Targeting mRNA for the treatment of facioscapulohumeral muscular dystrophy

Bao, Bo; Maruyama, Rika; Yokota, Toshifumi

doi:10.5582/irdr.2016.01056

Cited by 7 publications

(7 citation statements)

References 81 publications

(72 reference statements)

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“…Expression levels of CIC, ETV1, ETV4, ETV5, and WT1 were evaluated on both RNAseq platforms in comparison to other soft tissue tumors in each platform. The mRNA expression of known PEA3 family downstream target genes, including SPRY2, SPRY4, SPRED2, GPR20, DUSP6 GBX2, FGF8, POU5F1, MMP1/2/3/7/9, TWIST1, SNAI1/2, PTGS2, BAX, CCND2, ZEB1, PTK2, PLAU, ICAM1, VEGFA, NOTCH1, NOTCH4, and SPP1 was investigated from the whole transcriptome sequencing platform, while FRG1, PITX1, ZSCAN4, RFPL2, TRIM43, and LEUTX, were evaluated as DUX4 targets …”

Section: Methodsmentioning

confidence: 99%

“…The mRNA expression of known PEA3 family downstream target genes, including SPRY2, SPRY4, SPRED2, GPR20, DUSP6 GBX2, FGF8, POU5F1, MMP1/2/3/7/9, TWIST1, SNAI1/2, PTGS2, BAX, CCND2, ZEB1, PTK2, PLAU, ICAM1, VEGFA, NOTCH1, NOTCH4, and SPP1 10-19 was investigated from the whole transcriptome sequencing platform, while FRG1, PITX1, ZSCAN4, RFPL2, TRIM43, and LEUTX, were evaluated as DUX4 targets. [20][21][22][23] Cases studied by the whole transcriptome sequencing (n 5 10)…”

Section: Rna Sequencing Data Analysismentioning

confidence: 99%

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ETV transcriptional upregulation is more reliable than RNA sequencing algorithms and FISH in diagnosing round cell sarcomas with CIC gene rearrangements

Kao

Sung

Chen

et al. 2017

Genes Chromosomes & Cancer

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CIC rearrangements have been reported in two-thirds of EWSR1-negative small blue round cell tumors (SBRCTs). However, a number of SBRCTs remain unclassified despite exhaustive analysis. Fourteen SBRCTs lacking driver genetic events by RNA sequencing (RNAseq) analysis were collected. Unsupervised hierarchical clustering was performed using samples from our RNAseq database, including 13 SBRCTs with non-CIC genetic abnormalities and 2 CIC-rearranged angiosarcomas among others. Remarkably, all 14 study cases showed high mRNA levels of ETV1/4/5, and by unsupervised clustering most grouped into a distinct cluster, separate from other tumors. Based on these results indicating a close relationship with CIC-rearranged tumors, we manually inspected CIC reads in RNAseq data. FISH for CIC and DUX4 abnormalities and immunohistochemical stains for ETV4 were also performed. In the control group, only 2 CIC-rearranged angiosarcomas had high ETV1/4/5 expression. Upon manual inspection of CIC traces, 7 of 14 cases showed CIC-DUX4 fusion reads, 2 cases had DUX4-CIC reads, while the remaining 5 were negative. FISH showed CIC break-apart in 7 cases, including 5 cases lacking CIC-DUX4 or DUX4-CIC fusion reads on RNAseq manual inspection. However, no CIC abnormalities were detected by FISH in 6 cases with CIC-DUX4 or DUX4-CIC reads. ETV4 immunoreactivity was positive in 7 of 11 cases. Our results highlight the underperformance of FISH and RNAseq methods in diagnosing SBRCTs with CIC gene abnormalities. The downstream ETV1/4/5 transcriptional up-regulation appears highly sensitive and specific and can be used as a reliable molecular signature and diagnostic method for CIC fusion positive SBRCTs.

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Section: Methodsmentioning

confidence: 99%

Section: Rna Sequencing Data Analysismentioning

confidence: 99%

ETV transcriptional upregulation is more reliable than RNA sequencing algorithms and FISH in diagnosing round cell sarcomas with CIC gene rearrangements

Kao

Sung

Chen

et al. 2017

Genes Chromosomes & Cancer

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“…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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“…However, several trials of novel pharmaceutical treatments of FSHD are currently executed [5,6]. The recent discovery of an effective antisense oligonucleotide therapy in spinal muscular atrophy [7] gives rise to hope that RNA-based therapies could be effective also in patients with FSHD [8][9][10]. Indeed, at the time of writing, several genetic therapies aimed at repressing DUX4 and its downstream effects are being investigated as potential treatment options in FSHD [11].…”

Section: Introductionmentioning

confidence: 99%

The socioeconomic burden of facioscapulohumeral muscular dystrophy

et al. 2021

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Background Promising genetic therapies are being investigated in facioscapulohumeral muscular dystrophy (FSHD). However, the current cost of illness is largely unknown. Objective This study aimed at determining the socioeconomic burden of FSHD. Methods Adult patients with FSHD from the Dutch FSHD registry were invited to complete a questionnaire on medical consumption, work productivity and health-related quality of life (HR-QoL) using the EQ-5D-5L. Associated costs were calculated from a societal perspective. A generalized linear model was fitted to the data to investigate whether level of mobility was related to annual costs of illness. Results 172 patients with FSHD completed the questionnaire (response rate 65%). The per-patient annual direct medical costs of FSHD were estimated at €12,077, direct non-medical costs at €9179 and indirect costs at €5066, adding up to a total cost of illness of €26,322 per patient per year. The direct costs of illness were €21,256, approximately five times higher than the mean per-capita health expenditures in the Netherlands. Major cost-driving factors were formal home care and informal care. A decreased level of mobility was associated with higher direct costs of illness. HR-QoL was significantly reduced in patients with FSHD with a median health utility value of 0.63. Conclusions We show that FSHD is associated with substantial direct and indirect socioeconomic costs as well as a reduction in HR-QoL. These findings are important for health care decision makers and aids in allocation of research funds and evaluation of the cost-effectiveness of novel therapies.

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Targeting mRNA for the treatment of facioscapulohumeral muscular dystrophy

Cited by 7 publications

References 81 publications

ETV transcriptional upregulation is more reliable than RNA sequencing algorithms and FISH in diagnosing round cell sarcomas with CIC gene rearrangements

ETV transcriptional upregulation is more reliable than RNA sequencing algorithms and FISH in diagnosing round cell sarcomas with CIC gene rearrangements

Genetic Approaches for the Treatment of Facioscapulohumeral Muscular Dystrophy

The socioeconomic burden of facioscapulohumeral muscular dystrophy

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