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Автор: Grafiati

Опубліковано: 14 березня 2023

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1

Michorowska, Sylwia. "Ataluren—Promising Therapeutic Premature Termination Codon Readthrough Frontrunner." Pharmaceuticals 14, no. 8 (August 9, 2021): 785. http://dx.doi.org/10.3390/ph14080785.

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Анотація:

Around 12% of hereditary disease-causing mutations are in-frame nonsense mutations. The expression of genes containing nonsense mutations potentially leads to the production of truncated proteins with residual or virtually no function. However, the translation of transcripts containing premature stop codons resulting in full-length protein expression can be achieved using readthrough agents. Among them, only ataluren was approved in several countries to treat nonsense mutation Duchenne muscular dystrophy (DMD) patients. This review summarizes ataluren’s journey from its identification, via first in vitro activity experiments, to clinical trials in DMD, cystic fibrosis, and aniridia. Additionally, data on its pharmacokinetics and mechanism of action are presented. The range of diseases with underlying nonsense mutations is described for which ataluren therapy seems to be promising. What is more, experiments in which ataluren did not show its readthrough activity are also included, and reasons for their failures are discussed.

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2

Davies, S., N. Serradell, E. Rosa, and R. Castañer. "Ataluren." Drugs of the Future 33, no. 9 (2008): 733. http://dx.doi.org/10.1358/dof.2008.033.09.1252090.

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3

Mercuri, Eugenio, Francesco Muntoni, Andrés Nascimento Osorio, Már Tulinius, Filippo Buccella, Lauren P. Morgenroth, Heather Gordish-Dressman, et al. "Safety and effectiveness of ataluren: comparison of results from the STRIDE Registry and CINRG DMD Natural History Study." Journal of Comparative Effectiveness Research 9, no. 5 (April 2020): 341–60. http://dx.doi.org/10.2217/cer-2019-0171.

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Aim: Strategic Targeting of Registries and International Database of Excellence (STRIDE) is an ongoing, multicenter registry providing real-world evidence regarding ataluren use in patients with nonsense mutation Duchenne muscular dystrophy (nmDMD). We examined the effectiveness of ataluren + standard of care (SoC) in the registry versus SoC alone in the Cooperative International Neuromuscular Research Group (CINRG) Duchenne Natural History Study (DNHS), DMD genotype–phenotype/–ataluren benefit correlations and ataluren safety. Patients & methods: Propensity score matching was performed to identify STRIDE and CINRG DNHS patients who were comparable in established disease progression predictors (registry cut-off date, 9 July 2018). Results & conclusion: Kaplan–Meier analyses demonstrated that ataluren + SoC significantly delayed age at loss of ambulation and age at worsening performance in timed function tests versus SoC alone (p ≤ 0.05). There were no DMD genotype–phenotype/ataluren benefit correlations. Ataluren was well tolerated. These results indicate that ataluren + SoC delays functional milestones of DMD progression in patients with nmDMD in routine clinical practice. ClinicalTrials.gov identifier: NCT02369731. ClinicalTrials.gov identifier: NCT02369731.

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4

Kaushik, Diksha, Jiyuan Ma, Guodong Gu, Seongwoo Hwang, Young-Choon Moon, and Ronald Kong. "LC–MS/MS quantification of ataluren and ataluren acyl glucuronide in human plasma/urine: application in clinical studies." Bioanalysis 12, no. 21 (November 2020): 1545–55. http://dx.doi.org/10.4155/bio-2020-0214.

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Background: This paper describes for the first-time analytical procedures established to resolve the challenges associated with simultaneous and direct quantification of ataluren and ataluren- O-1β-acyl glucuronide (AAG) by LC–MS/MS in human plasma and urine matrices. Methodology/results: The plasma quantification method was validated for calibration range of 12.5–12500 ng/ml for ataluren and 6.25–2500 ng/ml for AAG. The urine quantification method was validated for calibration range of 0.01–10 and 1–1000 μg/ml for ataluren and AAG, respectively. Plasma and urine samples were stabilized upon collection and through storage to prevent hydrolysis and acyl migration of AAG. Conclusion: Methods described in this paper enabled successful completion of ataluren clinical pharmacology studies for simultaneous pharmacokinetic assessment of ataluren and AAG.

