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Mdx mouse

MDX laboratory mouse Animal model used to study Duchenne Muscular Dystrophy (DMD)

The mdx mouse is a popular model for studying Duchenne muscular dystrophy (DMD).[1][2] The mdx mouse has a point mutation in its DMD gene, changing the amino acid coding for a glutamine to STOP codon. This causes the muscle cells to produce a small, nonfunctional dystrophin protein.[3] As a result, the mouse has a mild form of DMD where there is increased muscle damage and weakness.

History

The mdx mouse was first described in 1984 by Bulfield et al. in a colony of C57BL/10ScSn mice, showing elevated muscle creatine kinase (CK) and histological lesions characteristic of muscular dystrophy.[4]

In 1989, Sicinski et al. identified the precise mutation: a C-to-T transition (nonsense point mutation) in exon 23 of the Dmd gene, creating a premature stop codon and abolishing full-length dystrophin expression. This makes mdx mice a key model for Duchenne muscular dystrophy.[5]

Limitations

Despite its widespread use, the mdx mouse has several important limitations as a model for Duchenne muscular dystrophy. The mdx mouse displays a considerably milder phenotype than human DMD patients, largely due to the compensatory upregulation of utrophin.[6]

In 2016, despite decades of successful preclinical studies in mdx mice, many promising therapies failed in human clinical trials, highlighting the translational gap between the mouse model and human disease.[7]

To overcome these limitations, researchers have developed improved models such as the mdx/utrophin double knockout mouse, which more closely resembles the severe human DMD phenotype, and humanized mdx models that allow testing of human-specific therapies such as exon skipping drugs.[6]

mdx Mouse and CRISPR-Cas9

Schematic of AAV-CRISPR-mediated dystrophin gene editing in DmdΔ8-34 mdx mice, showing restoration of Dp427 and Dp71f isoforms and functional outcomes in cardiac and diaphragm muscles[8].

The mdx mouse has been at the forefront of CRISPR-Cas9 gene editing research for Duchenne muscular dystrophy. In 2014, the first successful correction of the dystrophin mutation using CRISPR-Cas9 was demonstrated directly in mdx mice, marking a historic milestone in gene editing therapy.[9]

In 2018, researchers used AAV-delivered CRISPR-Cas9 to restore dystrophin expression in mdx mice following a single systemic injection, demonstrating the remarkable potential of this approach.[10]

These results in mdx mice directly led to the first CRISPR-based clinical trials for DMD in human patients, representing a direct translation from mouse model to human medicine.[5]

References

  1. ^ McArdle, Anne. (1993). Mechanisms skeletal muscle damage in the dystrophin-deficient MDX mouse (PhD thesis). University of Liverpool. OCLC 53496566. EThOS uk.bl.ethos.385144.
  2. ^ Bulfield, G.; Siller, W. G.; Wight, P. A.; Moore, K. J. (1984). "X chromosome-linked muscular dystrophy (mdx) in the mouse". Proceedings of the National Academy of Sciences of the United States of America. 81 (4): 1189–1192. Bibcode:1984PNAS...81.1189B. doi:10.1073/pnas.81.4.1189. PMC 344791. PMID 6583703.
  3. ^ "Animal Models - Parent Project Muscular Dystrophy". parentprojectmd.org. Retrieved 2016-05-03.
  4. ^ Bulfield, G; Siller, W G; Wight, P A; Moore, K J (February 1984). "X chromosome-linked muscular dystrophy (mdx) in the mouse". Proceedings of the National Academy of Sciences. 81 (4): 1189–1192. Bibcode:1984PNAS...81.1189B. doi:10.1073/pnas.81.4.1189. ISSN 0027-8424. PMC 344791. PMID 6583703.
  5. ^ a b Duan, Dongsheng; Goemans, Nathalie; Takeda, Shin’ichi; Mercuri, Eugenio; Aartsma-Rus, Annemieke (2021-02-18). "Duchenne muscular dystrophy". Nature Reviews Disease Primers. 7 (1) 13. doi:10.1038/s41572-021-00248-3. ISSN 2056-676X. PMC 10557455. PMID 33602943.
  6. ^ a b McGreevy, Joe W.; Hakim, Chady H.; McIntosh, Mark A.; Duan, Dongsheng (2015-03-01). "Animal models of Duchenne muscular dystrophy: from basic mechanisms to gene therapy". Disease Models & Mechanisms. 8 (3): 195–213. doi:10.1242/dmm.018424. ISSN 1754-8411. PMC 4348559. PMID 25740330.
  7. ^ Grounds, Miranda D.; Radley, Hannah G.; Lynch, Gordon S.; Nagaraju, Kanneboyina; De Luca, Annamaria (July 2008). "Towards developing standard operating procedures for pre-clinical testing in the mdx mouse model of Duchenne muscular dystrophy". Neurobiology of Disease. 31 (1): 1–19. doi:10.1016/j.nbd.2008.03.008. PMC 2518169. PMID 18499465.
  8. ^ Egorova, Tatiana V.; Polikarpova, Anna V.; Vassilieva, Svetlana G.; Dzhenkova, Marina A.; Savchenko, Irina M.; Velyaev, Oleg A.; Shmidt, Anna A.; Soldatov, Vladislav O.; Pokrovskii, Mikhail V.; Deykin, Alexey V.; Bardina, Maryana V. (September 2023). "CRISPR-Cas9 correction in the DMD mouse model is accompanied by upregulation of Dp71f protein". Molecular Therapy - Methods & Clinical Development. 30: 161–180. doi:10.1016/j.omtm.2023.06.006. PMC 10339130. PMID 37457303.
  9. ^ Long, Chengzu; McAnally, John R.; Shelton, John M.; Mireault, Alex A.; Bassel-Duby, Rhonda; Olson, Eric N. (2014-09-05). "Prevention of muscular dystrophy in mice by CRISPR/Cas9–mediated editing of germline DNA". Science. 345 (6201): 1184–1188. Bibcode:2014Sci...345.1184L. doi:10.1126/science.1254445. ISSN 0036-8075. PMC 4398027. PMID 25123483.
  10. ^ Amoasii, Leonela; Hildyard, John C. W.; Li, Hui; Sanchez-Ortiz, Efrain; Mireault, Alex; Caballero, Daniel; Harron, Rachel; Stathopoulou, Thaleia-Rengina; Massey, Claire; Shelton, John M.; Bassel-Duby, Rhonda; Piercy, Richard J.; Olson, Eric N. (2018-10-05). "Gene editing restores dystrophin expression in a canine model of Duchenne muscular dystrophy". Science. 362 (6410): 86–91. Bibcode:2018Sci...362...86A. doi:10.1126/science.aau1549. ISSN 0036-8075. PMC 6205228. PMID 30166439.
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