MicroRNA-29 overexpression by adeno-associated virus suppresses fibrosis and restores muscle function in combination with micro-dystrophin

Heller, Kristin N.; Mendell, Joshua T.; Mendell, Jerry R.; Rodino‐Klapac, Louise R.

doi:10.1172/jci.insight.93309

Cited by 25 publications

(18 citation statements)

References 35 publications

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“…Interestingly, it has been found that TGF-β induces the expression of Connective Tissue Growth Factor (CTGF/CCN2) in fibroblasts (Igarashi et al, 1993 ) and the pro-fibrotic effects of TGF-β may be CTGF-dependent (Grotendorst, 1997 ; Leask and Abraham, 2004 ; Leask et al, 2004 ). The expression of microRNA-29—a family of microRNAs whose downregulation is associated with fibrosis—not only decreased TGF-β1 and ECM proteins expression but also completely restored muscle strength in dystrophic muscle when combined with μDys treatment (Heller et al, 2017 ). Similarly, reducing CTGF expression genetically or blocking CTGF with neutralizing antibodies, decreased fibrosis, and increased muscle strength and the efficiency of cell therapy (Morales et al, 2013b ).…”

Section: Introductionmentioning

confidence: 99%

Combined Therapies for Duchenne Muscular Dystrophy to Optimize Treatment Efficacy

et al. 2018

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Duchene Muscular Dystrophy (DMD) is the most frequent muscular dystrophy and one of the most severe due to the absence of the dystrophin protein. Typical pathological features include muscle weakness, muscle wasting, degeneration, and inflammation. At advanced stages DMD muscles present exacerbated extracellular matrix and fat accumulation. Recent progress in therapeutic approaches has allowed new strategies to be investigated, including pharmacological, gene-based and cell-based therapies. Gene and cell-based therapies are still limited by poor targeting and low efficiency in fibrotic dystrophic muscle, therefore it is increasingly evident that future treatments will have to include “combined therapies” to reach maximal efficiency. The scope of this mini-review is to provide an overview of the current literature on such combined therapies for DMD. By “combined therapies” we mean those that include both a therapy to correct the genetic defect and an additional one to address one of the secondary pathological features of the disease. In this mini-review, we will not provide a comprehensive view of the literature on therapies for DMD, since many such reviews already exist, but we will focus on the characteristics, efficiency, and potential of such combined therapeutic strategies that have been described so far for DMD.

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Section: Introductionmentioning

confidence: 99%

Combined Therapies for Duchenne Muscular Dystrophy to Optimize Treatment Efficacy

et al. 2018

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“…An example of a typical GO annotation for a biological process regulated by a miRNA, including contextual details describing the cell and tissue in which the process is being regulated, is shown in row 3 of Table 3. Priority is given to biological processes that will be most beneficial to therapeutic applications, and within the process-based approach, priority is given to miRNAs that are proposed to be therapeutic targets and which have been selected for clinical trial, e.g., miR-15, the inhibition of which was shown to protect against cardiac ischaemia damage (Hullinger et al 2012); miR-29, which is under investigation for stabilizing atherosclerotic plaques (Ulrich et al 2016), alleviating pulmonary fibrosis (Montgomery et al 2014) and providing a therapy for Duchenne muscular dystrophy (Heller et al 2017); miR-155, which is being investigated for treating T cell lymphoma (Seto et al 2015); and miR-208 under investigation for treatment of heart failure (Montgomery et al 2011). Occasionally, experimental information is lacking for a given human miRNA, therefore experimental evidence from a mammalian ortholog may be curated instead.…”

Section: Curation Of Mirna-regulated Pathways and Processesmentioning

confidence: 99%

Expanding the horizons of microRNA bioinformatics

Huntley

Kramarz

Sawford

et al. 2018

RNA

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MicroRNA regulation of key biological and developmental pathways is a rapidly expanding area of research, accompanied by vast amounts of experimental data. This data, however, is not widely available in bioinformatic resources, making it difficult for researchers to find and analyze microRNA-related experimental data and define further research projects. We are addressing this problem by providing two new bioinformatics data sets that contain experimentally verified functional information for mammalian microRNAs involved in cardiovascular-relevant, and other, processes. To date, our resource provides over 4400 Gene Ontology annotations associated with over 500 microRNAs from human, mouse, and rat and over 2400 experimentally validated microRNA:target interactions. We illustrate how this resource can be used to create microRNA-focused interaction networks with a biological context using the known biological role of microRNAs and the mRNAs they regulate, enabling discovery of associations between gene products, biological pathways and, ultimately, diseases. This data will be crucial in advancing the field of microRNA bioinformatics and will establish consistent data sets for reproducible functional analysis of microRNAs across all biological research areas.

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“…Several studies have shown the potential of AAV8 and AAV9 to induce production of an internally deleted dystrophin protein in most of the muscles of the dystrophic mdx mice and of the dystrophic dog, with improvement of the histological parameters and of the clinical symptoms after systemic delivery. (31)(32)(33)(34)(35)(36)(37) Based on these encouraging results, several academic groups and industrial partners (Jerry Mendell at Nationwide Children Hospital in collaboration with Sarepta; Pfizer; Solid Bioscience; Genethon) are at the advanced planning stage for phase I clinical trials in which escalating doses of either AAV8 or 9 will be administered systemically to DMD boys. The primary outcome will be safety, but dystrophin protein production and exploratory clinical efficacy will also be essential outcomes of these studies.…”

Section: Dmd: Aav Gene Therapymentioning

confidence: 99%

Genetic therapies for inherited neuromuscular disorders

Scoto

Finkel

Mercuri

et al. 2018

The Lancet Child & Adolescent Health

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Inherited neuromuscular disorders encompass a broad group of genetic conditions, and the discovery of these underlying genes has expanded greatly in the past three decades. The discovery of such genes has enabled more precise diagnosis of these disorders and the development of specific therapeutic approaches that target the genetic basis and pathophysiological pathways. Such translational research has led to the approval of two genetic therapies by the US Food and Drug Administration: eteplirsen for Duchenne muscular dystrophy and nusinersen for spinal muscular atrophy, which are both antisense oligonucleotides that modify pre-mRNA splicing. In this Review we aim to discuss new genetic therapies and ongoing clinical trials for Duchenne muscular dystrophy, spinal muscular atrophy, and other less common childhood neuromuscular disorders.

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MicroRNA-29 overexpression by adeno-associated virus suppresses fibrosis and restores muscle function in combination with micro-dystrophin

Cited by 25 publications

References 35 publications

Combined Therapies for Duchenne Muscular Dystrophy to Optimize Treatment Efficacy

Combined Therapies for Duchenne Muscular Dystrophy to Optimize Treatment Efficacy

Expanding the horizons of microRNA bioinformatics

Genetic therapies for inherited neuromuscular disorders

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