Safety and efficacy of Igk-TATk-CDKL5 gene therapy in mosaic CDKL5 deficiency.

CDKL5 Deficiency Disorder (CDD) is a severe neurodevelopmental disorder caused by mutations in the X-linked CDKL5 gene, resulting in early-onset seizures, developmental delays, and cognitive and sensorimotor impairments. While emerging therapies show promise, substantial challenges remain in developing a cure for CDD. In our prior work, we developed an innovative gene therapy strategy based on an Igk-TATk-CDKL5 fusion protein, which enhances brain distribution of the therapeutic protein, significantly improving treatment efficacy in a Cdkl5 knockout male mouse model. However, CDKL5 dosage sensitivity may pose challenges in patients with mosaic loss of CDKL5 function, potentially limiting the treatment's effectiveness or even exacerbating clinical symptoms. In this study, we aimed to address this gap by evaluating the safety and efficacy of Igk-TATk-CDKL5 therapy in a heterozygous female mouse model (Cdkl5 +/-), which better represents the majority of human CDD patients. We found that introducing Igk-TATk-CDKL5 significantly improved behavioral phenotypes and corrected brain structural defects, such as dendritic morphology and connectivity. Importantly, no adverse effects were observed in the brain or peripheral organs (e.g., the heart), indicating that CDKL5 overexpression in the heterozygous condition was well tolerated. These findings support the therapeutic potential of Igk-TATk-CDKL5 and suggest that a possible cross-correction mechanism may contribute to its efficacy, even in the context of mosaic CDKL5 deficiency. This approach may therefore offer promising therapeutic outcomes for patients with CDD.