Song Xie, Xia Zijie, Martinez Dayne, Xu Bing, Spritzer Zachary, Zhang Yanjie, Nugent Erin, Ho Yugong, Terzic Barbara, Zhou Zhaolan
Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19102, USA; Department of Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250000, China.
Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19102, USA.
Cell Rep Med. 2025 Feb 18;6(2):101926. doi: 10.1016/j.xcrm.2024.101926. Epub 2025 Jan 23.
Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) 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.
细胞周期蛋白依赖性激酶样5（CDKL5）缺陷障碍（CDD）是一种由X连锁的CDKL5基因突变引起的神经发育综合征。CDD的早期发病表明CDKL5在发育过程中至关重要，但发育后重新表达可挽救半合子雄性小鼠中多种与CDD相关的表型。由于大多数患者是杂合子女性，因此在临床相关的雌性模型中进行研究至关重要。在这里，我们使用两种独立的CDD小鼠模型系统地比较了不同年龄和性别的表型逆转情况。我们发现，杂合子雌性小鼠中内源性Cdkl5的早期重新激活可逆转大多数表型，但工作记忆除外。后期重新表达改善了一些特征，但对认知功能的影响有限。在杂合子雌性小鼠中，早期干预预防癫痫更有效，但癫痫发作后效果会受限。这些发现证明了CDKL5重新表达在逆转两性中与CDD相关表型方面的强大潜力，同时强调了年龄和疾病阶段在设计临床试验中的关键影响。
