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

Bosnakovski, Darko; Shams, Ahmed S.; Yuan, Ce; Silva, Meiricris T. da; Ener, Elizabeth T.; Baumann, Cory W.; Lindsay, Angus; Verma, Mayank; Asakura, Atsushi; Lowe, Dawn A.; Kyba, Michael

doi:10.1172/jci133303

Cited by 47 publications

(69 citation statements)

References 48 publications

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“…FRG1 is another direct transcriptional target of DUX4, whose knockdown by RNAi reversed dystrophic histopathology and improved treadmill performance in FRG1-overexpressing mice (Bortolanza et al, 2011;Ferri et al, 2015). It would be interesting to see if similar effects could be observed if these strategies were used to treat DUX4-overexpressing mouse models such as FLExDUX4 (Jones and Jones, 2018), the doxycycline-inducible iDUX4pA (Bosnakovski et al, 2017a;Bosnakovski et al, 2020), or the tamoxifen-inducible TIC-DUX4 (Giesige et al, 2018).…”

Section: Oligonucleotide Therapiesmentioning

confidence: 99%

Genetic Approaches for the Treatment of Facioscapulohumeral Muscular Dystrophy

Lim

Yokota

2021

Front. Pharmacol.

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Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant disorder characterized by progressive, asymmetric muscle weakness at the face, shoulders, and upper limbs, which spreads to the lower body with age. It is the third most common inherited muscular disorder worldwide. Around 20% of patients are wheelchair-bound, and some present with extramuscular manifestations. FSHD is caused by aberrant expression of the double homeobox protein 4 (DUX4) gene in muscle. DUX4 codes for a transcription factor which, in skeletal muscle, dysregulates numerous signaling activities that culminate in cytotoxicity. Potential treatments for FSHD therefore aim to reduce the expression of DUX4 or the activity of its toxic protein product. In this article, we review how genetic approaches such as those based on oligonucleotide and genome editing technologies have been developed to achieve these goals. We also outline the challenges these therapies are facing on the road to translation, and discuss possible solutions and future directions

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Section: Oligonucleotide Therapiesmentioning

confidence: 99%

Genetic Approaches for the Treatment of Facioscapulohumeral Muscular Dystrophy

Lim

Yokota

2021

Front. Pharmacol.

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“…By designing a conditional and titratable model using the endogenous and low efficient DUX4 polyadenylation signal, Bosnakovski et al aimed at reducing the leaky DUX4 expression-mediated toxicity. An inducible mouse model was produced by knocking in a genomic fragment from the D4Z4 repeat belonging to the 4qA allele of a FSHD patient (including the DUX4 ORF, 3 UTR including the DUX4 p(A)) that was placed under the control of a doxycycline-inducible promoter called iDUX4pA [69,70]. The HSA-rTA driver allowed for a muscle-specific DUX4 expression-induction in animals.…”

Section: • D4z4-25/smchd1mommed1 Mice (2018)mentioning

confidence: 99%

“…Altogether, the authors designed a viable mouse model characterized by a muscle-specific and inducible DUX4 expression. They recently used this same animal model to create a chronic long-term muscle disease model [70]. Rather than daily injection, doxycycline was chow-administered for up to six months.…”

Section: • D4z4-25/smchd1mommed1 Mice (2018)mentioning

confidence: 99%

Therapeutic Strategies Targeting DUX4 in FSHD

Gall

Sidlauskaite

Mariot

et al. 2020

JCM

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Facioscapulohumeral muscular dystrophy (FSHD) is a common muscle dystrophy typically affecting patients within their second decade. Patients initially exhibit asymmetric facial and humeral muscle damage, followed by lower body muscle involvement. FSHD is associated with a derepression of DUX4 gene encoded by the D4Z4 macrosatellite located on the subtelomeric part of chromosome 4. DUX4 is a highly regulated transcription factor and its expression in skeletal muscle contributes to multiple cellular toxicities and pathologies ultimately leading to muscle weakness and atrophy. Since the discovery of the FSHD candidate gene DUX4, many cell and animal models have been designed for therapeutic approaches and clinical trials. Today there is no treatment available for FSHD patients and therapeutic strategies targeting DUX4 toxicity in skeletal muscle are being actively investigated. In this review, we will discuss different research areas that are currently being considered to alter DUX4 expression and toxicity in muscle tissue and the cell and animal models designed to date.

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“…Importantly, many of the phenotypes were dose dependent, which provides the opportunity to titrate for phenotype severity and to adjust the timing of induction. Additionally, this model has proven useful for long-term modeling of FSHD ( Bosnakovski et al, 2020 ). Providing the mice with a low dose of DOX in the chow for up to 6 months produced a progressive muscular dystrophy phenotype that recapitulated many aspects of FSHD, including loss of force generation, histological signs of dystrophy, infiltration of inflammatory and fibroadipogenic progenitor cells, compromised vasculature, fibrosis, and a gene expression signature similar to that found in patients.…”

Section: Animal Models Of Fshdmentioning

confidence: 99%

Cellular and animal models for facioscapulohumeral muscular dystrophy

DeSimone

Cohen

Lek

et al. 2020

Disease Models &Amp; Mechanisms

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Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common forms of muscular dystrophy and presents with weakness of the facial, scapular and humeral muscles, which frequently progresses to the lower limbs and truncal areas, causing profound disability. Myopathy results from epigenetic de-repression of the D4Z4 microsatellite repeat array on chromosome 4, which allows misexpression of the developmentally regulated DUX4 gene. DUX4 is toxic when misexpressed in skeletal muscle and disrupts several cellular pathways, including myogenic differentiation and fusion, which likely underpins pathology. DUX4 and the D4Z4 array are strongly conserved only in primates, making FSHD modeling in non-primate animals difficult. Additionally, its cytotoxicity and unusual mosaic expression pattern further complicate the generation of in vitro and in vivo models of FSHD. However, the pressing need to develop systems to test therapeutic approaches has led to the creation of multiple engineered FSHD models. Owing to the complex genetic, epigenetic and molecular factors underlying FSHD, it is difficult to engineer a system that accurately recapitulates every aspect of the human disease. Nevertheless, the past several years have seen the development of many new disease models, each with their own associated strengths that emphasize different aspects of the disease. Here, we review the wide range of FSHD models, including several in vitro cellular models, and an array of transgenic and xenograft in vivo models, with particular attention to newly developed systems and how they are being used to deepen our understanding of FSHD pathology and to test the efficacy of drug candidates.

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

Cited by 47 publications

References 48 publications

Genetic Approaches for the Treatment of Facioscapulohumeral Muscular Dystrophy

Genetic Approaches for the Treatment of Facioscapulohumeral Muscular Dystrophy

Therapeutic Strategies Targeting DUX4 in FSHD

Cellular and animal models for facioscapulohumeral muscular dystrophy

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