Rescue of amyotrophic lateral sclerosis phenotype in a mouse model by intravenous <scp>AAV</scp>9‐<scp><i>ADAR</i></scp><i>2</i> delivery to motor neurons

Yamashita, Takenari; Chai, Hui; Teramoto, Sayaka; Tsuji, Shoji; Shimazaki, Kuniko; Muramatsu, Shin‐ichi; Kwak, Shin

doi:10.1002/emmm.201302935

Cited by 64 publications

(48 citation statements)

References 29 publications

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“…2a, arrows). Because TDP-43 was cleaved by calpain and exhibited mislocalization and motor neuron death was induced in a Ca 2+ -dependent manner in the ADAR2-deficient motor neurons of AR2 mice21222728 (Supplementary Fig. S3), we compared the immunoreactivity to Nup62 and TDP-43 in motor neurons between the AR2 and AR2res mice.…”

Section: Resultsmentioning

confidence: 99%

Calpain-dependent disruption of nucleo-cytoplasmic transport in ALS motor neurons

Yamashita

Aizawa

Teramoto

et al. 2017

Sci Rep

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Nuclear dysfunction in motor neurons has been hypothesized to be a principal cause of amyotrophic lateral sclerosis (ALS) pathogenesis. Here, we investigated the mechanism by which the nuclear pore complex (NPC) is disrupted in dying motor neurons in a mechanistic ALS mouse model (adenosine deaminase acting on RNA 2 (ADAR2) conditional knockout (AR2) mice) and in ALS patients. We showed that nucleoporins (Nups) that constituted the NPC were cleaved by activated calpain via a Ca2+-permeable AMPA receptor-mediated mechanism in dying motor neurons lacking ADAR2 expression in AR2 mice. In these neurons, nucleo-cytoplasmic transport was disrupted, and the level of the transcript elongation enzyme RNA polymerase II phosphorylated at Ser2 was significantly decreased. Analogous changes were observed in motor neurons lacking ADAR2 immunoreactivity in sporadic ALS patients. Therefore, calpain-dependent NPC disruption may participate in ALS pathogenesis, and inhibiting Ca2+-mediated cell death signals may be a therapeutic strategy for ALS.

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Section: Resultsmentioning

confidence: 99%

Calpain-dependent disruption of nucleo-cytoplasmic transport in ALS motor neurons

Yamashita

Aizawa

Teramoto

et al. 2017

Sci Rep

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“…We selected the synapsin I promoter to drive expression in our curative AAV vector as it has already been used successfully in several mouse models [20], [24], [25]. The synapsin I promoter activates expression mainly in neural cells and has a reduced off-target effect when delivered systemically.…”

Section: Discussionmentioning

confidence: 99%

Gene therapy for a mouse model of glucose transporter-1 deficiency syndrome

Nakamura

Osaka

Muramatsu

et al. 2017

Molecular Genetics and Metabolism Reports

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ObjectiveWe generated an adeno-associated virus (AAV) vector in which the human SLC2A1 gene was expressed under the synapsin I promoter (AAV-hSLC2A1) and examined if AAV-hSLC2A1 administration can lead to functional improvement in GLUT1-deficient mice.MethodsAAV-hSLC2A1 was injected into heterozygous knock-out murine Glut1 (GLUT1+/−) mice intraperitoneally (systemic; 1.85 × 1011 vg/mouse) or intra-cerebroventricularly (local; 1.85 × 1010 vg/mouse). We analyzed GLUT1 mRNA and protein expression, motor function using rota-rod and footprint tests, and blood and cerebrospinal fluid (CSF) glucose levels.ResultsVector-derived RNA was detected in the cerebrum for both injection routes. In the intra-cerebroventricular injection group, exogenous GLUT1 protein was strongly expressed in the cerebral cortex and hippocampus near the injection site. In the intraperitoneal injection group, exogenous GLUT1 protein was mildly expressed in neural cells throughout the entire central nervous system. The motor function test and CSF/blood glucose ratio were significantly improved following intra-cerebroventricular injection.ConclusionsAAV-hSLC2A1 administration produced exogenous GLUT1 in neural cells and improved CSF glucose levels and motor function of heterozygous knock-out murine Glut1 mice.

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“…These include Rett syndrome (delivery of MeCP2: Garg et al, 2013), amyotrophic lateral sclerosis (ALS) (shRNA targeting SOD1: Foust et al, 2013; delivery of ADAR2: Yamashita et al, 2013; delivery of single chain antibody targeting misfolded SOD1: Patel et al, 2014), Huntington’s disease (shRNA targeting HTT: Harper et al, 2005; artificial miRNA targeting HTT: McBride et al, 2008; Dufour et al, 2014) and Machado-Joseph disease (artificial miRNA targeting ATXN3: Rodríguez-Lebrón et al, 2013). …”

Section: Different Modalities For Different Diseasesmentioning

confidence: 99%

Viral vectors for therapy of neurologic diseases

et al. 2017

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Neurological disorders – disorders of the brain, spine and associated nerves – are a leading contributor to global disease burden with a shockingly large associated economic cost. Various treatment approaches – pharmaceutical medication, device-based therapy, physiotherapy, surgical intervention, among others – have been explored to alleviate the resulting extent of human suffering. In recent years, gene therapy using viral vectors – encoding a therapeutic gene or inhibitory RNA into a “gutted” viral capsid and supplying it to the nervous system – has emerged as a clinically viable option for therapy of brain disorders. In this Review, we provide an overview of the current state and advances in the field of viral vector-mediated gene therapy for neurological disorders. Vector tools and delivery methods have evolved considerably over recent years, with the goal of providing greater and safer genetic access to the central nervous system. Better etiological understanding of brain disorders has concurrently led to identification of improved therapeutic targets. We focus on the vector technology, as well as preclinical and clinical progress made thus far for brain cancer and various neurodegenerative and neurometabolic disorders, and point out the challenges and limitations that accompany this new medical modality. Finally, we explore the directions that neurological gene therapy is likely to evolve towards in the future.

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Rescue of amyotrophic lateral sclerosis phenotype in a mouse model by intravenous AAV9‐ADAR2 delivery to motor neurons

Cited by 64 publications

References 29 publications

Calpain-dependent disruption of nucleo-cytoplasmic transport in ALS motor neurons

Calpain-dependent disruption of nucleo-cytoplasmic transport in ALS motor neurons

Gene therapy for a mouse model of glucose transporter-1 deficiency syndrome

Viral vectors for therapy of neurologic diseases

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