Gene therapy decreases seizures in a model of Incontinentia pigmenti

Godwin K. Dogbevia; Kathrin Töllner; Jakob Körbelin; Sonja Bröer; Dirk A. Ridder; Hanna Grasshoff; Claudia Brandt; Jan Wenzel; Beate K. Straub; Martin Trepel; Wolfgang Löscher; Markus Schwaninger

doi:10.1002/ana.24981

Gene therapy decreases seizures in a model of Incontinentia pigmenti

Godwin K. Dogbevia, Kathrin Töllner, Jakob Körbelin, Sonja Bröer, Dirk A. Ridder, Hanna Grasshoff, Claudia Brandt, Jan Wenzel, Beate K. Straub, Martin Trepel, Wolfgang Löscher, Markus Schwaninger^*

^*Korrespondierende/r Autor/-in für diese Arbeit

26 Zitate (Scopus)

Abstract

Objective: Incontinentia pigmenti (IP) is a genetic disease leading to severe neurological symptoms, such as epileptic seizures, but no specific treatment is available. IP is caused by pathogenic variants that inactivate the Nemo gene. Replacing Nemo through gene therapy might provide therapeutic benefits. Methods: In a mouse model of IP, we administered a single intravenous dose of the adeno-associated virus (AAV) vector, AAV-BR1-CAG-NEMO, delivering the Nemo gene to the brain endothelium. Spontaneous epileptic seizures and the integrity of the blood–brain barrier (BBB) were monitored. Results: The endothelium-targeted gene therapy improved the integrity of the BBB. In parallel, it reduced the incidence of seizures and delayed their occurrence. Neonate mice intravenously injected with the AAV-BR1-CAG-NEMO vector developed no hepatocellular carcinoma or other major adverse effects 11 months after vector injection, demonstrating that the vector has a favorable safety profile. Interpretation: The data show that the BBB is a target of antiepileptic treatment and, more specifically, provide evidence for the therapeutic benefit of a brain endothelial-targeted gene therapy in IP. Ann Neurol 2017;82:93–104.

Originalsprache	Englisch
Zeitschrift	Annals of Neurology
Jahrgang	82
Ausgabenummer	1
Seiten (von - bis)	93-104
Seitenumfang	12
ISSN	0364-5134
DOIs	https://doi.org/10.1002/ana.24981
Publikationsstatus	Veröffentlicht - 01.07.2017

Fördermittel

This work was supported by the German Research Foundation (DFG, grants TR448/11-1 to M.T., SCHW416/9-1 and SCHW416/5-2 to M.S., STR 1160/1-2 to B.K.S.), the Margarethe Clemens Foundation (endowed professorship to M.T.), and the Niedersachsen-Research Network on Neuroinfectiology (N-RENNT) of the Ministry of Science and Culture of Lower Saxony (Germany). We are grateful to Manolis Pasparakis, Institute for Genetics, University of Cologne, Germany, for providing NemoFl mice and to Rolf Sprengel, University of Heidelberg, Germany, for providing the plasmid p179. We also thank Beate Lembrich (University of L?beck, Germany) and Edith Kaczmarek (University of Veterinary Medicine Hannover, Germany), for expert support. Paraffin sections and H&E stains were performed by the tissue bank of the University Medical Center, Mainz.

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Forschungsschwerpunkt: Gehirn, Hormone, Verhalten - Center for Brain, Behavior and Metabolism (CBBM)

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10.1002/ana.24981

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Eine neue Generation Gehirn-endothelial zielgerichteter Gentherapievektoren zur Behandlung neuroinflammatorischer Erkrankungen
Schwaninger, M. (Sprecher*in) & Trepel, M. (Sprecher*in)
01.08.14 → 31.07.17
Projekt: DFG Einzelprojekte › DFG Einzelförderungen (Sachbeihilfen)

