China
Africa
Explore chapters and articles related to this topic
Translation
Published in Paul Pumpens, Single-Stranded RNA Phages, 2020
As stated in the Conditionally lethal mutations section of Chapter 8, the mechanism of suppression by specific tRNAs was discovered. In addition to the general data presented there, the yeast super-suppressors could be mentioned here (Capecchi et al. 1975). Such yeast super-suppressors were altered tRNAs capable of translating a nonsense codon in vitro. The suppression was assayed by translation of the Qβ coat amber mutant RNA in the cell-free protein-synthesizing system derived from mouse tissue culture cells, or L-cells. Remarkably, the L-cell protein-synthesizing system also responded to E. coli suppressor tRNA. This indicated that the biochemical mechanism for nonsense suppression was very similar in yeast and E. coli. Moreover, this finding provided additional evidence that the amber codon functions as one of the mammalian chain-terminating codons.
Current and future CFTR therapeutics
Published in Anthony J. Hickey, Heidi M. Mansour, Inhalation Aerosols, 2019
Marne C. Hagemeijer, Gimano D. Amatngalim, Jeffrey M. Beekman
PTC Therapeutics Inc. decided to discontinue the clinical development of Ataluren for CF patients harboring nonsense mutations (65). Currently, no effective nonsense suppression therapy for people with CF is available and thus a need for the development of novel effective read-through agents that target this specific class of mutations exists, perhaps in combination with other approved and/or investigational CFTR modulator therapies.
Is subretinal AAV gene replacement still the only viable treatment option for choroideremia?
Published in Expert Opinion on Orphan Drugs, 2021
Ruofan Connie Han, Lewis E. Fry, Ariel Kantor, Michelle E. McClements, Kanmin Xue, Robert E. MacLaren
Nonsense-suppression strategies are theoretically appealing as they can be delivered systemically and non-invasively, and have wide-ranging therapeutic targets beyond the eye. There are currently 34 trials registered for Ataluren (TranslarnaTM) on the Clinical Trials database, including a phase 2 trial for nonsense mutations in aniridia (NCT02647359). Unlike any targeted therapy delivered by subretinal injection, treatment is not limited spatially in the eye. However, previous clinical trials in cystic fibrosis [81] and Duchenne’s muscular dystrophy [82] have shown only small treatment effects limited to rigidly defined patient subgroups. By its nature, nonsense-suppression strategies are nonspecific and must promote near-cognate tRNA binding throughout all translation events, potentially increasing production of other anomalous proteins. Furthermore, the applicability of nonsense-suppression strategies may be much narrower than the number of nonsense mutations in CHM. Administration of Ataluren to patient-derived fibroblasts carrying a c.772A>T substitution leading to p.Lys258* failed to show a statistically significant trend in improving prenylation profile compared to non-treated fibroblasts, and did not increase levels of REP1 mRNA or detectable REP1 protein [83]. The authors’ in silico modeling suggested that the preferred amino acid substitutions provided by Ataluren-induced enhanced read-through were still damaging to REP1 function, and proposed that patients may require mutational screening and modeling before initiation of therapy.
Progress in the development of novel therapies for choroideremia
Published in Expert Review of Ophthalmology, 2019
Jasmina Cehajic Kapetanovic, Maria I Patrício, Robert E MacLaren
In addition to gene therapy, there are several alternative strategies under development with a potential to treat choroideremia. In-frame nonsense mutations, resulting in premature termination codons and nonsense-mediated decay could potentially be amenable to nonsense suppression therapy [36]. Small molecule drugs, based on aminoglycosides, could promote ribosomal read-through and thus potentially treat phenotypes caused by nonsense-mediated disease [37]. This nonsense suppression therapy has been investigated in other genetic disorders, including cystic fibrosis and Duchenne muscular dystrophy, with recent NICE approval of one of the oral compounds (PTC124, ataluren or Translarna™) for the treatment of Duchenne muscular dystrophy caused by a nonsense change in the dystrophin gene [37,38]. In-vitro and in-vivo pre-clinical testing of ataluren (and another optimized compound) in models of choroideremia, led to some promising results with improved REP1 expression [39]. One of the challenges in the future development of this potential treatment is the lack of specificity for the gene of interest with the potential to override normal stop codons and express unwanted nonsense mutations in other genes.
Translational readthrough inducing drugs for the treatment of inherited retinal dystrophies
Published in Expert Review of Ophthalmology, 2020
Christopher M Way, Dulce Lima Cunha, Mariya Moosajee
Nonsense suppression therapy is a method of pharmacological gene therapy that could help millions of patients across the globe. IRDs are a prime target for nonsense suppression due to their preponderance for nonsense mutations and the devastating blindness they currently cause. This review highlights the exciting preclinical promise of nonsense suppression therapy for the treatment of IRDs. Though TranslarnaTM has reached clinical trial (NCT02647359) for aniridia, the preclinical developments described create anticipation for more clinical trials, including for other compounds.