Therapeutic Strategies Targeting DUX4 in FSHD

Gall, Laura Le; Sidlauskaite, Eva; Mariot, Virginie; Dumonceaux, Julie

doi:10.3390/jcm9092886

Cited by 27 publications

(28 citation statements)

References 99 publications

(152 reference statements)

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“…During the past 10 years, several strategies aiming at inhibiting DUX4 expression have been developed (for review see [ 27 ]) and the poly(A) signal was already successfully targeted to inhibit DUX4 expression [ 19 , 21 ]. Targeting the key elements of DUX4 mRNA’s 3′UTR is attractive for several reasons: (i) correct polyadenylation of mRNAs is required for their stability, nuclear export and efficient translation, and targeting the polyadenylation signal can result in decreased gene expression (for review see [ 20 ]).…”

Section: Discussionmentioning

confidence: 99%

Gene Editing Targeting the DUX4 Polyadenylation Signal: A Therapy for FSHD?

Joubert

Mariot

Charpentier

et al. 2020

JPM

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Facioscapulohumeral dystrophy (FSHD, OMIM: 158900, 158901) is the most common dystrophy in adults and so far, there is no treatment. Different loci of the disease have been characterized and they all lead to the aberrant expression of the DUX4 protein, which impairs the function of the muscle, ultimately leading to cell death. Here, we used gene editing to try to permanently shut down DUX4 expression by targeting its poly(A) sequence. We used transcription activator-like effector nucleases (TALEN) and CRISPR-Cas9 nucleases in vitro on FSHD myoblasts. More than 150 TOPO clones were sequenced and only indels were observed in 4%. Importantly, in 2 of them, the DUX4 poly(A) signal was eliminated at the genomic level but DUX4 mRNA was still produced thanks to the use of a non-canonical upstream poly(A) signal sequence. These experiments show that targeting DUX4 PAS at the genomic level might not be an appropriate gene editing strategy for FSHD therapy.

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Section: Discussionmentioning

confidence: 99%

Gene Editing Targeting the DUX4 Polyadenylation Signal: A Therapy for FSHD?

Joubert

Mariot

Charpentier

et al. 2020

JPM

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“…We further reconcile these approaches via consideration of the immune system and muscle regeneration in FSHD. Understanding pathomechanisms underlying FSHD has clear implications for current clinical trials and developing novel therapies (Le Gall et al , 2020 ; Schatzl et al , 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Pathomechanisms and biomarkers in facioscapulohumeral muscular dystrophy: roles of DUX4 and PAX7

Banerji

Zammit

2021

EMBO Mol Med

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Facioscapulohumeral muscular dystrophy (FSHD) is characterised by progressive skeletal muscle weakness and wasting. FSHD is linked to epigenetic derepression of the subtelomeric D4Z4 macrosatellite at chromosome 4q35. Epigenetic derepression permits the distal‐most D4Z4 unit to transcribe DUX4, with transcripts stabilised by splicing to a poly(A) signal on permissive 4qA haplotypes. The pioneer transcription factor DUX4 activates target genes that are proposed to drive FSHD pathology. While this toxic gain‐of‐function model is a satisfying “bottom‐up” genotype‐to‐phenotype link, DUX4 is rarely detectable in muscle and DUX4 target gene expression is inconsistent in patients. A reliable biomarker for FSHD is suppression of a target gene score of PAX7, a master regulator of myogenesis. However, it is unclear how this “top‐down” finding links to genomic changes that characterise FSHD and to DUX4. Here, we explore the roles and interactions of DUX4 and PAX7 in FSHD pathology and how the relationship between these two transcription factors deepens understanding via the immune system and muscle regeneration. Considering how FSHD pathomechanisms are represented by “DUX4opathy” models has implications for developing therapies and current clinical trials.

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“…Currently there is no cure or pharmacological treatment available for FSHD, but since the discovery of its (epi)genetic mechanism, various therapeutic strategies are being investigated [2]. Multiple pharmaceutical companies have active drug development programs for FSHD, clinical trials are currently ongoing and more are expected to be initiated within the next few years [3,4].…”

Section: Introductionmentioning

confidence: 99%

The facioscapulohumeral muscular dystrophy Rasch‐built overall disability scale (FSHD‐RODS)

Mul

Hamadeh

Horlings

et al. 2021

Euro J of Neurology

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Background and objectives Facioscapulohumeral muscular dystrophy (FHSD) is a debilitating inherited muscle disease for which various therapeutic strategies are being investigated. Thus far, little attention has been given in FSHD to the development of scientifically sound outcome measures fulfilling regulatory authority requirements. The aim of this study was to design a patient‐reported Rasch‐built interval scale on activity and participation for FSHD. Methods A pre‐phase FSHD‐Rasch‐built overall disability scale (pre‐FSHD‐RODS; consisting of 159 activity/participation items), based on the World Health Organization international classification of disease‐related functional consequences was completed by 762 FSHD patients (Netherlands: n = 171; UK: n = 287; United States: n = 221; France: n = 52; Australia: n = 32). A proportion of the patient cohort completed it twice (n = 230; interval 2–4 weeks; reliability studies). The pre‐FSHD‐RODS was subjected to Rasch analyses to create a model fulfilling its requirements. Validity studies were performed through correlation with the motor function measure. Results The pre‐FSHD‐RODS did not meet the Rasch model expectations. Based on determinants such as misfit statistics and misfit residuals, differential item functioning, and local dependency, we systematically removed items until a final 38‐inquiry (originating from 32 items; six items split) FSHD‐RODS was constructed achieving Rasch model expectations. Adequate test‐retest reliability and (cross‐cultural and external) validity scores were obtained. Conclusions The FSHD‐RODS is a disease‐specific interval measure suitable for detecting activity and participation restrictions in patients with FSHD with good item/person reliability and validity scores. The use of this scale is recommended in the near future, to determine the functional deterioration slope in FSHD per year as a preparation for the upcoming clinical intervention trials in FSHD.

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Therapeutic Strategies Targeting DUX4 in FSHD

Cited by 27 publications

References 99 publications

Gene Editing Targeting the DUX4 Polyadenylation Signal: A Therapy for FSHD?

Gene Editing Targeting the DUX4 Polyadenylation Signal: A Therapy for FSHD?

Pathomechanisms and biomarkers in facioscapulohumeral muscular dystrophy: roles of DUX4 and PAX7

The facioscapulohumeral muscular dystrophy Rasch‐built overall disability scale (FSHD‐RODS)

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