Gene therapy decreases seizures in a model of <i>Incontinentia pigmenti</i>

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

doi:10.1002/ana.24981

Cited by 23 publications

(28 citation statements)

References 40 publications

(152 reference statements)

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“…This dose proved to be efficacious in previous studies. 22,23 For the treatment of neonatal Hexb À/À mice with the vectors, AAV-BR1-CAG-HEXA/B and AAV-BR1-CAG-Ø were injected intravenously into the temporal vein using a stereo microscope. Owing to increased lethality and neurotoxicity of isoflurane, neonatal mice were not anesthetized.…”

Section: Intravenous Injection Of Aav-br1-cag-hexa/b and Aav-br1-cag-mentioning

confidence: 99%

“…21 We have developed a unique AAV vector (AAV-BR1) which, when systemically administered, is capable of transducing CNS endothelial cells and leading to a sustained gene expression. 22,23 Importantly, AAV-BR1 shows an unprecedented degree of selectivity for the CNS endothelium over other cell types, resulting in a favorable safety profile. 22,23 Here, we show that by intravenously injecting the AAV-BR1 vector for expressing human HEXA and HEXB in CNS endothelial cells of Hexb À/À mice, we were able to increase b-hexosaminidase A activity, decrease lysosomal storage of GM2 and GA2, and prolong survival.…”

Section: Introductionmentioning

confidence: 99%

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Brain endothelial specific gene therapy improves experimental Sandhoff disease

Dogbevia

Othman

Penno

et al. 2019

J Cereb Blood Flow Metab

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In Tay-Sachs and Sandhoff disease, a deficiency of the lysosomal enzyme β-hexosaminidase causes GM2 and other gangliosides to accumulate in neurons and triggers neurodegeneration. Although the pathology centers on neurons, β-hexosaminidase is mainly expressed outside of neurons, suggesting that gene therapy of these diseases should target non-neuronal cells to reconstitute physiological conditions. Here, we tested in Hexb−/− mice, a model of Sandhoff disease, to determine whether endothelial expression of the genes for human β-hexosaminidase subunit A and B ( HEXA, HEXB) is able to reduce disease symptoms and prolong survival of the affected mice. The brain endothelial selective vectors AAV-BR1-CAG- HEXA and AAV-BR1-CAG- HEXB transduced brain endothelial cells, which subsequently released β-hexosaminidase enzyme. In vivo intravenous administration of the gene vectors to adult and neonatal mice prolonged survival. They improved neurological function and reduced accumulation of the ganglioside GM2 and the glycolipid GA2 as well as astrocytic activation. Overall, the data demonstrate that endothelial cells are a suitable target for intravenous gene therapy of GM2 gangliosidoses and possibly other lysosomal storage disorders.

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Section: Intravenous Injection Of Aav-br1-cag-hexa/b and Aav-br1-cag-mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Brain endothelial specific gene therapy improves experimental Sandhoff disease

Dogbevia

Othman

Penno

et al. 2019

J Cereb Blood Flow Metab

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“…Mice treated with AAV-BR1-Nemo showed less activation of astrocytes. Importantly, the occurrence of focal epileptic seizures was significantly reduced by the gene therapy [ 26 ]. Probably due to its high brain endothelial selectivity, the vector did not induce hepatocellular carcinoma or other adverse effects that have been observed in rodents during gene therapy with AAV vectors.…”

Section: The Blood–brain Barrier In Gene Therapy: Hurdle or Target?mentioning

confidence: 99%

Current research into brain barriers and the delivery of therapeutics for neurological diseases: a report on CNS barrier congress London, UK, 2017

Greenwood

Hammarlund‐Udenaes

Jones³

et al. 2017

Fluids Barriers CNS

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This is a report on the CNS barrier congress held in London, UK, March 22–23rd 2017 and sponsored by Kisaco Research Ltd. The two 1-day sessions were chaired by John Greenwood and Margareta Hammarlund-Udenaes, respectively, and each session ended with a discussion led by the chair. Speakers consisted of invited academic researchers studying the brain barriers in relation to neurological diseases and industry researchers studying new methods to deliver therapeutics to treat neurological diseases. We include here brief reports from the speakers.

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“…The data obtained may be used for family genetic counseling as well as guiding the treatment approaches and predicting the prognosis. With increasing availability of genetic diagnosis, precision therapy will also be an option of management for neonatal-onset epilepsy 12 . For example, encoding a voltage-gated potassium channel, electro-physiological analysis showed that the majority of KCNQ2 mutations lead to an increase in potassium current, which may be treated by retigabine to reduce the current amplitude or to depolarize shift of the activation curve 13, 14…”

Section: Discussionmentioning

confidence: 99%

Genetic diagnosis of neonatal-onset seizures

Yang

Zeng

2019

Genes & Diseases

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Many seizures in neonates are due to early-onset epilepsy, which is often difficult to diagnose, especially to explore the causes. Recently, the development of next-generation sequencing (NGS) has led to the discovery of a large number of genes involved in epilepsy. This may improve prompt detection of early-onset epilepsy in neonates. This study aimed at analyzing the genotype-phenotype correlations in neonates with seizures in a bid to improve the understanding of genetic diagnosis of early-onset epilepsy. Clinical features and prognosis of 15 children who underwent genetic testing having had unexplained seizures from February 2016 to May 2018 in Children's Hospital of Chongqing Medical University were analyzed retrospectively. The salient findings were: poor response to stimulus and abnormal electroencephalogram (EEG) in the initial period were observed in the group with concomitant genetic abnormalities. Despite the recent progress in genetic technology, molecular diagnosis for neonatal-onset epilepsy can be challenging due to genetic and phenotypic heterogeneities. However, some genotypes are associated with specific clinical manifestations and EEG patterns. Therefore, in-depth understanding of genotype-phenotype correlations would be useful to clinicians managing neonates with early-onset seizures.

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Gene therapy decreases seizures in a model of Incontinentia pigmenti

Abstract: 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.

Cited by 23 publications

References 40 publications

Brain endothelial specific gene therapy improves experimental Sandhoff disease

Brain endothelial specific gene therapy improves experimental Sandhoff disease

Current research into brain barriers and the delivery of therapeutics for neurological diseases: a report on CNS barrier congress London, UK, 2017

Genetic diagnosis of neonatal-onset seizures

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