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@article{03d6b78ef09449ca879b9e3a319a175f,

title = "Gene therapy decreases seizures in a model of Incontinentia pigmenti",

abstract = "Objective: Incontinentia pigmenti (IP) is a genetic disease leading to severe neurological symptoms, such as epileptic seizures, but no specific treatment is available. IP is caused by pathogenic variants that inactivate the Nemo gene. Replacing Nemo through gene therapy might provide therapeutic benefits. Methods: In a mouse model of IP, we administered a single intravenous dose of the adeno-associated virus (AAV) vector, AAV-BR1-CAG-NEMO, delivering the Nemo gene to the brain endothelium. Spontaneous epileptic seizures and the integrity of the blood–brain barrier (BBB) were monitored. Results: The endothelium-targeted gene therapy improved the integrity of the BBB. In parallel, it reduced the incidence of seizures and delayed their occurrence. Neonate mice intravenously injected with the AAV-BR1-CAG-NEMO vector developed no hepatocellular carcinoma or other major adverse effects 11 months after vector injection, demonstrating that the vector has a favorable safety profile. Interpretation: The data show that the BBB is a target of antiepileptic treatment and, more specifically, provide evidence for the therapeutic benefit of a brain endothelial-targeted gene therapy in IP. Ann Neurol 2017;82:93–104.",

author = "Dogbevia, \{Godwin K.\} and Kathrin T{\"o}llner and Jakob K{\"o}rbelin and Sonja Br{\"o}er and Ridder, \{Dirk A.\} and Hanna Grasshoff and Claudia Brandt and Jan Wenzel and Straub, \{Beate K.\} and Martin Trepel and Wolfgang L{\"o}scher and Markus Schwaninger",

year = "2017",

month = jul,

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doi = "10.1002/ana.24981",

language = "English",

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publisher = "John Wiley \& Sons Inc.",

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TY - JOUR

T1 - Gene therapy decreases seizures in a model of Incontinentia pigmenti

AU - Dogbevia, Godwin K.

AU - Töllner, Kathrin

AU - Körbelin, Jakob

AU - Bröer, Sonja

AU - Ridder, Dirk A.

AU - Grasshoff, Hanna

AU - Brandt, Claudia

AU - Wenzel, Jan

AU - Straub, Beate K.

AU - Trepel, Martin

AU - Löscher, Wolfgang

AU - Schwaninger, Markus

PY - 2017/7/1

Y1 - 2017/7/1

N2 - Objective: Incontinentia pigmenti (IP) is a genetic disease leading to severe neurological symptoms, such as epileptic seizures, but no specific treatment is available. IP is caused by pathogenic variants that inactivate the Nemo gene. Replacing Nemo through gene therapy might provide therapeutic benefits. Methods: In a mouse model of IP, we administered a single intravenous dose of the adeno-associated virus (AAV) vector, AAV-BR1-CAG-NEMO, delivering the Nemo gene to the brain endothelium. Spontaneous epileptic seizures and the integrity of the blood–brain barrier (BBB) were monitored. Results: The endothelium-targeted gene therapy improved the integrity of the BBB. In parallel, it reduced the incidence of seizures and delayed their occurrence. Neonate mice intravenously injected with the AAV-BR1-CAG-NEMO vector developed no hepatocellular carcinoma or other major adverse effects 11 months after vector injection, demonstrating that the vector has a favorable safety profile. Interpretation: The data show that the BBB is a target of antiepileptic treatment and, more specifically, provide evidence for the therapeutic benefit of a brain endothelial-targeted gene therapy in IP. Ann Neurol 2017;82:93–104.

AB - Objective: Incontinentia pigmenti (IP) is a genetic disease leading to severe neurological symptoms, such as epileptic seizures, but no specific treatment is available. IP is caused by pathogenic variants that inactivate the Nemo gene. Replacing Nemo through gene therapy might provide therapeutic benefits. Methods: In a mouse model of IP, we administered a single intravenous dose of the adeno-associated virus (AAV) vector, AAV-BR1-CAG-NEMO, delivering the Nemo gene to the brain endothelium. Spontaneous epileptic seizures and the integrity of the blood–brain barrier (BBB) were monitored. Results: The endothelium-targeted gene therapy improved the integrity of the BBB. In parallel, it reduced the incidence of seizures and delayed their occurrence. Neonate mice intravenously injected with the AAV-BR1-CAG-NEMO vector developed no hepatocellular carcinoma or other major adverse effects 11 months after vector injection, demonstrating that the vector has a favorable safety profile. Interpretation: The data show that the BBB is a target of antiepileptic treatment and, more specifically, provide evidence for the therapeutic benefit of a brain endothelial-targeted gene therapy in IP. Ann Neurol 2017;82:93–104.

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Gene therapy decreases seizures in a model of Incontinentia pigmenti

Abstract

Fördermittel

UN SDGs

Strategische Forschungsbereiche und Zentren

Dokumente

Weitere Links

Fingerprint

Projekte

Eine neue Generation Gehirn-endothelial zielgerichteter Gentherapievektoren zur Behandlung neuroinflammatorischer Erkrankungen

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