PTC124 targets genetic disorders caused by nonsense mutations.
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.
Welch
Ellen M
EM
PTC Therapeutics, 100 Corporate Court, South Plainfield, New Jersey 07080, USA.
Barton
Elisabeth R
ER
Zhuo
Jin
J
Tomizawa
Yuki
Y
Friesen
Westley J
WJ
Trifillis
Panayiota
P
Paushkin
Sergey
S
Patel
Meenal
M
Trotta
Christopher R
CR
Hwang
Seongwoo
S
Wilde
Richard G
RG
Karp
Gary
G
Takasugi
James
J
Chen
Guangming
G
Jones
Stephen
S
Ren
Hongyu
H
Moon
Young-Choon
YC
Corson
Donald
D
Turpoff
Anthony A
AA
Campbell
Jeffrey A
JA
Conn
M Morgan
MM
Khan
Atiyya
A
Almstead
Neil G
NG
Hedrick
Jean
J
Mollin
Anna
A
Risher
Nicole
N
Weetall
Marla
M
Yeh
Shirley
S
Branstrom
Arthur A
AA
Colacino
Joseph M
JM
Babiak
John
J
Ju
William D
WD
Hirawat
Samit
S
Northcutt
Valerie J
VJ
Miller
Langdon L
LL
Spatrick
Phyllis
P
He
Feng
F
Kawana
Masataka
M
Feng
Huisheng
H
Jacobson
Allan
A
Peltz
Stuart W
SW
Sweeney
H Lee
HL
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
D018389:Codon, Nonsense; D016189:Dystrophin; D010069:Oxadiazoles; D012333:RNA, Messenger; C515878:ataluren