title: Biological Efficacy and Toxicity of Diamidines in Myotonic Dystrophy Type 1 Models.
abstract: Myotonic dystrophy type 1 (DM1) is a disease characterized by errors in alternative splicing, or "mis-splicing". The causative agent of mis-splicing in DM1 is an inherited CTG repeat expansion located in the 3' untranslated region of the DM protein kinase gene. When transcribed, CUG repeat expansion RNA sequesters muscleblind-like (MBNL) proteins, which constitute an important family of alternative splicing regulators. Sequestration of MBNL proteins results in the mis-splicing of its regulated transcripts. Previous work has demonstrated that pentamidine, a diamidine which is currently FDA-approved as an antiparasitic agent, was able to partially reverse mis-splicing in multiple DM1 models, albeit at toxic concentrations. In this study, we characterized a series of pentamidine analogues to determine their ability to reverse mis-splicing and their toxicity in vivo. Experiments in cell and mouse models demonstrated that compound 13, also known as furamidine, effectively reversed mis-splicing with equal efficacy and reduced toxicity compared to pentamidine.
authors.forename: Ruth B
authors.initials: RB
authors.lastname: Siboni
authors.forename: Micah J
authors.initials: MJ
authors.lastname: Bodner
authors.forename: Muhammad M
authors.initials: MM
authors.lastname: Khalifa
authors.forename: Aaron G
authors.initials: AG
authors.lastname: Docter
authors.forename: Jessica Y
authors.initials: JY
authors.lastname: Choi
authors.affiliation: §Department of Neurology, University of Osaka Graduate School of Medicine, Osaka 565-0871, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Nakamori
authors.forename: Michael M
authors.initials: MM
authors.lastname: Haley
authors.forename: J Andrew
authors.initials: JA
authors.lastname: Berglund
mesh_terms: D000578:Amidines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D008297:Male; D009223:Myotonic Dystrophy / Q000188:drug therapy*; D013329:Structure-Activity Relationship
chemical_list: D000578:Amidines