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5

McDonald, CM, K. Bushby, M. Tulinius, R. Finkel, H. Topaloglu, JW Day, K. Flanigan, et al. "A.06 Ataluren: an overview of clinical trial results in nonsense mutation Duchenne Muscular Dystrophy (nmDMD)." Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques 43, S2 (June 2016): S8. http://dx.doi.org/10.1017/cjn.2016.58.

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Background: Ataluren is the first drug to treat the underlying cause of nmDMD. Methods: Phase 2 and 3 studies of ataluren in nmDMD were reviewed, with efficacy and safety/tolerability findings summarized. Results: Ataluren nmDMD trials include: a Phase 2a proof-of-concept study (N=38); a Phase 2b randomized controlled trial (RCT) (N=174); an ongoing US-based open-label safety extension study (N=108); an ongoing non-US-based open-label safety/efficacy extension study (N=94); and a Phase 3 RCT, ACT DMD (N=228), whose primary endpoint was change in six-minute walk distance (6MWD) over 48 weeks. The proof-of-concept study demonstrated increased dystrophin production in post-treatment muscle biopsies from ataluren-treated patients with nmDMD. The Phase 2b results demonstrated an ataluren treatment effect in 6MWD, timed function tests, and other measures of physical functioning, The Phase 3 ACT DMD results demonstrated an ataluren treatment effect in patients with nmDMD in both primary and secondary endpoints, particularly in those with a baseline 6MWD of 300-400m. Ataluren was consistently well-tolerated in all three trials, as well as in the ongoing extension studies. Trial findings will be presented in detail. Conclusions: The totality of the results demonstrates that ataluren enables nonsense mutation readthrough in the dystrophin mRNA, producing functional dystrophin and slowing disease progression.Supported by: PTC Therapeutics Inc.

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6

McDonald, Craig M., Francesco Muntoni, Vinay Penematsa, Joel Jiang, Allan Kristensen, Francesco Bibbiani, Elizabeth Goodwin, et al. "Ataluren delays loss of ambulation and respiratory decline in nonsense mutation Duchenne muscular dystrophy patients." Journal of Comparative Effectiveness Research 11, no. 3 (February 2022): 139–55. http://dx.doi.org/10.2217/cer-2021-0196.

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Aim: We investigated the effect of ataluren plus standard of care (SoC) on age at loss of ambulation (LoA) and respiratory decline in patients with nonsense mutation Duchenne muscular dystrophy (nmDMD) versus patients with DMD on SoC alone. Patients & methods: Study 019 was a long-term Phase III study of ataluren safety in nmDMD patients with a history of ataluren exposure. Propensity score matching identified Study 019 and CINRG DNHS patients similar in disease progression predictors. Results & conclusion: Ataluren plus SoC was associated with a 2.2-year delay in age at LoA (p = 0.0006), and a 3.0-year delay in decline of predicted forced vital capacity to <60% in nonambulatory patients (p = 0.0004), versus SoC. Ataluren plus SoC delays disease progression and benefits ambulatory and nonambulatory patients with nmDMD. ClinicalTrials.gov registration: NCT01557400 .

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7

Beryozkin, Avigail, Ananya Samanta, Prakadeeswari Gopalakrishnan, Samer Khateb, Eyal Banin, Dror Sharon, and Kerstin Nagel-Wolfrum. "Translational Read-Through Drugs (TRIDs) Are Able to Restore Protein Expression and Ciliogenesis in Fibroblasts of Patients with Retinitis Pigmentosa Caused by a Premature Termination Codon in FAM161A." International Journal of Molecular Sciences 23, no. 7 (March 24, 2022): 3541. http://dx.doi.org/10.3390/ijms23073541.

