PTC124 targets genetic disorders caused by nonsense mutations

@article{Welch2007PTC124TG,
  title={PTC124 targets genetic disorders caused by nonsense mutations},
  author={Ellen Marie Welch and Elisabeth R. Barton and Jin Zhuo and Yuki Tomizawa and Westley J Friesen and Panayiota Trifillis and Sergey Paushkin and Meenal Patel and Christopher R Trotta and Seongwoo Hwang and Richard G. Wilde and Gary Mitchell Karp and James Jan Takasugi and Guangming Chen and Stephen E. Jones and Hongyu Ren and Young-Choon Moon and Donald T Corson and Anthony A. Turpoff and Jeffrey Allen Campbell and M. Morgan Conn and Atiyya R. Khan and Neil Gregory Almstead and Jean Hedrick and Anna Mollin and Nicole Risher and Marla Weetall and Shirley Yeh and Arthur A. Branstrom and Joseph M. Colacino and John Babiak and William D. Ju and Samit Hirawat and Valerie Northcutt and Langdon L. Miller and Phyllis Spatrick and Feng He and Masataka Kawana and Huisheng Feng and Allan Jacobson and Stuart W Peltz and H. Lee Sweeney},
  journal={Nature},
  year={2007},
  volume={447},
  pages={87-91}
}
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… 

Pharmaceuticals Targeting Nonsense Mutations in Genetic Diseases

TLDR
The mechanistic underpinnings of PTC suppression are examined, including the nature of the interactions between agents that suppress PTCs and the eukaryotic ribosomes and the importance of the mRNA context in suppression.

Nonsense suppression therapies in human genetic diseases.

TLDR
The use of NMD inhibitors, or readthrough-compound potentiators, may enhance the efficiency of PTC suppression, and their role in personalized medicine is reviewed.

Nonsense suppression therapies in ocular genetic diseases

TLDR
The mechanisms that are involved in discriminating normal translation termination from premature termination codons are highlighted; the current understanding of nonsense-mediated mRNA decay models (NMD); the association and crosstalk between PTC and the underlying dynamic NMD process; and the suppression therapies that have been employed in nonsense-medicated ocular disease models are highlighted.

Chemotherapeutics overcoming nonsense mutation-associated genetic diseases: medicinal chemistry of negamycin

TLDR
Two natural negamycin analogs are discovered, 3-epi-deoxynegamycin and its leucine derivative, which are potent readthrough compounds effective against nonsense mutations of eukaryotes but not prokaryotes, and these compounds fail to display antimicrobial activity.

Synergy between Readthrough and Nonsense Mediated Decay Inhibition in a Murine Model of Cystic Fibrosis Nonsense Mutations

TLDR
Examination of combinations of known NMD inhibitors and readthrough agents using functional analysis of the CFTR protein in primary cells from a mouse model carrying a G542X nonsense mutation in Cftr indicates that treatment with N MD inhibitors can increase the quantity of functional protein following readthrough, and that combining NMD inhibitor and read through agents represents a potential therapeutic option for treating nonsense mutations.

Nonsense Mutations Causing Inherited Diseases: Therapeutic Approaches

TLDR
Nonsense mutations are single nucleotide variations within the coding sequence of a gene that result in a premature termination codon (PTC) that trigger transcript degradation through the nonsense-mediated mRNA decay (NMD) mechanism.

Ataluren—Promising Therapeutic Premature Termination Codon Readthrough Frontrunner

TLDR
Ataluren’s journey from its identification, via first in vitro activity experiments, to clinical trials in DMD, cystic fibrosis, and aniridia is summarized and the range of diseases with underlying nonsense mutations is described for which ataluren therapy seems to be promising.
...

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