Therapeutic gene editing: delivery and regulatory perspectives

Abstract

Gene-editing technology is an emerging therapeutic modality for manipulating the eukaryotic genome by using target-sequence-specific engineered nucleases. Because of the exceptional advantages that gene-editing technology offers in facilitating the accurate correction of sequences in a genome, gene editing-based therapy is being aggressively developed as a next-generation therapeutic approach to treat a wide range of diseases. However, strategies for precise engineering and delivery of gene-editing nucleases, including zinc finger nucleases, transcription activator-like effector nuclease, and CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats-associated nuclease Cas9), present major obstacles to the development of gene-editing therapies, as with other gene-targeting therapeutics. Currently, viral and non-viral vectors are being studied for the delivery of these nucleases into cells in the form of DNA, mRNA, or proteins. Clinical trials are already ongoing, and in vivo studies are actively investigating the applicability of CRISPR/Cas9 techniques. However, the concept of correcting the genome poses major concerns from a regulatory perspective, especially in terms of safety. This review addresses current research trends and delivery strategies for gene editing-based therapeutics in non-clinical and clinical settings and considers the associated regulatory issues.

Figure 1

Gene-editing nucleases. Gene-editing nucleases include ZFN (A), TALEN (B), and CRISPR/Cas9 (C).

Figure 2

Therapeutic gene-editing strategies. A schematic depiction of in vivo and ex vivo gene editing is shown. For in vivo gene editing, viral or non-viral vectors carrying nucleases are directly injected into the body. For ex vivo gene editing, the target cells are isolated and gene-edited with viral or non-viral vectors carrying nucleases, after which gene-edited cells are expanded and reinfused into the body.

Figure 3

Current status of gene-editing studies in non-clinical development. Therapeutic gene editing in non-clinical development, analyzed by country (A), target disease (B), editing type (C), and nuclease type (D).

Figure 4

Delivery strategies for gene-editing studies in non-clinical development. Therapeutic gene editing in non-clinical development, analyzed based on delivery strategy (A), viral vector type (B), and non-viral type (C).

Figure 5

Current status of therapeutic gene editing clinical trials. Clinical studies of therapeutic gene editing, analyzed by phase (A), country (B), delivery vector (C), editing strategy (D), nuclease type (E), and target gene (F).