iPSC clones show variations in differentiation efficiency, including clones derived from the same person119. These variations are important to consider when selecting control groups for disease modeling studies. Applying CRISPR/Cas9 technology may help address this issue, as discussed above. Multiple reports have now shown that gene correction of an iPSC mutation improves the disease phenotype of differentiated cells175–178. In addition to correcting gene mutations in disease iPSCs, researchers have also successfully introduced gene mutations into healthy iPSCs87,88. Although several challenges for the combination of CRISPR/Cas9 technology with iPSC technology remain, including the off-target effects of CRISPR/Cas9 editing, the high cost of assaying for them, and the limited application of gene editing to genetic diseases with unknown disease-causing mutations or risk variants14, the potential of this combiniation to dissect disease mechanisms and to develop novel cell therapies is high. Moreover, CRISPR/Cas9 or CRISPRi-based genome-wide genetic screening179,180 in human iPSCs could open a new avenue for understanding basic biological mechanisms underlying human iPSC pluripotency, maintenance and differentiation.
