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.
Highlights
Duchenne muscular dystrophy (DMD) is an X-linked, lethal neuromuscular disorder caused by frame-disrupting mutations in the DMD gene, which result in the lack of functional dystrophin protein [1]
Further evaluations of PMO and PNA derivatives e.g. B-MSPPMO (B refers to B peptide and MSP represents muscle-specific peptide), PNA-MSP and MOE PS (29O-Methoxyethyl with phosphorothioate backbone), which were evaluated in mdx mice previously [25,27,34,35], in C57BL6 revealed that effective exon skipping can be induced in C57BL6 at 48 hr after local intramuscular injection, with B-MSP-PMO being better than PNA-MSP and MOE PS
Our study demonstrated that wild-type mice can be used as alternative animal models for DMD antisense oligonucleotide (AO) screen and a means to ascertain variation in efficacy of AOs in mice with different genetic backgrounds, which can inform about the potential variation in therapeutic efficacy that might be present in the patient population
Summary
Duchenne muscular dystrophy (DMD) is an X-linked, lethal neuromuscular disorder caused by frame-disrupting mutations in the DMD gene, which result in the lack of functional dystrophin protein [1]. Numerous approaches for treating DMD are being investigated with antisense oligonucleotide (AO)-mediated exon-skipping therapeutics showing great promise from pre-clinical studies and phase II clinical trials [5,6,7,8,9]. Recent failure with Drisapersen from GSK and Prosensa phase III clinical trials highlights the importance of identifying safer and more effective AOs. Animal models play a critical role in identifying effective treatments for DMD. Mdx has been the most commonly used animal model for pre-clinical studies, for DMD AO drug screen, which greatly contributes to ongoing clinical trials [10,13,22,23]. A readily available and more cost-effective alternative in vivo model which allows researchers to identify uptake in different genetic background before optimization will further speed up the development of DMD AOs
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