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Ataluren and Gentamicin are translational readthrough drugs (TRIDs) that induce premature termination codon (PTC) readthrough, resulting in the production of full-length proteins that usually harbor a single missense substitution. FAM161A is a ciliary protein which is expressed in photoreceptors, and pathogenic variants in this gene cause retinitis pigmentosa (RP). Applying TRIDs on fibroblasts from RP patients due to PTC in the FAM161A (p.Arg523*) gene may uncover whether TRIDs can restore expression, localization and function of this protein. Fibroblasts from six patients and five age-matched controls were starved prior to treatment with ataluren or gentamicin, and later FAM161A expression, ciliogenesis and cilia length were analyzed. In contrast to control cells, fibroblasts of patients did not express the FAM161A protein, showed a lower percentage of ciliated cells and grew shorter cilia after starvation. Ataluren and Gentamicin treatment were able to restore FAM161A expression, localization and co-localization with α-tubulin. Ciliogenesis and cilia length were restored following Ataluren treatment almost up to a level which was observed in control cells. Gentamicin was less efficient in ciliogenesis compared to Ataluren. Our results provide a proof-of-concept that PTCs in FAM161A can be effectively suppressed by Ataluren or Gentamicin, resulting in a full-length functional protein.

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8

Roy, Bijoyita, Westley J. Friesen, Yuki Tomizawa, John D. Leszyk, Jin Zhuo, Briana Johnson, Jumana Dakka, et al. "Ataluren stimulates ribosomal selection of near-cognate tRNAs to promote nonsense suppression." Proceedings of the National Academy of Sciences 113, no. 44 (October 4, 2016): 12508–13. http://dx.doi.org/10.1073/pnas.1605336113.

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Анотація:

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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9

Djayet, Celia, Dominique Bremond-Gignac, Justine Touchard, Philippe-Henri Secretan, Fabrice Vidal, Matthieu P. Robert, Alejandra Daruich, Salvatore Cisternino, and Joël Schlatter. "Formulation and Stability of Ataluren Eye Drop Oily Solution for Aniridia." Pharmaceutics 13, no. 1 (December 22, 2020): 7. http://dx.doi.org/10.3390/pharmaceutics13010007.

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Congenital aniridia is a rare and severe panocular disease characterized by a complete or partial iris defect clinically detectable at birth. The most common form of aniridia occurring in around 90% of cases is caused by PAX6 haploinsufficiency. The phenotype includes ptosis, nystagmus, corneal limbal insufficiency, glaucoma, cataract, optic nerve, and foveal hypoplasia. Ataluren eye drops aim to restore ocular surface PAX6 haploinsufficiency in aniridia-related keratopathy (ARK). However, there are currently no available forms of the ophthalmic solution. The objective of this study was to assess the physicochemical and microbiological stability of ataluren 1% eye drop in preservative-free low-density polyethylene (LDPE) bottle with an innovative insert that maintains sterility after opening. Because ataluren is a strongly lipophilic compound, the formulation is complex and involves a strategy based on co-solvents in an aqueous phase or an oily formulation capable of totally dissolving the active ingredient. The visual aspect, ataluren quantification by a stability-indicating chromatographic method, and microbiological sterility were analyzed. The oily formulation in castor oil and DMSO (10%) better protects ataluren hydrolysis and oxidative degradation and permits its complete solubilization. Throughout the 60 days period, the oily solution in the LDPE bottle remained clear without any precipitation or color modification, and no drug loss and no microbial development were detected. The demonstrated physical and microbiological stability of ataluren 1% eye drop formulation at 22–25 °C might facilitate clinical research in aniridia.

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10

Ryan, Nicola J. "Ataluren: First Global Approval." Drugs 74, no. 14 (September 2014): 1709–14. http://dx.doi.org/10.1007/s40265-014-0287-4.

