Pfizer Inc., Cambridge, Massachusetts, USA.
Toxicol Pathol. 2023 Oct;51(7-8):400-404. doi: 10.1177/01926233231201408. Epub 2023 Sep 29.
This article reviews the presentation given at the 2023 annual meeting of the Society of Toxicologic Pathology (STP) on liver toxicity observed with adeno-associated viral vector (AAV) gene therapy. After decades as a therapeutic modality largely confined to the academic research environment, gene therapy has emerged in recent years as a rapidly expanding therapeutic approach in the biopharmaceutical industry with AAV as the most commonly used viral vector for gene delivery. This interest in the field of gene therapy by industry has been enhanced by the recent success of approved therapies for curing genetic diseases such as ZOLGENSMA for spinal muscular atrophy and LUXTURNA for Leber congenital amaurosis. However, recently reported clinical and nonclinical toxicities highlight the challenges in safely developing AAV gene therapies that require high dose systemic administration. The presentation reviewed general attributes of AAV as a gene therapy vector, clinical and nonclinical liver toxicity associated with AAV gene therapy and the potential for a multimodal immune suppression strategy that may mitigate toxicities.
这篇文章回顾了在 2023 年毒理学病理学学会（STP）年会上发表的关于腺相关病毒（AAV）基因治疗中观察到的肝脏毒性的报告。经过几十年作为一种主要局限于学术研究环境的治疗方式，基因治疗近年来已成为生物制药行业中一种快速发展的治疗方法，AAV 作为最常用的基因传递病毒载体。由于最近批准的治疗遗传疾病的疗法取得了成功，如治疗脊髓性肌萎缩症的 ZOLGENSMA 和治疗莱伯先天性黑蒙的 LUXTURNA，行业对基因治疗领域的兴趣有所增强。然而，最近报告的临床和非临床毒性强调了安全开发需要高剂量全身给药的 AAV 基因治疗的挑战。该报告回顾了 AAV 作为基因治疗载体的一般特性、与 AAV 基因治疗相关的临床和非临床肝脏毒性，以及可能减轻毒性的多模式免疫抑制策略的潜力。
