title: PTC124 targets genetic disorders caused by nonsense mutations.
abstract: Nonsense mutations promote premature translational termination and cause anywhere from 5-70% of the individual cases of most inherited diseases. Studies on nonsense-mediated cystic fibrosis have indicated that boosting specific protein synthesis from <1% to as little as 5% of normal levels may greatly reduce the severity or eliminate the principal manifestations of disease. To address the need for a drug capable of suppressing premature termination, we identified PTC124-a new chemical entity that selectively induces ribosomal readthrough of premature but not normal termination codons. PTC124 activity, optimized using nonsense-containing reporters, promoted dystrophin production in primary muscle cells from humans and mdx mice expressing dystrophin nonsense alleles, and rescued striated muscle function in mdx mice within 2-8 weeks of drug exposure. PTC124 was well tolerated in animals at plasma exposures substantially in excess of those required for nonsense suppression. The selectivity of PTC124 for premature termination codons, its well characterized activity profile, oral bioavailability and pharmacological properties indicate that this drug may have broad clinical potential for the treatment of a large group of genetic disorders with limited or no therapeutic options.
authors: PTC Therapeutics, 100 Corporate Court, South Plainfield, New Jersey 07080, USA.
authors: Ellen M
authors: EM
authors: Welch
authors: Elisabeth R
authors: ER
authors: Barton
authors: Jin
authors: J
authors: Zhuo
authors: Yuki
authors: Y
authors: Tomizawa
authors: Westley J
authors: WJ
authors: Friesen
authors: Panayiota
authors: P
authors: Trifillis
authors: Sergey
authors: S
authors: Paushkin
authors: Meenal
authors: M
authors: Patel
authors: Christopher R
authors: CR
authors: Trotta
authors: Seongwoo
authors: S
authors: Hwang
authors: Richard G
authors: RG
authors: Wilde
authors: Gary
authors: G
authors: Karp
authors: James
authors: J
authors: Takasugi
authors: Guangming
authors: G
authors: Chen
authors: Stephen
authors: S
authors: Jones
authors: Hongyu
authors: H
authors: Ren
authors: Young-Choon
authors: YC
authors: Moon
authors: Donald
authors: D
authors: Corson
authors: Anthony A
authors: AA
authors: Turpoff
authors: Jeffrey A
authors: JA
authors: Campbell
authors: M Morgan
authors: MM
authors: Conn
authors: Atiyya
authors: A
authors: Khan
authors: Neil G
authors: NG
authors: Almstead
authors: Jean
authors: J
authors: Hedrick
authors: Anna
authors: A
authors: Mollin
authors: Nicole
authors: N
authors: Risher
authors: Marla
authors: M
authors: Weetall
authors: Shirley
authors: S
authors: Yeh
authors: Arthur A
authors: AA
authors: Branstrom
authors: Joseph M
authors: JM
authors: Colacino
authors: John
authors: J
authors: Babiak
authors: William D
authors: WD
authors: Ju
authors: Samit
authors: S
authors: Hirawat
authors: Valerie J
authors: VJ
authors: Northcutt
authors: Langdon L
authors: LL
authors: Miller
authors: Phyllis
authors: P
authors: Spatrick
authors: Feng
authors: F
authors: He
authors: Masataka
authors: M
authors: Kawana
authors: Huisheng
authors: H
authors: Feng
authors: Allan
authors: A
authors: Jacobson
authors: Stuart W
authors: SW
authors: Peltz
authors: H Lee
authors: HL
authors: Sweeney
mesh_terms: D000483:Alleles; D000818:Animals; D001682:Biological Availability; D018389:Codon, Nonsense / Q000235:genetics*; D016189:Dystrophin / Q000096:biosynthesis / Q000235:genetics; D030342:Genetic Diseases, Inborn / Q000097:blood / Q000188:drug therapy* / Q000235:genetics*; D006801:Humans; D051379:Mice; D018101:Mice, Inbred mdx; D010069:Oxadiazoles / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use*; D010641:Phenotype; D014176:Protein Biosynthesis / Q000187:drug effects* / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013379:Substrate Specificity
chemical_list: D018389:Codon, Nonsense; D016189:Dystrophin; D010069:Oxadiazoles; D012333:RNA, Messenger; C515878:ataluren