Figure 1.

The path from a lethal mutation to a CRISPR therapeutic

(A) The genic context of, and genome editing reagents for, the mutation that killed the infant treated by Lev et al.⁷ The mutation (mutant allele, shown, is an A; wild-type allele is a G) drives aberrant splicing of LCP2 (genomic coordinates in hg38 are indicated). The gRNA spacer for DSB-driven editing and the cognate ODN repair template,⁸ are shown below the sequence. The ODN specifies the correct allele (highlighted in red); the ODN does not contain a “PAM-blocking” mutation because the SNP lies in the “seed” region. (B) An accelerated timeline to engineering, derisking, and putting through regulatory review an edited HPSC product to treat terminally ill pediatric subjects such as the one described by Lev et al.⁷ Every step in the process will require formidable scientific and regulatory innovation; a realistic, actionable path to such innovation exists across the entire problem space.