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11

Campbell, Craig, Richard J. Barohn, Enrico Bertini, Brigitte Chabrol, Giacomo Pietro Comi, Basil T. Darras, Richard S. Finkel, et al. "Meta-analyses of ataluren randomized controlled trials in nonsense mutation Duchenne muscular dystrophy." Journal of Comparative Effectiveness Research 9, no. 14 (October 2020): 973–84. http://dx.doi.org/10.2217/cer-2020-0095.

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Aim: Assess the totality of efficacy evidence for ataluren in patients with nonsense mutation Duchenne muscular dystrophy (nmDMD). Materials & methods: Data from the two completed randomized controlled trials (ClinicalTrials.gov: NCT00592553; NCT01826487) of ataluren in nmDMD were combined to examine the intent-to-treat (ITT) populations and two patient subgroups (baseline 6-min walk distance [6MWD] ≥300–<400 or <400 m). Meta-analyses examined 6MWD change from baseline to week 48. Results: Statistically significant differences in 6MWD change with ataluren versus placebo were observed across all three meta-analyses. Least-squares mean difference (95% CI): ITT (n = 342), +17.2 (0.2–34.1) m, p = 0.0473; ≥300–<400 m (n = 143), +43.9 (18.2–69.6) m, p = 0.0008; <400 m (n = 216), +27.7 (6.4–49.0) m, p = 0.0109. Conclusion: These meta-analyses support previous evidence for ataluren in slowing disease progression versus placebo in patients with nmDMD over 48 weeks. Treatment benefit was most evident in patients with a baseline 6MWD ≥300–<400 m (the ambulatory transition phase), thereby informing future trial design.

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12

Ng, Martin Y., Hong Li, Mikel D. Ghelfi, Yale E. Goldman, and Barry S. Cooperman. "Ataluren and aminoglycosides stimulate read-through of nonsense codons by orthogonal mechanisms." Proceedings of the National Academy of Sciences 118, no. 2 (January 7, 2021): e2020599118. http://dx.doi.org/10.1073/pnas.2020599118.

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During protein synthesis, nonsense mutations, resulting in premature stop codons (PSCs), produce truncated, inactive protein products. Such defective gene products give rise to many diseases, including cystic fibrosis, Duchenne muscular dystrophy (DMD), and some cancers. Small molecule nonsense suppressors, known as TRIDs (translational read-through–inducing drugs), stimulate stop codon read-through. The best characterized TRIDs are ataluren, which has been approved by the European Medicines Agency for the treatment of DMD, and G418, a structurally dissimilar aminoglycoside. Previously [1], we applied a highly purified in vitro eukaryotic translation system to demonstrate that both aminoglycosides like G418 and more hydrophobic molecules like ataluren stimulate read-through by direct interaction with the cell’s protein synthesis machinery. Our results suggested that they might do so by different mechanisms. Here, we pursue this suggestion through a more-detailed investigation of ataluren and G418 effects on read-through. We find that ataluren stimulation of read-through derives exclusively from its ability to inhibit release factor activity. In contrast, G418 increases functional near-cognate tRNA mispairing with a PSC, resulting from binding to its tight site on the ribosome, with little if any effect on release factor activity. The low toxicity of ataluren suggests that development of new TRIDs exclusively directed toward inhibiting termination should be a priority in combatting PSC diseases. Our results also provide rate measurements of some of the elementary steps during the eukaryotic translation elongation cycle, allowing us to determine how these rates are modified when cognate tRNA is replaced by near-cognate tRNA ± TRIDs.

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13

Ghelfi, Mikel D., Saleem Y. Bhat, Hong Li, and Barry S. Cooperman. "A High-Throughput Assay for In Vitro Determination of Release Factor-Dependent Peptide Release from a Pretermination Complex by Fluorescence Anisotropy—Application to Nonsense Suppressor Screening and Mechanistic Studies." Biomolecules 13, no. 2 (January 27, 2023): 242. http://dx.doi.org/10.3390/biom13020242.

