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^*

^*Corresponding author for this work

26 Citations (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.

Original language	English
Journal	Annals of Neurology
Volume	82
Issue number	1
Pages (from-to)	93-104
Number of pages	12
ISSN	0364-5134
DOIs	https://doi.org/10.1002/ana.24981
Publication status	Published - 01.07.2017

Funding

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.

Research Areas and Centers

Academic Focus: Center for Brain, Behavior and Metabolism (CBBM)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1002/ana.24981

Cite this

@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,

day = "1",

doi = "10.1002/ana.24981",

language = "English",

volume = "82",

pages = "93--104",

journal = "Annals of Neurology",

issn = "0364-5134",

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

number = "1",

}

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.

UR - https://www.scopus.com/pages/publications/85025607298

U2 - 10.1002/ana.24981

DO - 10.1002/ana.24981

M3 - Journal articles

C2 - 28628231

AN - SCOPUS:85025607298

SN - 0364-5134

VL - 82

SP - 93

EP - 104

JO - Annals of Neurology

JF - Annals of Neurology

IS - 1

ER -

Gene therapy decreases seizures in a model of Incontinentia pigmenti

Abstract

Funding

Research Areas and Centers

UN SDGs

Access to Document

Other files and links

Fingerprint

Novel brain endothelial-targeted gene therapy vectors to treat neuroinflammatory disease

Cite this

Gene therapy decreases seizures in a model of Incontinentia pigmenti

Abstract

Funding

Research Areas and Centers

UN SDGs

Access to Document

Other files and links

Fingerprint

Projects

Novel brain endothelial-targeted gene therapy vectors to treat neuroinflammatory disease

Cite this