Novel gene-editing technologies: applications of CRISPR-Cas9, base editing, and prime editing in SCID gene therapy

Abstract

The use of autologous haematopoietic stem cell gene therapy is increasingly recognised as a promising treatment option for severe combined immunodeficiency diseases (SCID). This approach seeks to correct the underlying genetic cause of SCID conditions, potentially allowing a single treatment to restore a healthy immune system for the lifespan of the patient. To date, such gene therapy has relied on the use of gamma-retroviruses or lentiviruses to deliver genetic material to a patient’s haematopoietic stem cells before reinfusion. This approach has had notable successes in the clinic for conditions including X-linked severe combined immunodeficiency (SCID-X1), Artemis-SCID, and adenosine deaminase-SCID. However, significant hurdles have been met when using viral-mediated gene addition, primarily linked to the potential risk of insertional mutagenesis; however, for certain SCID forms, there are also limitations associated with the regulation and levels of gene expression achievable. This has driven the development of new gene editing technologies for the treatment of SCID conditions. CRISPR (clustered regularly interspaced short palindromic repeats)-Cas9 (CRISPR-associated protein 9), base editing and prime editors are all actively under investigation, mainly in the preclinical stage to understand their potential applications. In this review, we explore gene editing approaches that are in development for the treatment of SCID. While initial results look promising, significant challenges need to be overcome before their clinical use. Such technologies represent an exciting new wave of treatment options for SCID patients.

Keywords

SCID / gene therapy / autologous stem cell transplant / haematopoietic stem progenitor cells / gene editing / CRISPR-Cas9 / base editors / prime editing

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