AAV-mediated follistatin gene therapy improves functional outcomes in the TIC-DUX4 mouse model of FSHD

Giesige, Carlee R.; Wallace, Lindsay; Heller, Kristin N.; Eidahl, Jocelyn O.; Saad, Nizar Y.; Fowler, Allison M.; Pyne, Nettie K.; Al-Kharsan, Mustafa; Rashnonejad, Afrooz; Chermahini, Gholamhossein Amini; Domire, Jacqueline S.; Mukweyi, Diana; Garwick-Coppens, Sara E; Guckes, S.; McLaughlin, K. John; Meyer, Kathrin; Rodino‐Klapac, Louise R.; Harper, Scott Q.

doi:10.1172/jci.insight.123538

Cited by 60 publications

(58 citation statements)

References 51 publications

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“…Thus, these bi-transgenic FSHD-like models allow investigators to recapitulate the chronic, low-levels of DUX4 using the mild model, or investigate more severe DUX4-mediated pathology by an investigator-controlled increase in DUX4 expression using TMX. In addition, the bi-transgenic model is the only available DUX4 model mouse that lives a normal lifespan (up to 2 years) while continually expressing detectable levels of mosaic DUX4-FL protein throughout its skeletal musculature [78,91,113], making it the only choice for long-term therapeutic knockdown studies of DUX4-fl.…”

Section: Discussionmentioning

confidence: 99%

Transgenic mice expressing tunable levels of DUX4 develop characteristic facioscapulohumeral muscular dystrophy-like pathophysiology ranging in severity

et al. 2020

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Background: All types of facioscapulohumeral muscular dystrophy (FSHD) are caused by the aberrant activation of the somatically silent DUX4 gene, the expression of which initiates a cascade of cellular events ultimately leading to FSHD pathophysiology. Typically, progressive skeletal muscle weakness becomes noticeable in the second or third decade of life, yet there are many individuals who are genetically FSHD but develop symptoms much later in life or remain relatively asymptomatic throughout their lives. Conversely, FSHD may clinically present prior to 5-10 years of age, ultimately manifesting as a severe early-onset form of the disease. These phenotypic differences are thought to be due to the timing and levels of DUX4 misexpression. Methods: FSHD is a dominant gain-of-function disease that is amenable to modeling by DUX4 overexpression. We have recently created a line of conditional DUX4 transgenic mice, FLExDUX4, that develop a myopathy upon induction of human DUX4-fl expression in skeletal muscle. Here, we use the FLExDUX4 mouse crossed with the skeletal muscle-specific and tamoxifen-inducible line ACTA1-MerCreMer to generate a highly versatile bi-transgenic mouse model with chronic, low-level DUX4-fl expression and cumulative mild FSHD-like pathology that can be reproducibly induced to develop more severe pathology via tamoxifen induction of DUX4-fl in skeletal muscles. Results: We identified conditions to generate FSHD-like models exhibiting reproducibly mild, moderate, or severe DUX4-dependent pathophysiology and characterized progression of pathology. We assayed DUX4-fl mRNA and protein levels, fitness, strength, global gene expression, and histopathology, all of which are consistent with an FSHD-like myopathic phenotype. Importantly, we identified sex-specific and muscle-specific differences that should be considered when using these models for preclinical studies.

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Section: Discussionmentioning

confidence: 99%

Transgenic mice expressing tunable levels of DUX4 develop characteristic facioscapulohumeral muscular dystrophy-like pathophysiology ranging in severity

et al. 2020

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“…There are now 3 mouse models that show muscle pathology in response to muscle-specific DUX4 expression. The first of these used doxycycline (dox) induction via a muscle fiber-restricted rtTA (21), while the 2 more recent models use muscle fiberspecific Cre-lox recombination (22,23) to express DUX4 in muscle fibers. Although Cre-based models can give low overall expression through use of an inefficient Cre, the per-cell expression level in those cells that do express is relatively high due to the use of a Facioscapulohumeral muscular dystrophy (FSHD) is caused by loss of repression of the DUX4 gene; however, the DUX4 protein is rare and difficult to detect in human muscle biopsies, and pathological mechanisms are obscure.…”

Section: Introductionmentioning

confidence: 99%

Transcriptional and cytopathological hallmarks of FSHD in chronic DUX4-expressing mice

Bosnakovski

Shams

Yuan³

et al. 2020

Journal of Clinical Investigation

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“…These derepressing epigenetic lesions permit DUX4 transcription, and if this occurs on a chromosome 4 allele containing an adjacent poly A signal for DUX4 (called the 4qA haplotype), the mRNA is polyadenylated and can be translated by the ribosome. The resultant DUX4 protein is toxic to muscle, cultured myocytes, and other nonmuscle cells in vitro (Lemmers et al 2010(Lemmers et al , 2012Wallace et al 2011;Giesige et al 2018).…”

Section: Introductionmentioning

confidence: 99%

RNAscope in situ hybridization-based method for detecting DUX4 RNA expression in vitro

Chermahini

Rashnonejad

Harper

2019

RNA

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Facioscapulohumeral muscular dystrophy (FSHD) is among the most common forms of muscular dystrophy. FSHD is caused by aberrant expression of the toxic DUX4 gene in muscle. Detecting endogenous DUX4 in patient tissue using conventional methods can be challenging, due to the low level of DUX4 expression. Therefore, developing simple and trustworthy DUX4 detection methods is an important need in the FSHD field. Here, we describe such a method, which uses the RNAscope assay, an RNA in situ hybridization (ISH) technology. We show that a custom-designed RNAscope assay can detect overexpressed DUX4 mRNA in transfected HEK293 cells and endogenous DUX4 mRNA in FSHD patientderived myotubes. The RNAscope assay was highly sensitive for tracking reductions in DUX4 mRNA following treatment with our therapeutic mi405 microRNA, suggesting that RNAscope-based DUX4 expression assays could be developed as a prospective outcome measure in therapy trials. This study could set the stage for optimizing and developing a new, rapid RNA ISH-based molecular diagnostic assay for future clinical use in the FSHD field.

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AAV-mediated follistatin gene therapy improves functional outcomes in the TIC-DUX4 mouse model of FSHD

Cited by 60 publications

References 51 publications

Transgenic mice expressing tunable levels of DUX4 develop characteristic facioscapulohumeral muscular dystrophy-like pathophysiology ranging in severity

Transgenic mice expressing tunable levels of DUX4 develop characteristic facioscapulohumeral muscular dystrophy-like pathophysiology ranging in severity

Transcriptional and cytopathological hallmarks of FSHD in chronic DUX4-expressing mice

RNAscope in situ hybridization-based method for detecting DUX4 RNA expression in vitro

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