Gene manipulation approaches to curing genetic disease. (A) Gene addition. Usually a viral vector such as a modified lentivirus containing a copy of the corrected gene is incubated with autologous hematopoietic stem and progenitor cells. In transduced cells, nucleic acid including the corrected gene is randomly integrated into the host genome, and normal protein is produced. (B) Gene editing. CRISPR/Cas9 induce DNA double strand breaks at targeted sites, which include the mutated gene of interest and promotors. Using a donor DNA template containing the rectified gene sequence, the ubiquitous homology-directed repair machinery corrects the defect, leaving the normal gene in situ. (C) Gene silencing. Rather than correct a mutated gene, in a dominant gain-of-function genetic disease, correction may be achieved by silencing the mutated gene, leaving restoration of normal function, on condition that haploinsufficiency of the gene does not cause disease. ∗, WHIM mutation location in Cxcr4. cDNA, complementary DNA; DSB, double strand break; HDR, homology-directed repair; HSC, hematopoietic stem cell; PAM, protospacer adjacent motif; sgRNA, single guide RNA; WT, wild type. See Figure 1A in the article by Gao et al that begins on page 23. Professional illustration by Patrick Lane, ScEYEnce Studios.