PTC124 targets genetic disorders caused by nonsense mutations

  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},
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

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.

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

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

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

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

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

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.



Pharmacologic therapy for stop mutations: how much CFTR activity is enough?

  • E. Kerem
  • Biology, Medicine
    Current opinion in pulmonary medicine
  • 2004
It is as yet unknown how much corrected mutant CFTR must reach the apical membrane to induce a clinically relevant beneficial effect, and the future goal is to maximize the effect of stop-codon supressors on CFTR while minimizing side effects.

Gentamicin treatment of Duchenne and Becker muscular dystrophy due to nonsense mutations

In the mdx mouse, where muscular dystrophy is due to a nonsense mutation in the dystrophin gene, gentamicin suppressed truncation of the protein and ameliorated the phenotype, and full‐length dyStrophin was not detected in pre‐ and post‐treatment muscle biopsies.

Safety, Tolerability, and Pharmacokinetics of PTC124, a Nonaminoglycoside Nonsense Mutation Suppressor, Following Single‐ and Multiple‐Dose Administration to Healthy Male and Female Adult Volunteers

Data support initiation of phase II studies of PTC124 in patients with nonsense mutation–mediated cystic fibrosis and Duchenne muscular dystrophy.

Nonsense surveillance regulates expression of diverse classes of mammalian transcripts and mutes genomic noise

Novel results document that nonsense surveillance is a crucial post-transcriptional regulatory event that influences the expression of broad classes of physiologic transcripts, has been functionally incorporated into essential homeostatic mechanisms and suppresses expression of evolutionary remnants.

Sequence specificity of aminoglycoside‐induced stop codon readthrough: Potential implications for treatment of Duchenne muscular dystrophy

Analysis of aminoglycoside‐induced readthrough of each stop codon in human tissue culture cells using a dual luciferase reporter system showed significant differences in the efficiency, with UGA showing greater translational readthrough than UAG or UAA.

Gentamicin-induced correction of CFTR function in patients with cystic fibrosis and CFTR stop mutations.

In patients with cystic fibrosis who have premature stop codons, gentamicin can cause translational "read through," resulting in the expression of full-length CFTR protein at the apical cell membrane, and thus can correct the typical electrophysiological abnormalities caused by CFTR dysfunction.

Gentamicin administration in Duchenne patients with premature stop codon. Preliminary results.

  • L. PolitanoG. Nigro L. Comi
  • Medicine, Biology
    Acta myologica : myopathies and cardiomyopathies : official journal of the Mediterranean Society of Myology
  • 2003
Results suggest that gentamicin is able to recover dystrophin expression in a subset of Duchenne patients with nonsense mutations, raising the possibility of the first pharmacological treatment for muscular dystrophy.

A faux 3′-UTR promotes aberrant termination and triggers nonsense- mediated mRNA decay

It is found that efficient termination and mRNA stability are dependent on a properly configured 3′-UTR, and a primer extension inhibition (toeprinting) assay is used to delineate ribosome positioning and finds that premature translation termination in yeast extracts is indeed aberrant.

Identification and characterization of mutations in the UPF1 gene that affect nonsense suppression and the formation of the Upf protein complex but not mRNA turnover

The identification and biochemical characterization of mutations in the amino-terminal cysteine- and histidine-rich region of Upf1p that have normal nonsense-mediated mRNA decay activities but are able to suppress leu2-2 and tyr7-1 nonsense alleles are described.

Evidence that systemic gentamicin suppresses premature stop mutations in patients with cystic fibrosis.

Gentamicin treatment can suppress premature stop mutations in airway cells from patients with CF, and produce small increases in CFTR Cl(-) conductance (as measured by the nasal PD) in vivo.