, legal, regulatory, social, and commercial issues, which enables the advancement and progress of therapeutic procedures leading to improved patient outcomes, and ultimately, to curing diseases.
期刊最新文献
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