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Premature termination codons (PTCs) account for ~12% of all human disease mutations. Translation readthrough-inducing drugs (TRIDs) are prominent among the several therapeutic approaches being used to overcome PTCs. Ataluren is the only TRID that has been approved for treating patients suffering from a PTC disease, Duchenne muscular dystrophy, but it gives variable readthrough results in cells isolated from patients suffering from other PTC diseases. We recently elucidated ataluren’s mechanism of action as a competitive inhibitor of release factor complex (RFC) catalysis of premature termination and identified ataluren’s binding sites on the ribosome responsible for such an inhibition. These results suggest the possibility of discovering new TRIDs, which would retain ataluren’s low toxicity while displaying greater potency and generality in stimulating readthrough via the inhibition of termination. Here we present a detailed description of a new in vitro plate reader assay that we are using both to screen small compound libraries for the inhibition of RFC-dependent peptide release and to better understand the influence of termination codon identity and sequence context on RFC activity.

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14

Samanta, Ananya, Katarina Stingl, Susanne Kohl, Jessica Ries, Joshua Linnert, and Kerstin Nagel-Wolfrum. "Ataluren for the Treatment of Usher Syndrome 2A Caused by Nonsense Mutations." International Journal of Molecular Sciences 20, no. 24 (December 12, 2019): 6274. http://dx.doi.org/10.3390/ijms20246274.

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The identification of genetic defects that underlie inherited retinal diseases (IRDs) paves the way for the development of therapeutic strategies. Nonsense mutations caused approximately 12% of all IRD cases, resulting in a premature termination codon (PTC). Therefore, an approach that targets nonsense mutations could be a promising pharmacogenetic strategy for the treatment of IRDs. Small molecules (translational read-through inducing drugs; TRIDs) have the potential to mediate the read-through of nonsense mutations by inducing expression of the full-length protein. We provide novel data on the read-through efficacy of Ataluren on a nonsense mutation in the Usher syndrome gene USH2A that causes deaf-blindness in humans. We demonstrate Ataluren´s efficacy in both transiently USH2AG3142*-transfected HEK293T cells and patient-derived fibroblasts by restoring USH2A protein expression. Furthermore, we observed enhanced ciliogenesis in patient-derived fibroblasts after treatment with TRIDs, thereby restoring a phenotype that is similar to that found in healthy donors. In light of recent findings, we validated Ataluren´s efficacy to induce read-through on a nonsense mutation in USH2A-related IRD. In line with published data, our findings support the use of patient-derived fibroblasts as a platform for the validation of preclinical therapies. The excellent biocompatibility combined with sustained read-through efficacy makes Ataluren an ideal TRID for treating nonsense mutations based IRDs.

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15

Goemans, N., C. Campbell, CM McDonald, T. Voit, X. Luo, G. Elfring, H. Kroger, et al. "D.08 ACT DMD (Ataluren Confirmatory Trial in Duchenne Muscular Dystrophy): effect of Ataluren on timed function tests (TFT) in nonsense mutation (nm) DMD." Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques 43, S2 (June 2016): S15. http://dx.doi.org/10.1017/cjn.2016.81.

