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Review
. 2021 Mar 31:3:618378.
doi: 10.3389/fgeed.2021.618378. eCollection 2021.

Gene Editing of Hematopoietic Stem Cells: Hopes and Hurdles Toward Clinical Translation

Samuele Ferrari  1   2 , Valentina Vavassori  1   2 , Daniele Canarutto  1   2   3 , Aurelien Jacob  1   4 , Maria Carmina Castiello  1   5 , Attya Omer Javed  1 , Pietro Genovese  6   7   8   9
Affiliations
Review

Gene Editing of Hematopoietic Stem Cells: Hopes and Hurdles Toward Clinical Translation

Samuele Ferrari et al. Front Genome Ed. .

Abstract

In the field of hematology, gene therapies based on integrating vectors have reached outstanding results for a number of human diseases. With the advent of novel programmable nucleases, such as CRISPR/Cas9, it has been possible to expand the applications of gene therapy beyond semi-random gene addition to site-specific modification of the genome, holding the promise for safer genetic manipulation. Here we review the state of the art of ex vivo gene editing with programmable nucleases in human hematopoietic stem and progenitor cells (HSPCs). We highlight the potential advantages and the current challenges toward safe and effective clinical translation of gene editing for the treatment of hematological diseases.

Keywords: CRISPR/Cas; gene editing; gene therapy; hematological diseases; hematopoietic stem cell.

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Conflict of interest statement

SF, VV, AJac, MC, and PG are inventors of patent applications on gene editing in HSPCs and cell selection owned and managed by the San Raffaele Scientific Institute and the Telethon Foundation. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Schematic of the main DNA double strand break repair mechanisms in human cells and their possible applications for targeted genome editing. NHEJ pathway engagement may be exploited for knocking-out a gene, correcting a gene by restoring its open reading frame (ORF), inserting a targeted deletion. HDR pathway engagement may be exploited for gene correction of point or multiple mutations, gene addition in a safe harbor locus or targeted transgene expression using endogenous regulatory elements. Mut. GOI, Mutated Gene Of Interest.
Figure 2
Figure 2
Schematic of cellular responses triggered by targeted genome editing in human HSPCs. Gene editing reagents, procedure and ex vivo manipulation may trigger complex cellular responses in HSPCs, ultimately leading to differentiation, cell cycle arrest, senescence, and apoptosis. DDR, DNA Damage Response; PRR, Pattern Recognition Receptor.
Figure 3
Figure 3
Schematic of challenges toward clinical translation of HSPC gene editing for hematological diseases. DP, Drug Product; QA, Quality Assay; QC, Quality Control.
See this image and copyright information in PMC

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