Viral vector-based gene therapies in the clinic

Abstract

Gene therapies are currently one of the most investigated therapeutic modalities in both the preclinical and clinical settings and have shown promise in treating a diverse spectrum of diseases. Gene therapies aim at introducing a gene material in target cells and represent a promising approach to cure diseases that were thought to be incurable by conventional modalities. In many cases, a gene therapy requires a vector to deliver gene therapeutics into target cells; viral vectors are among the most widely studied vectors owing to their distinguished advantages such as outstanding transduction efficiency. With decades of development, viral vector-based gene therapies have achieved promising clinical outcomes with many products approved for treating a range of diseases including cancer, infectious diseases and monogenic diseases. In addition, a number of active clinical trials are underway to further expand their therapeutic potential. In this review, we highlight the diversity of viral vectors, review approved products, and discuss the current clinical landscape of in vivo viral vector-based gene therapies. We have reviewed 13 approved products and their clinical applications. We have also analyzed more than 200 active trials based on various viral vectors and discussed their respective therapeutic applications. Moreover, we provide a critical analysis of the major translational challenges for in vivo viral vector-based gene therapies and discuss possible strategies to address the same.

Keywords: adenovirus; adeno‐associated virus; clinical translation; clinical trials; gene; gene therapy; gene transfer; herpes simplex virus; viral vector.

FIGURE 1

Major clinically relevant viral vectors and active clinical trials analyzed in this review. Structure of representative viral capsids (AAV, Ad, HSV and retrovirus) reconstructed from Cryo‐EM was presented. Images of structure of viral capsids were adapted/reprinted from the following literature: adeno‐associated virus, adapted from Reference ; Ad, reprinted from Reference ; HSV, reprinted from Reference with permission from the American Association for the Advancement of Science; retrovirus, reprinted from Reference

FIGURE 2

Clinical landscape of viral vector‐based in vivo gene therapies. Overview of current clinical trials based on (a) phase, (b) vector type, (c) administration method, and (d) indication

FIGURE 3

Landscape of adeno‐associated virus‐based in vivo gene therapy clinical trials. A total of 137 active clinical trials were identified and further analyzed according to (a) phase, (b) serotype, and (c) indication

FIGURE 4

Landscape of adenovirus‐based in vivo gene therapy clinical trials. A total of 83 active clinical trials were identified and further analyzed according to (a) phase, (b) serotype, and (c) indication

FIGURE 5

Landscape of herpes simplex virus‐based in vivo gene therapy clinical trials. A total of 46 active clinical trials were identified and further analyzed according to (a) phase, (b) serotype, and (c) indication