Nonclinical strategies and considerations to enable the redosing of gene therapies.

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.