Gene Editing for the Treatment of Primary Immunodeficiency Diseases

Abstract

With conventional treatments for primary immunodeficiency diseases (PIDs), such as allogeneic stem cell transplantation or autologous gene therapy, still facing important challenges, the rapid development of genome editing technologies to more accurately correct the mutations underlying the onset of genetic disorders has provided a new alternative, yet promising platform for the treatment of such diseases. The prospect of a more efficient and specific therapeutic tool has pushed many researchers to apply these editing tools to correct genetic, phenotypic, and functional defects of numerous devastating PIDs with extremely promising results to date. Despite these achievements, lingering concerns about the safety and efficacy of genome editing are currently being addressed in preclinical studies. This review summarizes the progress made toward the development of gene editing technologies to treat PIDs and the optimizations that still need to be implemented to turn genome editing into a next-generation treatment for rare monogenic life-threatening disorders.

Keywords: blood disorders; gene editing; primary immunodeficiency diseases.

Figure 1.

HDR-mediated genome editing strategies to achieve physiological expression of the correct gene. Gene editing platforms, such as ZFNs, TALENs, and CRISPR/Cas9, are delivered to the target cell in either a plasmid, RNA, and/or protein format (blue box). Strategies to introduce these reagents into the cells include electroporation, viral vectors, and lipid nanoparticles (purple box). Once the endonucleases reach the cell nucleus, upon binding to the DNA, they induce double-strand breaks (blue scissors) at specific sites. Two major HDR-based strategies can be implemented to revert a disease phenotype caused by a genetic mutation (red spark), while preserving endogenous regulation and wild-type levels of expression of the correct protein. In the case of gene correction, the delivery of a mini-gene or a ssODN donor template can replace small fragments of the mutated region or correct a few base-pair mutation. In the case of gene insertion, a wild-type cDNA donor template can be knocked-in close to or in frame with the translation start codon (ATG) of the mutated gene. Both strategies will result in the functional restoration of regulated and physiological protein expression, driven by endogenous transcriptional and post-transcriptional regulatory regions. CRISPR/Cas9, clustered regularly interspaced short palindromic repeats/associated Cas9 nuclease; HDR, homology directed repair; ssODN, single-strand oligo DNA; TALEN, transcription activator effector nuclease; ZFN, zinc finger nuclease. Color images are available online.