Therapeutic Approaches in Facioscapulohumeral Muscular Dystrophy

Cohen, Justin; DeSimone, Alec M.; Lek, Monkol; Lek, Angela

doi:10.1016/j.molmed.2020.09.008

Cited by 28 publications

(28 citation statements)

References 121 publications

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“…Several approaches have been developed to inhibit DUX4 in skeletal muscles. They have been recently reviewed [103], therefore we will just outline these strategies to discuss their relevance for DUX4-related cancer treatment. Targeting DUX4 mRNA by using antisense oligonucleotides (AOs), phoshporodiamidate morpholino oligomer (PMO) or locked nucleic acid (LNA) gapmer AOs targeting different parts of the DUX4 ORF is the most straightforward approach to selectively repress DUX4 [27,[104][105][106][107][108][109].…”

Section: Fshdmentioning

confidence: 99%

“…Several small molecules decreasing DUX4 expression in FSHD muscle cells were identified, they include inhibitors of the bromodomain and extra-terminal (BET) family of proteins, agonists of the beta-2 adrenergic receptor [112,113] and inhibitors of p38 mitogen-activated protein kinase [114,115], although clinical trials of these compounds have not yet produced encouraging results [103]. Finally, a possible, though complicated, therapeutic strategy would be to target DUX4 protein.…”

Section: Fshdmentioning

confidence: 99%

“…The molecular mechanisms leading to FSHD are outlined in Box 1. Currently there is no effective FSHD treatment; the potential therapeutic approaches are extensively discussed in a recent review [103].…”

Section: Facioscapulohumeral Dystrophymentioning

confidence: 99%

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Control of DUX4 Expression in Facioscapulohumeral Muscular Dystrophy and Cancer

Karpukhina

Tiukacheva

Dib

et al. 2021

Trends in Molecular Medicine

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DUX4, a gene encoding a transcription factor involved in early embryogenesis, is heavily repressed in most somatic tissues while its aberrant expression is linked to facioscapulohumeral muscular dystrophy (FSHD). Recently, the deregulation of DUX4 expression was found in many cancers. While DUX4 role in FSHD is well studied, its relevance in cancer is less explored. Here we discuss multiple levels of control of DUX4 expression, including enhancer-promoter interactions, epigenetic modifications, non-coding RNAs and telomere positioning effect. We also connect disparate data on intrachromosomal contacts involving DUX4 and emphasize feedback loops in DUX4 regulation. Finally, we bridge data on DUX4 in FSHD and cancer and discuss prospective approaches for future FSHD therapies and the potential outcomes of DUX4 inhibition in cancer.

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Section: Fshdmentioning

confidence: 99%

Section: Fshdmentioning

confidence: 99%

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Control of DUX4 Expression in Facioscapulohumeral Muscular Dystrophy and Cancer

Karpukhina

Tiukacheva

Dib

et al. 2021

Trends in Molecular Medicine

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“…CRISPR/Cas9 with gRNAs against the intronic sequences flanking this pseudoexon restored the SMCHD1 reading frame and increased wild-type SMCHD1 expression in primary and immortalized patient myotubes, resulting in reduced DUX4 mRNA expression. It has been suggested that CRISPR be used to edit the permissive 4qA to the restrictive 4qB haplotype (Cohen et al, 2020), but attempts on realizing this approach have not yet been reported in the literature. In addition to genome editing, CRISPR can also be used for the targeted modulation of gene expression.…”

Section: Crisprmentioning

confidence: 99%

“…In response to developing a more targeted form of treatment, reducing muscle-specific DUX4 expression and DUX4-mediated toxicity have become attractive goals for FSHD therapy (Bao et al, 2016;Bouwman et al, 2020;Cohen et al, 2020). Indeed, a number of genetic methods have been employed to achieve one or both of these, including oligonucleotide-based strategies to knockdown DUX4 transcript levels or reduce DUX4 protein activity, and genome editing to correct FSHD-associated mutations.…”

Section: Introductionmentioning

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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First‐trimester noninvasive prenatal diagnosis of seven facioscapulohumeral muscular dystrophy type 1 families using SNP‐based amplicon sequencing: An earlier, rapid and safer way

Fu,

Zhao,

Kong

et al. 2024

American J of Med Genetics Pt A

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The study is to explore the feasibility and value of SNP‐based noninvasive prenatal diagnosis (NIPD) for facioscapulohumeral muscular dystrophy type 1 (FSHD1) in early pregnancy weeks. We prospectively collected seven FSHD1 families, with an average gestational age of 8+6. Among these seven couples, there were three affected FSHD1 mothers and four affected fathers. A multiplex‐PCR panel comprising 402 amplicons was designed to selective enrich for highly heterozygous SNPs upstream of the DUX4 gene. Risk haplotype was constructed based on familial linkage analysis. Fetal genotypes were accurately inferred through relative haplotype dosage analysis using Bayes Factor. All tests were successfully completed in a single attempt, and no recombination events were detected. NIPD results were provided within a week, which is 4 weeks earlier than karyomapping and 7 weeks earlier than Bionano single‐molecule optical mapping (BOM). Ultimately, five FSHD1 fetuses and two normal fetuses were successfully identified, with a 100% concordance rate with karyomapping and BOM. Therefore, SNP‐based NIPD for FSHD1 was demonstrated to be feasible and accurate in early weeks of gestation, although the risk of recombination events cannot be completely eliminated. In the future, testing of more cases is still necessary to fully determine the clinical utility.

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Therapeutic Approaches in Facioscapulohumeral Muscular Dystrophy

Cited by 28 publications

References 121 publications

Control of DUX4 Expression in Facioscapulohumeral Muscular Dystrophy and Cancer

Control of DUX4 Expression in Facioscapulohumeral Muscular Dystrophy and Cancer

Genetic Approaches for the Treatment of Facioscapulohumeral Muscular Dystrophy

First‐trimester noninvasive prenatal diagnosis of seven facioscapulohumeral muscular dystrophy type 1 families using SNP‐based amplicon sequencing: An earlier, rapid and safer way

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