Skipping Multiple Exons to Treat DMD—Promises and Challenges
| Autor: | Tejal Aslesh, Toshifumi Yokota, Rika Maruyama |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Drug congenital hereditary and neonatal diseases and abnormalities Morpholino Clustered Regularly Interspaced Short Palindromic Repeat/CRISPR associated protein 9 (CRISPR/Cas9)-mediated genome editing media_common.quotation_subject Duchenne muscular dystrophy antisense oligonucleotides (AOs) Medicine (miscellaneous) Review golodirsen Eteplirsen Bioinformatics General Biochemistry Genetics and Molecular Biology 03 medical and health sciences Exon golden retriever muscular dystrophy (GRMD) Medicine eteplirsen media_common canine X-linked muscular dystrophy (CXMD) business.industry Functional protein phosphorodiamidate morpholino oligomer (PMO actin binding domain (ABD) Therapeutic effect medicine.disease Exon skipping 3. Good health 030104 developmental biology morpholino) business multi-exon skipping Duchenne/Becker muscular dystrophy (DMD/BMD) |
| Zdroj: | Biomedicines |
| ISSN: | 2227-9059 |
| DOI: | 10.3390/biomedicines6010001 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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