title: Dystromirs as serum biomarkers for monitoring the disease severity in Duchenne muscular Dystrophy.
abstract: Duchenne muscular Dystrophy (DMD) is an inherited disease caused by mutations in the dystrophin gene that disrupt the open reading frame, while in frame mutations result in Becker muscular dystrophy (BMD). Ullrich congenital muscular dystrophy (UCMD) is due to mutations affecting collagen VI genes. Specific muscle miRNAs (dystromirs) are potential non-invasive biomarkers for monitoring the outcome of therapeutic interventions and disease progression. We quantified miR-1, miR-133a,b, miR-206 and miR-31 in serum from patients with DMD, BMD, UCMD and healthy controls. MiR-1, miR-133a,b and miR-206 were upregulated in DMD, but unchanged in UCMD compared to controls. Milder DMD patients had higher levels of dystromirs than more severely affected patients. Patients with low forced vital capacity (FVC) values, indicating respiratory muscle weakness, had low levels of serum miR-1 and miR-133b. There was no significant difference in the level of the dystromirs in BMD compared to controls. We also assessed the effect of dystrophin restoration on the expression of the five dystromirs in serum of DMD patients treated systemically for 12 weeks with antisense oligomer eteplirsen that induces skipping of exon 51 in the dystrophin gene. The dystromirs were also analysed in muscle biopsies of DMD patients included in a single dose intramuscular eteplirsen clinical trial. Our analysis detected a trend towards normalization of these miRNA between the pre- and post-treatment samples of the systemic trial, which however failed to reach statistical significance. This could possibly be due to the small number of patients and the short duration of these clinical trials. Although longer term studies are needed to clarify the relationship between dystrophin restoration following therapeutic intervention and the level of circulating miRNAs, our results indicate that miR-1 and miR-133 can be considered as exploratory biomarkers for monitoring the progression of muscle weakness and indirectly the remaining muscle mass in DMD.
authors.affiliation: The Dubowitz Neuromuscular Centre, Institute of Child Health, University College London, London, United Kingdom.
authors.forename: Irina T
authors.initials: IT
authors.lastname: Zaharieva
authors.forename: Mattia
authors.initials: M
authors.lastname: Calissano
authors.forename: Mariacristina
authors.initials: M
authors.lastname: Scoto
authors.forename: Mark
authors.initials: M
authors.lastname: Preston
authors.forename: Sebahattin
authors.initials: S
authors.lastname: Cirak
authors.forename: Lucy
authors.initials: L
authors.lastname: Feng
authors.forename: James
authors.initials: J
authors.lastname: Collins
authors.forename: Ryszard
authors.initials: R
authors.lastname: Kole
authors.forename: Michela
authors.initials: M
authors.lastname: Guglieri
authors.forename: Volker
authors.initials: V
authors.lastname: Straub
authors.forename: Kate
authors.initials: K
authors.lastname: Bushby
authors.forename: Alessandra
authors.initials: A
authors.lastname: Ferlini
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Morgan
authors.forename: Francesco
authors.initials: F
authors.lastname: Muntoni
mesh_terms: D015415:Biomarkers / Q000097:blood; D018450:Disease Progression; D006801:Humans; D035683:MicroRNAs / Q000097:blood*; D018908:Muscle Weakness / Q000235:genetics; D020388:Muscular Dystrophy, Duchenne / Q000097:blood / Q000235:genetics*; D015854:Up-Regulation
chemical_list: D015415:Biomarkers; C544547:MIRN1 microRNA, human; C548234:MIRN133 microRNA, human; C546087:MIRN206 microRNA, human; C534612:MIRN31 microRNA, human; D035683:MicroRNAs