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Background: Ataluren is the first drug to treat the underlying cause of nmDMD. Methods: ACT DMD is a Phase 3, randomized, double-blind study. Males 7-16 years with nmDMD and a screening six-minute walk distance (6MWD) ≥150 m and <80%-predicted were randomized to ataluren 40 mg/kg/day or placebo for 48 weeks. A pre-specified subgroup included patients with baseline 6MWD 300-400 m. A meta-analysis of the overall ACT DMD population and the ‘ambulatory decline phase’ subgroup of the Phase 2b study (those patients meeting ACT DMD entry criteria) was pre-specified in the statistical plan. Results: In the overall ACT DMD population (N=228), changes in TFTs favored ataluren over placebo: 10-meter walk/run, -1.2s (p=0.117); 4-stair climb, -1.8s (p=0.058); 4-stair descend, -1.8s (p=0.012). In the pre-specified subgroup (n=99), these differences increased to -2.1s, -3.6s, and -4.3s, respectively, and were statistically significant (p<0.01) for 4-stair climb and descend. Results are supported by the meta-analysis (N=291), which demonstrated significant differences (p<0.05) in 10-meter walk/run, 4-stair climb, 4-stair descend. Conclusions: TFT results showed a benefit for ataluren in ACT DMD, and a larger treatment effect in the pre-specified baseline 6MWD 300-400 m subgroup as well as the pre-specified meta-analysis of ACT DMD and the Phase 2b study decline subgroup.Supported By: PTC Therapeutics Inc.

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16

Berger, Joachim, Mei Li, Silke Berger, Michelle Meilak, Jeanette Rientjes, and Peter D. Currie. "Effect of Ataluren on dystrophin mutations." Journal of Cellular and Molecular Medicine 24, no. 12 (April 28, 2020): 6680–89. http://dx.doi.org/10.1111/jcmm.15319.

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17

Peltz, S. W., E. M. Welch, A. Jacobson, C. R. Trotta, N. Naryshkin, H. L. Sweeney, and D. M. Bedwell. "Nonsense suppression activity of PTC124 (ataluren)." Proceedings of the National Academy of Sciences 106, no. 25 (June 8, 2009): E64. http://dx.doi.org/10.1073/pnas.0901936106.

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18

Bezzerri, Valentino, Antonio Vella, Elisabetta D'Aversa, Martina Api, Marisole Allegri, Elena Marinelli Busilacchi, Giovanna D'Amico, et al. "Breakthroughs in Preclinical Development of Ataluren (PTC124) As Therapeutic Option for Patients Affected By Shwachman-Diamond Syndrome: Towards the First Clinical Trial." Blood 134, Supplement_1 (November 13, 2019): 451. http://dx.doi.org/10.1182/blood-2019-127866.

