Current and future CFTR therapeutics
Anthony J. Hickey, Heidi M. Mansour in Inhalation Aerosols, 2019
Ataluren (PTC124, Translarna™) is an oxadiazole of which the chemical structure is depicted in Figure 14.4. The drug is taken as an oral suspension and is metabolized by uridine diphosphate glucuronosyltransferase (UGT) enzymes in the liver into ataluren-O-1β-acyl glucuronide with (i) a tissue half-life of 2–6 hours, (ii) peak plasma levels being reached around 1.5 hours after administration, and (iii) 99.6% bound to plasma proteins (53). Ataluren was initially developed to treat Duchene muscular dystrophy (DMD) (54), for which it has been authorized in the European Union (53), but also seemed to be effective in clinical studies in individuals with CFTR premature termination mutations (55–57). The mechanism of action of Ataluren is not completely understood. It promotes translational read-through by stimulating insertion of near-cognate tRNAs at the premature termination codon with specific codon-anticodon preference for amino acid substitutions, for which direct binding to ribosomes seems to be required (58). The sequence surrounding the premature termination codon also seems to be important for this selection (59).
New pharmacotherapies for genetic neuromuscular disorders: opportunities and challenges
Published in Expert Review of Clinical Pharmacology, 2019
Federica Ricci, Martina Vacchetti, Chiara Brusa, Liliana Vercelli, Chiara Davico, Benedetto Vitiello, Tiziana Mongini
Ataluren is an oral drug which can be prescribed in DMD patients with premature stop codon mutations (about 10% of overall Xp21 mutated DMD patients) [46]. When a point mutation determines a premature stop codon in pre-mRNA, the translational ribosomal complex stops, resulting in a prematurely truncated and non-functional protein [45]. Ataluren acts by binding to ribosomal RNA subunits, thus allowing stop codons readthrough to take place. Interestingly, some nonsense mutations are associated with a more benign phenotype, more similar to BMD, possibly due to a point mutation induced exon skipping mechanism, i.e., exclusion of the nonsense mutation-containing exon [47]. According to some models, the exon skipping event could be linked critical disruption of exonic splicing enhancer (ESE) or creation of exonic splicing suppressor (ESS) motifs by point mutation [48].
SCN1A as a therapeutic target for Dravet syndrome
Published in Expert Opinion on Therapeutic Targets, 2023
Ataluren, also known as PTC124, is a drug designed to increase protein expression in patients with nonsense pathogenic variants. A nonsense pathogenic variant is a nucleotide change that results in a ‘stop codon,’ which leads to one of UAA, UAG, or UGA in the mRNA coding sequence. Normally, a stop codon triggers premature termination of translation, and the truncated polypeptide is degraded. However, certain agents, such as aminoglycoside antibiotics, have been shown to promote read-through of nonsense codons, allowing continued translation and ultimately production of a full-length protein product [62]. Gentamicin has been trialed in Duchenne muscular dystrophy and cystic fibrosis due to nonsense pathogenic variants, albeit with limited clinical benefit and concern for side effects such as ototoxicity and nephrotoxicity [63–66].
Therapeutic advances in Dravet syndrome: a targeted literature review
Published in Expert Review of Neurotherapeutics, 2020
Adam Strzelczyk, Susanne Schubert-Bast
A number of agents are in development for the treatment of DS (Figure 1). Soticlestat (TAK-935/OV935), a novel highly selective first-in-class inhibitor of the brain-specific enzyme cholesterol 24-hydroxylase (CH24H) [72], is being evaluated in two phase II trials for DEEs including DS: the ELEKTRA trial (NCT03650452) [73], and the ENDYMION trial [74]. Ataluren, which is already indicated for the treatment of Duchenne muscular dystrophy, where it promotes readthrough of a nonsense mutation to produce full-length functional dystrophin protein [75], is being evaluated in a phase II trial in patients with DS resulting from a nonsense mutation (NCT02758626) [76]. Verapamil, a voltage-gated calcium channel blocker currently used to treat hypertension, angina, and certain heart rhythm disorders [77], showed a partial (reduction of 50–99%) response for all types of seizures over a 14-month period in a pilot study in 3/4 patients with DS [77]. Verapamil has also been assessed in a phase II trial in children and young adults with DS (NCT01607073) [78], although while the trial was completed in 2015, the data have yet to be reported. Phenotypic screening of drug libraries in a preclinical model using zebrafish scn1 mutants identified the serotonin (5-HT) modulators clemizole (EPX-100), lorcaserin (EPX-200) and trazodone (EPX-300) as potential clinical treatments for DS [79,80], with clemizole being assessed in a phase I trial in healthy subjects (NCT04069689) [81].
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