title: Dmpk gene deletion or antisense knockdown does not compromise cardiac or skeletal muscle function in mice.
abstract: Myotonic dystrophy type 1 (DM1) is a genetic disorder in which dominant-active DM protein kinase (DMPK) transcripts accumulate in nuclear foci, leading to abnormal regulation of RNA processing. A leading approach to treat DM1 uses DMPK-targeting antisense oligonucleotides (ASOs) to reduce levels of toxic RNA. However, basal levels of DMPK protein are reduced by half in DM1 patients. This raises concern that intolerance for further DMPK loss may limit ASO therapy, especially since mice with Dmpk gene deletion reportedly show cardiac defects and skeletal myopathy. We re-examined cardiac and muscle function in mice with Dmpk gene deletion, and studied post-maturity knockdown using Dmpk-targeting ASOs in mice with heterozygous deletion. Contrary to previous reports, we found no effect of Dmpk gene deletion on cardiac or muscle function, when studied on two genetic backgrounds. In heterozygous knockouts, the administration of ASOs reduced Dmpk expression in cardiac and skeletal muscle by > 90%, yet survival, electrocardiogram intervals, cardiac ejection fraction and muscle strength remained normal. The imposition of cardiac stress by pressure overload, or muscle stress by myotonia, did not unmask a requirement for DMPK. Our results support the feasibility and safety of using ASOs for post-transcriptional silencing of DMPK in muscle and heart.
authors: Department of Biomedical Genetics.
authors: Samuel T
authors: ST
authors: Carrell
authors: Department of Pharmacology and Physiology.
authors: Ellie M
authors: EM
authors: Carrell
authors: Division of Cardiology, Department of Medicine.
authors: David
authors: D
authors: Auerbach
authors: Ionis Pharmaceuticals, Carlsbad, California, CA, USA.
authors: Sanjay K
authors: SK
authors: Pandey
authors: Ionis Pharmaceuticals, Carlsbad, California, CA, USA.
authors: C Frank
authors: CF
authors: Bennett
authors: Department of Pharmacology and Physiology.
authors: Robert T
authors: RT
authors: Dirksen
authors: Department of Neurology, University of Rochester, Rochester, New York, NY, USA and Charles_Thornton@urmc.rochester.edu.
authors: Charles A
authors: CA
authors: Thornton
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D017353:Gene Deletion; D055785:Gene Knockdown Techniques; D015316:Genetic Therapy; D006801:Humans; D051379:Mice; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009223:Myotonic Dystrophy / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D065636:Myotonin-Protein Kinase / Q000096:biosynthesis* / Q000235:genetics; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage* / Q000235:genetics; D012313:RNA / Q000037:antagonists & inhibitors / Q000235:genetics
chemical_list: C585516:DMPK protein, mouse; D016376:Oligonucleotides, Antisense; D012313:RNA; D065636:Myotonin-Protein Kinase