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Shwachman-Diamond syndrome (SDS) is one of the more common inherited bone marrow failure syndromes (IBMFS). Almost 90% of patients with SDS present mutations in the Shwachman-Bodian-Diamond syndrome gene (SBDS) which encodes for the homonymous small protein involved in ribogenesis. SDS is a multiple-organ disease mostly characterized by exocrine pancreas insufficiency, bone malformations, and more importantly bone marrow failure. Most patients with SDS present severe neutropenia, whereas thrombocytopenia and anemia are less frequent. Furthermore, 15-20% of patients develop myelodysplastic syndrome with high risk of acute myeloid leukemia (AML). STAT3 pathway is upregulated both in primary SDS leukocytes and immortalized B cells. Being STAT3 a key regulator of interleukin-6 (IL-6), we postulated that STAT3 hyper-activation could lead to a dysregulation of the IL-6 signaling cascade. Increased levels of IL-6 have been found in pediatric patients with AML and it has been associated with poorer outcomes in these patients, highlighting IL-6 as a cytokine potentially involved in the development of AML. Thus, our hypothesis is that STAT3-IL6 axis may contribute to leukemogenesis in SDS. Almost 55% of patients with SDS carry a specific nonsense mutations, namely the c.183-184TA>CT, which cause a premature termination codon (PTC). Ataluren (PTC124, PTC Therapeutics Inc, NJ) is a small PTC suppressor molecule already approved by the European Medicines Agency as a therapeutic option for Duchenne muscular dystrophy. Interestingly, we recently reported that ataluren can restore SBDS expression in bone marrow progenitors and in peripheral blood mononuclear cells isolated from patients with SDS. Moreover, we have shown that ataluren can reduce mTOR hyper-phosphorylation and excessive apoptotic rate observed in SDS leukocytes. More importantly, we reported that ataluren can improve myeloid differentiation in a small cohort of patients (Bezzerri et al, Am J Hematol 2018). In this further analysis considering an enlarged cohort of 20 SDS patients carrying nonsense mutations we found the following: Ataluren can significantly improve both myeloid colony-forming unit-granulocyte/macrophage (CFU-GM) and colony-forming unit granulocyte, erythrocyte, monocyte, megakaryocyte (CFU-GEMM) generation from bone marrow mononuclear stem cells obtained from an enlarged cohort of 20 patients with SDS carrying nonsense mutations. Ataluren indeed almost doubled the number of CFU-GM and CFU-GEMM after 7 and 14 days of treatment.Colony-forming unit erythroid (CFU-E) generation was not affected by the treatment.Ataluren induces neutrophil maturation in SDS bone marrow mononuclear stem cells (mean increase of 61% CD16+ CD11b+ cells over untreated controls) after 24-48 hours of treatment.Consistently with STAT3 hyper-activation observed in SDS cells, here we show that patients with SDS present a significantly increased level of IL-6 in plasma (4.3-fold higher expression than the healthy control group). Also lymphoblastoid cell lines (LCL) and primary bone marrow mesenchymal stromal cells (MSC) obtained from patients with SDS show increased IL-6 release in culture supernatants compared to healthy controls (2.5-fold and 6.8-fold higher levels, respectively).Of note, ataluren can reduce IL-6 expression in SDS cells restoring normal levels both in LCL and MSC. In conclusion, these new data support the enrollment of patients for the first clinical trial for this drug in SDS. Furthermore, this study could pave the way for the use of ataluren for other nonsense mutation-mediated IBMFS where STAT3-IL6 axis and similar pro-leukemic pathways are involved. Disclosures Bezzerri: Marco Cipolli, Valentino Bezzerri, Baroukh Maurice Assael: Patents & Royalties: WO2018/050706 A1 "Method of treatment of Shwachman-Diamond syndrome". Cipolli:Marco Cipolli, Valentino Bezzerri, Baroukh Maurice Assael: Patents & Royalties: WO2018/050706 A1 "Method of treatment of Shwachman-Diamond syndrome".

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19

Podkletnova, Tatyana V., Lyudmila M. Kuzenkova, Alexey L. Kurenkov, Evgeniya V. Uvakina, Sofya G. Popovich, and Anastasiya A. Lyalina. "A clinical case of successful management of a patient with Duchenne muscular dystrophy caused by a nonsense mutation in the DMD gene." L.O. Badalyan Neurological Journal 3, no. 2 (June 30, 2022): 96–100. http://dx.doi.org/10.46563/2686-8997-2022-3-2-96-100.

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Duchenne muscular dystrophy (DMD) is a hereditary progressive muscular dystrophy with an X-linked recessive type of inheritance, mainly manifested in boys, characterized by an onset at an early age, rapidly progressive atrophy of the striated muscles of the limbs, trunk, and damage of cardiac muscle. This process leads to a gradual loss of motor skills, cardiovascular and respiratory complications, deterioration of the musculoskeletal system, which, ultimately, significantly worsens the patient’s quality of life and reduces its duration. Currently, there are new drugs for the pathogenetic therapy of DMD. Their effectiveness is maximum with early initiation of therapy in the outpatient stage of the disease. Therefore, the age of diagnosis and the ability to suspect pathology in its early stages has become especially relevant in recent years. One of the new treatments for DMD is ataluren therapy. This therapy refers to pathogenetic and similar affects a number of patients with a nonsense mutation in the DMD gene. The combination of ataluren and glucocorticosteroids can increase the duration of the outpatient period and stabilize the state of respiratory and cardiac functions. The article presents a clinical example of a three-year follow-up of a patient suffering from DMD due to a nonsense mutation in the DMD gene, receiving combination therapy with glucocorticosteroids and ataluren.

