ArticleNeurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics2022
Expression of a Secretable, Cell-Penetrating CDKL5 Protein Enhances the Efficacy of Gene Therapy for CDKL5 Deficiency Disorder.
Article in Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 23 citations in OpenAlex.
- Ganaxolone, an approved therapy for CDKL5-deficiency disorder, is an inhibitor of PTP1B.The Journal of biological chemistry · 2026Article
- Article
- The delivery challenge of adeno-associated virus vector-based gene therapies for neurological diseases.Frontiers in neuroscience · 2026Review
- Safety and efficacy of Igk-TATk-CDKL5 gene therapy in mosaic CDKL5 deficiency.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2025Article
- Xist condensates: perspectives for therapeutic intervention.Genome biology · 2025Review
- Adult-Onset Deletion of CDKL5 in Forebrain Glutamatergic Neurons Impairs Synaptic Integrity and Behavior in Mice.International journal of molecular sciences · 2025Article
- Article
- Characterisation of sleep apneas and respiratory circuitry in mice lacking CDKL5.Journal of sleep research · 2025Article
- Beneficial Antioxidant Effects of Coenzyme Q10 in In Vitro and In Vivo Models of CDKL5 Deficiency Disorder.International journal of molecular sciences · 2025Article
- A cross-correction gene therapy approach for CDKL5 deficiency disorder improves the pathological phenotype of CDD patient-derived cortical organoids.Frontiers in bioengineering and biotechnology · 2025Article
- Detection of central and obstructive sleep apneas in mice: A new surgical and recording protocol.PloS one · 2025Article
- Effects of a ciliary neurotrophic factor (CNTF) small-molecule peptide mimetic in an in vitro and in vivo model of CDKL5 deficiency disorder.Journal of neurodevelopmental disorders · 2024Article
- Article
- Preclinical studies of gene replacement therapy for CDKL5 deficiency disorder.Molecular therapy : the journal of the American Society of Gene Therapy · 2024Article
- Voluntary Running Improves Behavioral and Structural Abnormalities in a Mouse Model of CDKL5 Deficiency Disorder.Biomolecules · 2023Article
- Novel Cross-Correction-Enabled Gene Therapy for CDKL5-Deficiency Disorder.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2022Article
- Novel advanced patient-derivedFrontiers in neurologyReview
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Authors and funding
20 authors at 7 institutions in 3 countries.
Funding
Abstract
Although delivery of a wild-type copy of the mutated gene to cells represents the most effective approach for a monogenic disease, proof-of-concept studies highlight significant efficacy caveats for treatment of brain disorders. Herein, we develop a cross-correction-based strategy to enhance the efficiency of a gene therapy for CDKL5 deficiency disorder, a severe neurodevelopmental disorder caused by CDKL5 gene mutations. We created a gene therapy vector that produces an Igk-TATk-CDKL5 fusion protein that can be secreted via constitutive secretory pathways and, due to the cell-penetration property of the TATk peptide, internalized by cells. We found that, although AAVPHP.B_Igk-TATk-CDKL5 and AAVPHP.B_CDKL5 vectors had similar brain infection efficiency, the AAVPHP.B_Igk-TATk-CDKL5 vector led to higher CDKL5 protein replacement due to secretion and penetration of the TATk-CDKL5 protein into the neighboring cells. Importantly, Cdkl5 KO mice treated with the AAVPHP.B_Igk-TATk-CDKL5 vector showed a behavioral and neuroanatomical improvement in comparison with vehicle or AAVPHP.B_CDKL5 vector-treated Cdkl5 KO mice. In conclusion, we provide the first evidence that a gene therapy based on a cross-correction approach is more effective at compensating Cdkl5-null brain defects than gene therapy based on the expression of the native CDKL5, opening avenues for the development of this innovative approach for other monogenic diseases.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.