Base editing restores CDKL5 expression and rescues neuronal deficits in a patient-derived model of CDKL5 deficiency disorder.

Cyclin-dependent kinase like 5 (CDKL5) deficiency disorder (CDD) is a rare monogenic neurodevelopmental disorder caused by pathogenic mutations in the CDKL5 gene, with approximately 50% of reported variants being point mutations. Base editing presents a promising therapeutic strategy to correct such mutations, restore endogenous CDKL5 expression, and pave the way for novel treatments for CDD. To assess the therapeutic potential of base editing for CDD, we applied adenine base editing (ABE) to correct a CDKL5-R550* (c.1648 C > T) mutation in induced pluripotent stem cells (iPSCs) derived from a CDD patient. Isogenic control, CDKL5-R550* mutant, and ABE-corrected iPSCs were differentiated into neurons and the restoration of CDKL5-related and functional recovery were assessed. In this study, we demonstrated that ABE successfully restored CDKL5 protein levels and CDKL5-dependent signalling pathways in edited iPSC-differentiated neurons to levels comparable to the isogenic control. Morphological deficits, and genes expression were normalized in the ABE-corrected neurons. This study provides evidence that ABE can precisely correct pathogenic mutation and functionally rescue some CDD-associated neuronal phenotypes in patient-derived cells, supporting its potential as a valuable gene therapy for CDD. Moreover, these findings underscore the broader applicability of base editing for treating other monogenic neurodevelopmental disorders caused by point mutations.