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

Overview

1. School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, SAR China
2. Shenzhen Key Laboratory of Translational Research for Brain Diseases, The Brain Cognition and Brain Disease Institute, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen-Hong Kong Institute of Brain Science—Shenzhen Fundamental Research Institutions, Shenzhen, China
3. Guangdong Provincial Key Laboratory of Brain Science, Disease and Drug Development, HKUST Shenzhen Research Institute, Shenzhen, China
4. Division of Life Science, The Hong Kong University of Science and Technology, Hong Kong, SAR China
5. CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, China
6. Gerald Choa Neuroscience Institute, The Chinese University of Hong Kong, Hong Kong, SAR China

Abstract

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.

Supplementary Information: The online version contains supplementary material available at 10.1038/s41598-026-48097-y.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data

Datasets cited

• geo:GSE325168, at NCBI GEO; found in “Data availability”

Data availability

The datasets generated and analysed during the current study are available in the Gene Expression Omnibus (GEO) repository (Accession No: GSE325168 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE325168)).

Reproduced under the paper's license (CC BY), from the paper cited above.

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Version 1, 29 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 9 authors, 8 keywords, 9 MeSH terms, 5 funders, 47 references.

Cite

This paper

Chai, Y., Zhu, Y., Zhu, J., Guan, M., Zheng, Z., Chen, Y., Tsang, H. W. S., Ye, T., & Ip, J. P. K. (2026). Base editing restores CDKL5 expression and rescues neuronal deficits in a patient-derived model of CDKL5 deficiency disorder. Scientific reports, 16(1), 16151. https://doi.org/10.1038/s41598-026-48097-y

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