Skipping Multiple Exons to Treat DMD-Promises and Challenges

被引:34
作者
Aslesh, Tejal [1 ]
Maruyama, Rika [1 ]
Yokota, Toshifumi [1 ,2 ]
机构
[1] Univ Alberta, Fac Med & Dent, Dept Med Genet, 8812-112 St, Edmonton, AB T6G 2H7, Canada
[2] Friends Garrett Cumming Res & Muscular Dystrophy, 8812-112 St, Edmonton, AB T6G 2H7, Canada
基金
加拿大健康研究院; 加拿大创新基金会;
关键词
Duchenne/Becker muscular dystrophy (DMD/BMD); antisense oligonucleotides (AOs); multi-exon skipping; phosphorodiamidate morpholino oligomer (PMO; morpholino); eteplirsen; golodirsen; canine X-linked muscular dystrophy (CXMD); golden retriever muscular dystrophy (GRMD); Clustered Regularly Interspaced Short Palindromic Repeat/CRISPR associated protein 9 (CRISPR/Cas9)-mediated genome editing; actin binding domain (ABD); DUCHENNE-MUSCULAR-DYSTROPHY; ANTISENSE OLIGONUCLEOTIDE DRUGS; POLYMERASE-CHAIN-REACTION; SYSTEMIC DELIVERY; DOG-MODEL; MOUSE MODEL; EXPRESSION; GENE; EFFICACY; DELETION;
D O I
10.3390/biomedicines6010001
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
Duchenne muscular dystrophy (DMD) is a lethal disorder caused by mutations in the DMD gene. Antisense-mediated exon-skipping is a promising therapeutic strategy that makes use of synthetic nucleic acids to skip frame-disrupting exon(s) and allows for short but functional protein expression by restoring the reading frame. In 2016, the U.S. Food and Drug Administration (FDA) approved eteplirsen, which skips DMD exon 51 and is applicable to approximately 13% of DMD patients. Multiple exon skipping, which is theoretically applicable to 80-90% of DMD patients in total, have been demonstrated in animal models, including dystrophic mice and dogs, using cocktail antisense oligonucleotides (AOs). Although promising, current drug approval systems pose challenges for the use of a cocktail AO. For example, both exons 6 and 8 need to be skipped to restore the reading frame in dystrophic dogs. Therefore, the cocktail of AOs targeting these exons has a combined therapeutic effect and each AO does not have a therapeutic effect by itself. The current drug approval system is not designed to evaluate such circumstances, which are completely different from cocktail drug approaches in other fields. Significant changes are needed in the drug approval process to promote the cocktail AO approach.
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页数:12
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