Moffit Jeffrey S, Alatsis Kathila R, Blanset Diann L, Buss Nicholas, Rana Payal
Carbon Biosciences, Waltham, MA 02451, USA.
Spark Therapeutics, Philadelphia, PA 19104, USA.
Mol Ther Methods Clin Dev. 2025 Jun 25;33(3):101520. doi: 10.1016/j.omtm.2025.101520. eCollection 2025 Sep 11.
Adeno-associated viral therapies offer the potential for many years of gene expression, yet some patients could benefit from subsequent doses to achieve or maintain an effective response. Reasons for inadequate or waning efficacy include immune response to the vector or transgene, insufficient dose for ideal therapeutic expression, and waning expression. Strategies to overcome these factors are needed to maximize the benefits of gene therapy through redosing of patients who did not fully benefit from a single dose. Maintenance dosing is also important to counteract any decrease in efficacy caused by cell turnover or disease progression. Current gene therapies administered systemically cannot be readministered due to an immune response against the delivery vector. The immune response can eliminate the vector from circulation, targeting transduced cells for removal and/or can lead to adverse immune reactions. However, new immune modifying techniques and emerging delivery platforms are being developed to overcome these limitations. Despite these advances, there is currently no regulatory guidance on how to design nonclinical studies to enable clinical redosing. This article provides an overview of potential therapeutic approaches to address redosing and proposes nonclinical strategies to support clinical development of gene therapies intended for repeated administration.
腺相关病毒疗法具有实现多年基因表达的潜力，但一些患者可能需要后续剂量才能实现或维持有效的反应。疗效不足或减弱的原因包括对载体或转基因的免疫反应、理想治疗性表达的剂量不足以及表达减弱。需要克服这些因素的策略，以通过对未从单剂量中充分获益的患者重新给药来最大化基因治疗的益处。维持给药对于抵消因细胞更新或疾病进展导致的疗效降低也很重要。目前，由于针对递送载体的免疫反应，全身性给药的现有基因疗法无法再次给药。免疫反应可将载体从循环中清除，靶向转导细胞以进行清除和/或可导致不良免疫反应。然而，正在开发新的免疫调节技术和新兴的递送平台来克服这些限制。尽管取得了这些进展，但目前尚无关于如何设计非临床研究以实现临床重新给药的监管指南。本文概述了应对重新给药的潜在治疗方法，并提出了支持旨在重复给药的基因疗法临床开发的非临床策略。
