Facioscapulohumeral muscular dystrophy (FSHD) is an inherited autosomal dominant disorder characterized clinically by progressive muscle degeneration. Currently, no curative treatment for this disorder exists. FSHD patients are managed through physiotherapy to improve function and quality of life. Over the last two decades, FSHD has been better understood as a disease genetically characterized by a pathogenic contraction of a subset of macrosatellite repeats on chromosome 4. Specifically, several studies support an FSHD pathogenesis model involving the aberrant expression of the double homeobox protein 4 (DUX4) gene. Hence, potential therapies revolving around inhibition of DUX4 have been explored. One of the potential treatment options is the use of effective antisense oligonucleotides (AOs) to knockdown expression of the myopathic DUX4 gene and its downstream molecules including paired-like homeodomain transcription factor 1 (PITX1). Success in the suppression of PITX1 expression has already been demonstrated systemically in vivo in recent studies. In this article, we will review the pathogenesis of FSHD and the latest research involving the use of antisense knockdown therapy.
Keywords: Antisense oligonucleotide therapy; DUX4; PITX1; gene therapy; morpholino; skeletal muscle.
Antisense Oligonucleotides Used to Target the DUX4 mRNA as Therapeutic Approaches in FaciosScapuloHumeral Muscular Dystrophy (FSHD).Genes (Basel). 2017 Mar 3;8(3):93. doi: 10.3390/genes8030093. Genes (Basel). 2017. PMID: 28273791 Free PMC article.
DUX4, a candidate gene of facioscapulohumeral muscular dystrophy, encodes a transcriptional activator of PITX1.Proc Natl Acad Sci U S A. 2007 Nov 13;104(46):18157-62. doi: 10.1073/pnas.0708659104. Epub 2007 Nov 5. Proc Natl Acad Sci U S A. 2007. PMID: 17984056 Free PMC article.
Clinically Advanced p38 Inhibitors Suppress DUX4 Expression in Cellular and Animal Models of Facioscapulohumeral Muscular Dystrophy.J Pharmacol Exp Ther. 2019 Aug;370(2):219-230. doi: 10.1124/jpet.119.259663. Epub 2019 Jun 12. J Pharmacol Exp Ther. 2019. PMID: 31189728
DUX4 Signalling in the Pathogenesis of Facioscapulohumeral Muscular Dystrophy.Int J Mol Sci. 2020 Jan 22;21(3):729. doi: 10.3390/ijms21030729. Int J Mol Sci. 2020. PMID: 31979100 Free PMC article. Review.
Facioscapulohumeral dystrophy: the path to consensus on pathophysiology.Skelet Muscle. 2014 Jun 10;4:12. doi: 10.1186/2044-5040-4-12. eCollection 2014. Skelet Muscle. 2014. PMID: 24940479 Free PMC article. Review.
Cited by 1 article
ETV transcriptional upregulation is more reliable than RNA sequencing algorithms and FISH in diagnosing round cell sarcomas with CIC gene rearrangements.Genes Chromosomes Cancer. 2017 Jun;56(6):501-510. doi: 10.1002/gcc.22454. Epub 2017 Mar 31. Genes Chromosomes Cancer. 2017. PMID: 28233365 Free PMC article.