Long-Term Systemic Treatment of a Mouse Model Displaying Chronic FSHD-like Pathology with Antisense Therapeutics That Inhibit DUX4 Expression

被引:11
|
作者
Lu-Nguyen, Ngoc [1 ]
Dickson, George [1 ]
Malerba, Alberto [1 ]
Popplewell, Linda [1 ,2 ]
机构
[1] Royal Holloway Univ London, Sch Life Sci & Environm, Dept Biol Sci, Egham TW20 0EX, Surrey, England
[2] Teesside Univ, Natl Horizons Ctr, Darlington DL1 1HG, Durham, England
关键词
FSHD; DUX4; inhibition; systemic antisense therapy; ACTA1-MCM/FLExDUX4; FACIOSCAPULOHUMERAL MUSCULAR-DYSTROPHY; INVOLVEMENT; THERAPY; CELLS;
D O I
10.3390/biomedicines10071623
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Silencing the expression of the double homeobox 4 (DUX4) gene offers great potential for the treatment of facioscapulohumeral muscular dystrophy (FSHD). Several research groups have recently reported promising results using systemic antisense therapy in a transgenic small animal model of FSHD, the ACTA1-MCM/FLExDUX4 mouse model. However, the treatment was applied in non-DUX4-induced mice or shortly after DUX4 activation, which resulted in conditions that do not correctly represent the situation in a clinic. Here, we generated progressive FSHD-like pathology in ACTA1-MCM/FLExDUX4 mice and then treated the animals with vivoPMO-PACS4, an antisense compound that efficiently downregulates DUX4. To best mimic the translation of this treatment in clinical settings, the systemic antisense oligonucleotide administration was delayed to 3 weeks after the DUX4 activation so that the pathology was established at the time of the treatment. The chronic administration of vivoPMO-PACS4 for 8 weeks downregulated the DUX4 expression by 60%. Consequently, the treated mice showed an increase by 18% in body-wide muscle mass and 32% in muscle strength, and a reduction in both myofiber central nucleation and muscle fibrosis by up to 29% and 37%, respectively. Our results in a more suitable model of FSHD pathology confirm the efficacy of vivoPMO-PACS4 administration, and highlight the significant benefit provided by the long-term treatment of the disease.
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页数:18
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