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作者

Xie Song Zijie Xia Dayne Martinez Bing Xu Zachary Spritzer Yanjie Zhang Erin Nugent Yugong Ho Barbara Terzic Zhaolan Zhou

作者单位

³Department of Urology, The First Affiliated Hospital of Shandong First Medical University & Shandong Qianfoshan Hospital, Shandong Medicine and Health Key Laboratory of Organ Transplantation and Nephrosis, Shandong Institute of Nephrology, Jinan, Shandong 250000, China ¹Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19102, USA ²Department of Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250000, China ⁴Department of Neuroscience, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19102, USA ⁶Lead contact ⁵The Epigenetics Institute, University of Pennsylvania, Philadelphia, PA 19102, USA

刊名

Cell Reports Medicine

年份

2025

页码

101926

ISSN

2666-3791

关键词

CDKL5 deficiency disorder CDD genetic reversal behavioral phenotype learning and memory epilepsy mouse model clinical trial design

摘要

Cyclin-dependent kinase-like 5 deficiency disorder is a neurodevelopmental syndrome caused by mutations in the X-linked CDKL5 gene. The early onset of CDD suggests that CDKL5 is essential during development, but post-developmental re-expression rescues multiple CDD-related phenotypes in hemizygous male mice. Since most patients are heterozygous females, studies in clinically relevant female models are essential. Here, we systematically compare phenotype reversal across age and sex using two in...更多

Cyclin-dependent kinase-like 5 deficiency disorder is a neurodevelopmental syndrome caused by mutations in the X-linked CDKL5 gene. The early onset of CDD suggests that CDKL5 is essential during development, but post-developmental re-expression rescues multiple CDD-related phenotypes in hemizygous male mice. Since most patients are heterozygous females, studies in clinically relevant female models are essential. Here, we systematically compare phenotype reversal across age and sex using two independent mouse models of CDD. We find that early re-activation of endogenous Cdkl5 in heterozygous females reverses most phenotypes, except working memory. Later re-expression improves several traits but has limited effects on cognitive function. Seizure prevention is more effective with early intervention in heterozygous females but becomes limited after seizure onset. These findings demonstrate the robust potential of CDKL5 re-expression to reverse CDD-related phenotypes in both sexes while underscoring the critical impact of age and disease stage in designing clinical trials.收起

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