Targeting mRNA for the treatment of facioscapulohumeral muscular dystrophy.
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.
Department of Medical Genetics, School of Human Development, Faculty of Medicine and Dentistry, University of Alberta, Edmonton AB, Canada.
Bo
B
Bao
Department of Medical Genetics, School of Human Development, Faculty of Medicine and Dentistry, University of Alberta, Edmonton AB, Canada.
Rika
R
Maruyama
Department of Medical Genetics, School of Human Development, Faculty of Medicine and Dentistry, University of Alberta, Edmonton AB, Canada; Muscular Dystrophy Canada Research Chair, University of Alberta, Edmonton AB, Canada.
Toshifumi
T
Yokota
Antisense oligonucleotide therapy; DUX4; PITX1; gene therapy; morpholino; skeletal muscle
Development. 2008 May;135(10):1735-43
18403413
J Neurosci Methods. 2012 Jan 30;203(2):354-60
22027492
Dev Cell. 2012 Jan 17;22(1):38-51
22209328
Biochim Biophys Acta. 2010 Dec;1798(12):2296-303
20170628
PLoS Genet. 2013 Nov;9(11):e1003947
24278031
Skelet Muscle. 2014 Jun 10;4:12
24940479
Nature. 2011 Oct 05;478(7367):127-31
21979053
Ann N Y Acad Sci. 2009 Sep;1175:55-60
19796077
N Engl J Med. 2015 Apr 23;372(17):1672
25901434
Pract Neurol. 2016 Jun;16(3):201-7
26862222
BMC Evol Biol. 2010 Nov 26;10:364
21110847
Skelet Muscle. 2014 Feb 01;4(1):4
24484587
Biotechniques. 2014 May 01;56(5):251-6
24806225
Ann Neurol. 2009 Jun;65(6):667-76
19288467
Mol Ther Nucleic Acids. 2012 Aug 14;1:e38
23344180
Am J Hum Genet. 2007 Nov;81(5):884-94
17924332
Am J Hum Genet. 2005 Mar;76(3):375-86
15674778
Expert Opin Investig Drugs. 2015;24(7):867-81
25911060
J Med Genet. 1997 Jun;34(6):476-9
9192267
Antisense Nucleic Acid Drug Dev. 1996 Winter;6(4):267-72
9012862
Curr Neurol Neurosci Rep. 2016 Jul;16(7):66
27215221
Proc Natl Acad Sci U S A. 1978 Jan;75(1):285-8
75546
PLoS One. 2015 Mar 05;10(3):e0118813
25742305
Mol Ther. 2011 Jul;19(7):1295-303
21505427
Am J Pathol. 2011 Jul;179(1):12-22
21703390
Nature. 2004 Sep 16;431(7006):343-9
15372041
Hum Gene Ther. 2009 Sep;20(9):955-65
19469709
EMBO J. 2008 Oct 22;27(20):2766-79
18833193
PLoS Genet. 2010 Oct 28;6(10):e1001181
21060811
Nat Genet. 2016 May;48(5):569-74
27019113
Nature. 2006 Feb 23;439(7079):973-7
16341202
Mol Ther. 2011 Nov;19(11):2048-54
21730972
PLoS One. 2011;6(10 ):e26820
22053214
Nucleic Acid Ther. 2012 Oct;22(5):306-15
22888777
Expert Opin Biol Ther. 2014 Jun;14(6):809-19
24620745
Mol Ther. 2009 May;17(5):864-71
19277018
Antimicrob Agents Chemother. 2014 Nov;58(11):6639-47
25155593
Mol Ther. 2011 Nov;19(11):2055-64
21829175
Hum Mol Genet. 2011 Feb 1;20(3):413-21
21062902
Acta Myol. 2007 Dec;26(3):179-84
18646569
Exp Neurol. 2008 Nov;214(1):87-96
18723017
Muscle Nerve. 2014 Apr;49(4):520-7
23873337
Nucleic Acids Res. 2014 Mar;42(5):3207-17
24366877
Proc Natl Acad Sci U S A. 2007 Nov 13;104(46):18157-62
17984056
Gene. 1999 Aug 5;236(1):25-32
10433963
Mol Ther. 2010 Jan;18(1):198-205
19844193
Neuromuscul Disord. 2008 Aug;18(8):597-605
18602263
Antisense Nucleic Acid Drug Dev. 1997 Apr;7(2):63-70
9149841
Nat Genet. 1992 Sep;2(1):26-30
1363881
Oncogene. 2012 Feb 23;31(8):1024-33
21765469
Neurology. 2014 Sep 16;83(12):1056-9
25122204
Mol Ther. 2014 Feb;22(2):390-6
24232919
Molecules. 2015 May 08;20(5):8304-15
26007167
Biol Open. 2012 Jul;1(7):629-639
23125914
Hum Gene Ther. 2013 Mar;24(3):331-42
23339722
PLoS One. 2013 Apr 22;8(4):e62114
23630626
Clin Genet. 2009 Jun;75(6):550-5
19320656
Antisense Nucleic Acid Drug Dev. 1997 Jun;7(3):187-95
9212909
Nat Genet. 2012 Dec;44(12):1370-4
23143600
Hum Mol Genet. 2013 Dec 15;22(24):4914-28
23882132
Hum Mol Genet. 2008 Dec 15;17(24):3909-18
18784278
Mol Ther. 2012 Jul;20(7):1417-23
22508491
Lancet Neurol. 2014 Oct;13(10):963-5
25209737
Mol Ther Nucleic Acids. 2014 Mar 11;3:e152
24618851
Neurology. 2015 Jul 28;85(4):357-64
26215877
PLoS Genet. 2013 Apr;9(4):e1003415
23593020
Hum Mol Genet. 2009 Jul 1;18(13):2414-30
19359275
Nature. 2011 Oct 05;478(7367):123-6
21979052
Antimicrob Agents Chemother. 2009 May;53(5):2089-99
19223614
Science. 2010 Sep 24;329(5999):1650-3
20724583
Mol Ther. 2013 Aug;21(8):1536-50
23752310
J Cell Biol. 2012 Oct 1;199(1):21-5
23027901
J Biol Chem. 1996 Jul 19;271(29):17445-52
8663413
Nature. 2006 May 25;441(7092):537-41
16724069
Expert Opin Emerg Drugs. 2015 Sep;20(3):353-6
25920617
Proc Natl Acad Sci U S A. 2008 Apr 15;105(15):5868-73
18398004
Neuromuscul Disord. 2007 Aug;17(8):611-23
17588759
Rev Neurol (Paris). 2012 Dec;168(12):910-8
22551571