Expression of a Secretable, Cell-Penetrating CDKL5 Protein Enhances the Efficacy of Gene Therapy for CDKL5 Deficiency Disorder
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Published:2022-09-15
Issue:6
Volume:19
Page:1886-1904
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ISSN:1933-7213
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Container-title:Neurotherapeutics
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language:en
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Short-container-title:Neurotherapeutics
Author:
Medici Giorgio, Tassinari Marianna, Galvani Giuseppe, Bastianini Stefano, Gennaccaro Laura, Loi Manuela, Mottolese Nicola, Alvente Sara, Berteotti Chiara, Sagona Giulia, Lupori Leonardo, Candini Giulia, Baggett Helen Rappe, Zoccoli Giovanna, Giustetto Maurizio, Muotri Alysson, Pizzorusso Tommaso, Nakai Hiroyuki, Trazzi Stefania, Ciani ElisabettaORCID
Abstract
AbstractAlthough 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.
Funder
Fondazione Telethon Fondation Jérôme Lejeune Orphan Disease Center, Perelman School of Medicine, University of Pennsylvania Alma Mater Studiorum - Università di Bologna
Publisher
Springer Science and Business Media LLC
Subject
Pharmacology (medical),Neurology (clinical),Pharmacology
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