01 · MechanismLink
How far does DMPK have to fall to correct the splicing?
Human Molecular Genetics ·
Myotonic dystrophy type 1 is driven by expanded (CUG)n DMPK transcripts that sequester MBNL1 and derail splicing. Every antisense programme in the clinic works by lowering DMPK. The field has lacked a clear answer to how far it has to fall.
Using CRISPR activation and interference, the group tuned DMPK in isogenic patient myoblasts carrying around 2,900 triplets. They raised it more than threefold, then cut it by about 80 per cent. Free nucleoplasmic MBNL1 moved with it in both directions. CLASP1 splicing reversed completely. MBNL1 and NFIX corrected only partly. Different exons appear to have different thresholds, rather than there being a single target level.