Read-through compound 13 restores dystrophin expression and improves muscle function in the mdx mouse model for Duchenne muscular dystrophy.
Molecules that induce ribosomal read-through of nonsense mutations in mRNA and allow production of a full-length functional protein hold great therapeutic potential for the treatment of many genetic disorders. Two such read-through compounds, RTC13 and RTC14, were recently identified by a luciferase-independent high-throughput screening assay and were shown to have potential therapeutic functions in the treatment of nonsense mutations in the ATM and the dystrophin genes. We have now tested the ability of RTC13 and RTC14 to restore dystrophin expression into skeletal muscles of the mdx mouse model for Duchenne muscular dystrophy (DMD). Direct intramuscular injection of compound RTC14 did not result in significant read-through activity in vivo and demonstrated the levels of dystrophin protein similar to those detected using gentamicin. In contrast, significant higher amounts of dystrophin were detected after intramuscular injection of RTC13. When administered systemically, RTC13 was shown to partially restore dystrophin protein in different muscle groups, including diaphragm and heart, and improved muscle function. An increase in muscle strength was detected in all treated animals and was accompanied by a significant decrease in creatine kinase levels. These studies establish the therapeutic potential of RTC13 in vivo and advance this newly identified compound into preclinical application for DMD.
Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
Refik
R
Kayali
Jin-Mo
JM
Ku
Gregory
G
Khitrov
Michael E
ME
Jung
Olga
O
Prikhodko
Carmen
C
Bertoni
D000818:Animals; D018389:Codon, Nonsense; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D016189:Dystrophin / Q000235:genetics* / Q000378:metabolism; D005663:Furans / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D005839:Gentamicins / Q000008:administration & dosage / Q000494:pharmacology; D007273:Injections, Intramuscular; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism; D053580:Muscle Strength / Q000187:drug effects; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D020388:Muscular Dystrophy, Duchenne / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D010069:Oxadiazoles / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D010636:Phenols / Q000008:administration & dosage / Q000494:pharmacology*; D011500:Protein Synthesis Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D016364:Reading Frames; D012545:Schiff Bases / Q000008:administration & dosage / Q000494:pharmacology*; D053778:Thiazolidines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects*
C577431:2-imino-5-((5-(2-nitrophenyl)furan-2-yl)methylene)thiazolidin-4-one; D018389:Codon, Nonsense; D016189:Dystrophin; D005663:Furans; D005839:Gentamicins; D010069:Oxadiazoles; D010636:Phenols; D011500:Protein Synthesis Inhibitors; D012545:Schiff Bases; D053778:Thiazolidines; C515878:ataluren