DNA aptamers against the DUX4 protein reveal novel therapeutic implications for FSHD

Klingler, Christian; Ashley, Jon; Shi, Ke; Stiefvater, Adeline; Kyba, Michael; Sinnreich, Michael; Aihara, Hideki; Kinter, Jochen

doi:10.1096/fj.201902696

Cited by 21 publications

(16 citation statements)

References 105 publications

(209 reference statements)

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“…Several laboratories are developing therapeutic approaches targeting DUX4 by either blocking DUX4 mRNA synthesis [ 31 , 51 , 52 , 54 ], targeting DUX4 mRNA using antisense oligonucleotides [ 66 , 73 , 74 , 75 , 76 ], or targeting the DUX4 protein or its downstream consequences [ 77 , 78 , 79 ]. One phase 2 clinical trial (NCT04003974) aiming at inhibiting or reducing its expression in skeletal muscle is already on-going and may enable a better understanding of the role of DUX4 in the pathophysiology of FSHD.…”

Section: Discussionmentioning

confidence: 99%

DUX4 Expression in FSHD Muscles: Focus on Its mRNA Regulation

Sidlauskaite

Gall

Mariot

et al. 2020

JPM

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Facioscapulohumeral dystrophy (FSHD) is the most frequent muscular disease in adults. FSHD is characterized by a weakness and atrophy of a specific set of muscles located in the face, the shoulder, and the upper arms. FSHD patients may present different genetic defects, but they all present epigenetic alterations of the D4Z4 array located on the subtelomeric part of chromosome 4, leading to chromatin relaxation and, ultimately, to the aberrant expression of one gene called DUX4. Once expressed, DUX4 triggers a cascade of deleterious events, eventually leading to muscle dysfunction and cell death. Here, we review studies on DUX4 expression in skeletal muscle to determine the genetic/epigenetic factors and regulatory proteins governing DUX4 expression, with particular attention to the different transcripts and their very low expression in muscle.

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Section: Discussionmentioning

confidence: 99%

DUX4 Expression in FSHD Muscles: Focus on Its mRNA Regulation

Sidlauskaite

Gall

Mariot

et al. 2020

JPM

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“…As a transcription factor, DUX4 uncovers a vast, complex gene regulatory network. Inhibition of DUX4 can be achieved by utilizing DNA aptamers, short oligonucleotides, engineered bind to the DNA binding site of DUX4 and thus inhibiting DUX4 from binding to its transcriptional activator sites [ 68 ].…”

Section: Therapeutic Approachesmentioning

confidence: 99%

Current Therapeutic Approaches in FSHD

Wang

Tawil

2021

JND

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Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common muscular dystrophies. Over the last decade, a consensus was reached regarding the underlying cause of FSHD allowing—for the first time—a targeted approach to treatment. FSHD is the result of a toxic gain-of-function from de-repression of the DUX4 gene, a gene not normally expressed in skeletal muscle. With a clear therapeutic target, there is increasing interest in drug development for FSHD, an interest buoyed by the recent therapeutic successes in other neuromuscular diseases. Herein, we review the underlying disease mechanism, potential therapeutic approaches as well as the state of trial readiness in the planning and execution of future clinical trials in FSHD.

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“…The DNA decoys were also tested in AAV-DUX4 mice, where administration either by intramuscular electroporation or AAV delivery led to decreased expression of Tm7sf4, another DUX4 downstream target. On a related note, single-stranded DNA aptamers have recently been developed with high, preferential affinity to the DUX4 DNA-binding domain (Klingler et al, 2020). However, these aptamers have yet to be tested for their therapeutic potential.…”

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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DNA aptamers against the DUX4 protein reveal novel therapeutic implications for FSHD

Cited by 21 publications

References 105 publications

DUX4 Expression in FSHD Muscles: Focus on Its mRNA Regulation

DUX4 Expression in FSHD Muscles: Focus on Its mRNA Regulation

Current Therapeutic Approaches in FSHD

Genetic Approaches for the Treatment of Facioscapulohumeral Muscular Dystrophy

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