European Medicines Agency review of ataluren for the treatment of ambulant patients aged 5 years and older with Duchenne muscular dystrophy resulting from a nonsense mutation in the dystrophin gene

Haas, Manuel; Vlcek, Viktor; Balabanov, Pavel; Salmonson, Tomas; Bakchine, Serge; Markey, Greg; Weise, Martina; Schlosser-Weber, Gabriele; Brohmann, Henning; Yerro, Concepción Prieto; Mendizabal, Macarena Rodriguez; Stoyanova-Beninska, Violeta; Hillege, Hans L.

doi:10.1016/j.nmd.2014.11.011

Cited by 137 publications

(107 citation statements)

References 13 publications

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“…1 and SI Appendix, Fig. S3) (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)23); (ii) the effects on luciferase activity could not be independently replicated by others (24) or by us (SI Appendix , Fig. S3C); (iii) ataluren's putative luciferase inhibitory activity depends on a specific enzyme substrate (25); and (iv) most of the hypothetical inhibitory molecule, PTC124-AMP (22), is rapidly converted to the active readthrough molecule PTC124 (ataluren) under conditions of in vitro translation (SI Appendix, Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Multiple experimental approaches with cell lines, patient cells, animal models, and genetic disorder patients have demonstrated that the drug ataluren can restore expression to genes and mRNAs otherwise inactive because of the presence of premature nonsense codons (1,(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)23). Collectively, such experiments have strongly suggested that ataluren promotes nonsense suppression, i.e., the insertion of near-cognate tRNAs at PTCs, but direct evidence for this activity has been lacking.…”

Section: Discussionmentioning

confidence: 99%

“…To date, ataluren has been shown to restore function to more than 20 different disease-specific or reporter nonsense alleles in systems ranging in complexity from in vitro translation to cell culture to mouse models and human patients (1,(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14). In the latter, Translarna clinical trials have demonstrated restoration of full-length functional protein in Duchenne muscular dystrophy and cystic fibrosis nonsense mutation patients (10,11,13,15,16). However, a lack of activity has been reported for some cell systems (17,18).…”

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confidence: 99%

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Ataluren stimulates ribosomal selection of near-cognate tRNAs to promote nonsense suppression

Roy

Friesen

Tomizawa

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

188

218

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A premature termination codon (PTC) in the ORF of an mRNA generally leads to production of a truncated polypeptide, accelerated degradation of the mRNA, and depression of overall mRNA expression. Accordingly, nonsense mutations cause some of the most severe forms of inherited disorders. The small-molecule drug ataluren promotes therapeutic nonsense suppression and has been thought to mediate the insertion of near-cognate tRNAs at PTCs. However, direct evidence for this activity has been lacking. Here, we expressed multiple nonsense mutation reporters in human cells and yeast and identified the amino acids inserted when a PTC occupies the ribosomal A site in control, ataluren-treated, and aminoglycoside-treated cells. We find that ataluren’s likely target is the ribosome and that it produces full-length protein by promoting insertion of near-cognate tRNAs at the site of the nonsense codon without apparent effects on transcription, mRNA processing, mRNA stability, or protein stability. The resulting readthrough proteins retain function and contain amino acid replacements similar to those derived from endogenous readthrough, namely Gln, Lys, or Tyr at UAA or UAG PTCs and Trp, Arg, or Cys at UGA PTCs. These insertion biases arise primarily from mRNA:tRNA mispairing at codon positions 1 and 3 and reflect, in part, the preferred use of certain nonstandard base pairs, e.g., U-G. Ataluren’s retention of similar specificity of near-cognate tRNA insertion as occurs endogenously has important implications for its general use in therapeutic nonsense suppression.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Ataluren stimulates ribosomal selection of near-cognate tRNAs to promote nonsense suppression

Roy

Friesen

Tomizawa

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

188

218

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“…[19][20][21] Even very small quantities of dystrophin, hardly detectable by immunohistochemistry (IHC) or Western blot (WB), might ameliorate the disease and delay LoA by several years. This is particularly relevant for the development of dystrophin-restoring treatments, such as exon skipping by antisense oligonucleotides (AONs) [22][23][24][25][26][27][28][29][30] and stop codon readthrough, [31][32][33] as variation in baseline levels of dystrophin may confound evaluations of efficacy in clinical trials.…”

mentioning

confidence: 99%

DMD genotypes and loss of ambulation in the CINRG Duchenne natural history study

Bello

Morgenroth

Gordish‐Dressman

et al. 2016

Neuromuscular Disorders

101

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“…PTC Therapeutics have also announced commencement of a rolling submission of a new drug application (NDA) to the US Food and Drug Administration (FDA). [16] Similarly, intensive effort is made to demonstrate the safety and efficacy of exon skipping therapy for exon 51, which has shown considerable promise in phase II and III clinical trials. In October 2014, Prosensa Therapeutics announced that the FDA had given drisapersen (an exon skipping agent for exon 51) a fast track designation.…”

Section: Into the Future Genetic Therapiesmentioning

confidence: 99%

Duchenne muscular dystrophy in the Western Cape, South Africa: Where do we come from and where are we going?

Esterhuizen¹,

Greenberg²,

Ballo³

et al. 2016

S Afr Med J

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Duchenne muscular dystrophy (DMD) is one of the most common and severe of the inherited dystrophies, with an incidence of 1 in 3 500 live, male births worldwide. Becker muscular dystrophy (BMD) has a lower incidence of 1:14 000 -18 000 boys and a milder progression and longer life expectancy. Over the last two decades, better understanding of the underlying disease aetiology as well as major advances in medical technology have brought about significantly improved genetic diagnosis and clinical care for B/DMD patients. Exciting developments in the field of gene-based therapies have once again put B/DMD in the limelight, with renewed focus on the importance of comprehensive genetic testing protocols. We present a historical overview of the medical and molecular service for B/DMD offered over the last three decades in South Africa, specifically in the Western Cape, from a clinical as well as a laboratory perspective.

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European Medicines Agency review of ataluren for the treatment of ambulant patients aged 5 years and older with Duchenne muscular dystrophy resulting from a nonsense mutation in the dystrophin gene

Cited by 137 publications

References 13 publications

Ataluren stimulates ribosomal selection of near-cognate tRNAs to promote nonsense suppression

Ataluren stimulates ribosomal selection of near-cognate tRNAs to promote nonsense suppression

DMD genotypes and loss of ambulation in the CINRG Duchenne natural history study

Duchenne muscular dystrophy in the Western Cape, South Africa: Where do we come from and where are we going?

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