Viral delivery of miR-196a ameliorates the SBMA phenotype via the silencing of CELF2

Miyazaki, Yu; Adachi, Hiroaki; Katsuno, Masahisa; Minamiyama, Makoto; Jiang, Yue-Mei; Huang, Zhe; Doi, Hideki; Matsumoto, Shinjiro; Kondo, Naohide; Iida, Madoka; Tohnai, Genki; Tanaka, Fumiaki; Muramatsu, Shin‐ichi; Sobue, Gen

doi:10.1038/nm.2791

Cited by 140 publications

(120 citation statements)

References 35 publications

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“…With a clinical setting in mind, experiments were done in human patient fibroblasts. miR-196a overexpression in an SBMA mouse model significantly downregulated both CELF2 and AR mRNA levels, improving SBMA phenotypes, suggesting miR-196a-mediated treatment as a potential clinical therapy for SBMA patients [141].…”

Section: Spinobulbar Muscular Atrophymentioning

confidence: 94%

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Recent Advances in RNA Interference Therapeutics for CNS Diseases

2013

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Over the last decade, RNA interference technology has shown therapeutic promise in rodent models of dominantly inherited brain diseases, including those caused by polyglutamine repeat expansions in the coding region of the affected gene. For some of these diseases, proof-of concept studies in model organisms have transitioned to safety testing in larger animal models, such as the nonhuman primate. Here, we review recent progress on RNA interference-based therapies in various model systems. We also highlight outstanding questions or concerns that have emerged as a result of an improved (and ever advancing) understanding of the technologies employed.

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Section: Spinobulbar Muscular Atrophymentioning

confidence: 94%

“…Recently, Miyazaki et al [141] demonstrated a potential SBMA therapy using a novel approach exploiting the miRNA pathway. They identified miR-196a expression as significantly upregulated in the spinal cord of transgenic mice at advanced disease stages.…”

Section: Spinobulbar Muscular Atrophymentioning

confidence: 99%

Recent Advances in RNA Interference Therapeutics for CNS Diseases

2013

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“…It has been demonstrated that they can significantly improve the phenotype of SBMA mice but has never been tested in human patients [78].…”

Section: Experimental Treatmentsmentioning

confidence: 99%

Kennedy disease (X-linked recessive bulbospinal neuronopathy): A comprehensive review from pathophysiology to therapy

2017

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Acknowledgments: the authors thank AFM-Téléthon, Téléthon Biobank, Institut pour la Recherche sur la Moelle épinière et l'Encéphale (IRME), Association pour la Recherche sur la SLA (ARSla) and the University of Padova for their research support.Kennedy disease (X-Linked recessive Bulbospinal Neuronopathy): a comprehensive review from pathophysiology to therapy. AbstractKennedy's disease, also known as spinal and bulbar muscular atrophy (SBMA), is a rare, adult-onset, Xlinked recessive neuromuscular disease. It is caused by expansion of a CAG repeat sequence in exon 1 of the androgen-receptor (AR) gene, encoding a poly-glutamine (polyQ) tract. Poly-Q-expanded AR accumulates in nuclei and initiates degeneration and loss of motor neurons and dorsal root ganglia. The disease has been retained to be a pure lower motor neuron disease for a long time, but recently the presence of important hyper-Creatine-Kinase-emia and of myopathic alterations on muscle biopsy has suggested the presence of a primary myopathy underlying a wide proportion of clinical manifestations. The disease, that affects male adults, is characterized by muscle weakness and atrophy localized proximally in the limbs and by bulbar involvement. Sensory disturbances are associated to the motor phenotype but may be subclinical. The most frequent systemic symptom is gynecomastia related to androgen insensitivity, but other abnormalities, such as heart rhythm and urinary disturbances, have also been reported. The course of the disease is slowly progressive with normal life expectancy. The diagnosis of SBMA is based on genetic testing, with 38 CAG repeats retained to be pathogenic. Even though several therapeutic attempts have been made in mouse models, no effective disease modifying therapy is available but symptomatic therapy is beneficial for the management of weakness, fatigability and bulbar symptoms.

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“…Two major approaches have been tested to deliver miR-mimics: (I) miR-mimic viral based overexpression ( Figure 1C) and (II) injection (intravenously or directly into the affected tissue) of miR-mimics that are linked to liposomal nanoparticles, atelocollagen or polyethyleneimine (81)(82)(83) (Figure 1C). Systemically viral based overexpression of a miR-mimic can be performed by using adeno-associated viruses (AAVs) (84,85) (Figure 1C). Due to the natural tropism of AAVs to cell types, receptors or organs, a cardiac-specific expression of the miR-mimicking constructs could also be realized (86).…”

Section: Mir Mimicsmentioning

confidence: 99%

MicroRNAs: pleiotropic players in congenital heart disease and regeneration

et al. 2017

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Congenital heart disease (CHD) is the leading cause of infant death, affecting approximately 4-14 live births per 1,000. Although surgical techniques and interventions have improved significantly, a large number of infants still face poor clinical outcomes. MicroRNAs (miRs) are known to coordinately regulate cardiac development and stimulate pathological processes in the heart, including fibrosis or hypertrophy and impair angiogenesis. Dysregulation of these regulators could therefore contribute (I) to the initial development of CHD and (II) at least partially to the observed clinical outcomes of many CHD patients by stimulating the aforementioned pathways. Thus, miRs may exhibit great potential as therapeutic targets in regenerative medicine. In this review we provide an overview of miR function and elucidate their role in selected CHDs, including hypoplastic left heart syndrome (HLHS), tetralogy of Fallot (TOF), ventricular septal defects (VSDs) and Holt-Oram syndrome (HOS). We then bridge this knowledge to the potential usefulness of miRs and/or their targets in therapeutic strategies for regenerative purposes in CHDs.

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Viral delivery of miR-196a ameliorates the SBMA phenotype via the silencing of CELF2

Cited by 140 publications

References 35 publications

Recent Advances in RNA Interference Therapeutics for CNS Diseases

Recent Advances in RNA Interference Therapeutics for CNS Diseases

Kennedy disease (X-linked recessive bulbospinal neuronopathy): A comprehensive review from pathophysiology to therapy

MicroRNAs: pleiotropic players in congenital heart disease and regeneration

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