title: Wild-type mouse models to screen antisense oligonucleotides for exon-skipping efficacy in Duchenne muscular dystrophy.
abstract: A readily available animal model is essential for rapidly identifying effective treatments for Duchenne muscular dystrophy (DMD), a devastating neuromuscular disorder caused by the lack of dystrophin protein, which results from frame-disrupting mutations in the DMD gene. Currently, the mdx mouse is the most commonly used model for antisense oligonucleotide (AO)-mediated exon skipping pre-clinical studies, with a mild phenotype. However, the accessibility of mdx mouse colonies particularly in developing countries can constrain research. Therefore in this study we explore the feasibility of using wild-type mice as models to establish exon-skipping efficiency of various DMD AO chemistries and their conjugates. Four different strains of wild-type mice and six different AO chemistries were investigated intramuscularly and the results indicated that the same exon-skipping efficiency was achieved for all tested AOs as that from mdx mice. Notably, levels of exon-skipping obtained in C57BL6 and C3H and mdx mice were most closely matched, followed by ICR and BALB/C mice. Systemic validation revealed that wild-type mice are less responsive to AO-mediated exon skipping than mdx mice. Our study provides evidence for the first time that wild-type mice can be appropriate models for assessing DMD AO exon-skipping efficiency with similar sensitivity to that of mdx mice and this finding can further accelerate the development of effective DMD AOs.
authors.affiliation: Research Centre of Basic Medical Science and Department of Cell Biology, Tianjin Medical University, Heping District, Tianjin, China.
authors.forename: Limin
authors.initials: L
authors.lastname: Cao
authors.affiliation: Research Centre of Basic Medical Science and Department of Cell Biology, Tianjin Medical University, Heping District, Tianjin, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Han
authors.affiliation: Research Centre of Basic Medical Science and Department of Cell Biology, Tianjin Medical University, Heping District, Tianjin, China.
authors.forename: Ben
authors.initials: B
authors.lastname: Gu
authors.affiliation: Research Centre of Basic Medical Science and Department of Cell Biology, Tianjin Medical University, Heping District, Tianjin, China.
authors.forename: HaiFang
authors.initials: H
authors.lastname: Yin
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D004195:Disease Models, Animal; D016189:Dystrophin; D005091:Exons; D015316:Genetic Therapy; D007273:Injections, Intramuscular; D051379:Mice; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics* / Q000628:therapy; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage* / Q000235:genetics*; D017422:Sequence Analysis, DNA
chemical_list: D016189:Dystrophin; D016376:Oligonucleotides, Antisense