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Morkous, Sameh S. "Treatment with Ataluren for Duchene Muscular Dystrophy." Pediatric Neurology Briefs 34 (December 4, 2020): 12. http://dx.doi.org/10.15844/pedneurbriefs-34-12.

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Shoseyov, David, Malena Cohen-Cymberknoh, and Michael Wilschanski. "Ataluren for the treatment of cystic fibrosis." Expert Review of Respiratory Medicine 10, no. 4 (February 24, 2016): 387–91. http://dx.doi.org/10.1586/17476348.2016.1150181.

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Siddiqui, Nadeem, and Nahum Sonenberg. "Proposing a mechanism of action for ataluren." Proceedings of the National Academy of Sciences 113, no. 44 (October 19, 2016): 12353–55. http://dx.doi.org/10.1073/pnas.1615548113.

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Ma, Jiyuan, Nicole Risher, Valerie Northcutt, Young-Choon Moon, Marla Weetall, Ellen Welch, Joseph Colacino, Neil Almstead та Ronald Kong. "Ataluren metabolism: Ataluren-O-1β-acyl glucuronide is a stable circulating metabolite in mouse, rat, dog and human". Drug Metabolism and Pharmacokinetics 38 (червень 2021): 100393. http://dx.doi.org/10.1016/j.dmpk.2021.100393.

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Muntoni, Francesco, Isabelle Desguerre, Michela Guglieri, Andrés Nascimento Osorio, Janbernd Kirschner, Már Tulinius, Filippo Buccella, et al. "Ataluren use in patients with nonsense mutation Duchenne muscular dystrophy: patient demographics and characteristics from the STRIDE Registry." Journal of Comparative Effectiveness Research 8, no. 14 (October 2019): 1187–200. http://dx.doi.org/10.2217/cer-2019-0086.

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Aim: Strategic Targeting of Registries and International Database of Excellence (STRIDE) is an ongoing, multicenter registry providing real-world evidence regarding ataluren use in patients with nonsense mutation Duchenne muscular dystrophy (DMD) in clinical practice (NCT02369731). Here, we describe the initial demographic characteristics of the registry population. Patients & methods: Patients will be followed up from enrollment for ≥5 years or until study withdrawal. Results & conclusion: As of 9 July 2018, 213 DMD boys were enrolled from 11 countries. Mean (standard deviation) ages at first symptoms and at study treatment start were 2.7 (1.7) years and 9.8 (3.7) years, respectively. Corticosteroids were used by 190 patients (89.2%) before data cut-off. Mean (standard deviation) ataluren exposure was 639.0 (362.9) days. Six patients withdrew. STRIDE is the first drug registry for patients with DMD and represents the largest real-world registry of patients with nmDMD to date.

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Bezzerri, Valentino, Laura Lentini, Martina Api, Elena Marinelli Busilacchi, Vincenzo Cavalieri, Antonella Pomilio, Francesca Diomede, et al. "Novel Translational Read-through–Inducing Drugs as a Therapeutic Option for Shwachman-Diamond Syndrome." Biomedicines 10, no. 4 (April 12, 2022): 886. http://dx.doi.org/10.3390/biomedicines10040886.

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Shwachman-Diamond syndrome (SDS) is one of the most commonly inherited bone marrow failure syndromes (IBMFS). In SDS, bone marrow is hypocellular, with marked neutropenia. Moreover, SDS patients have a high risk of developing myelodysplastic syndrome (MDS), which in turn increases the risk of acute myeloid leukemia (AML) from an early age. Most SDS patients are heterozygous for the c.183-184TA>CT (K62X) SBDS nonsense mutation. Fortunately, a plethora of translational read-through inducing drugs (TRIDs) have been developed and tested for several rare inherited diseases due to nonsense mutations so far. The authors previously demonstrated that ataluren (PTC124) can restore full-length SBDS protein expression in bone marrow stem cells isolated from SDS patients carrying the nonsense mutation K62X. In this study, the authors evaluated the effect of a panel of ataluren analogues in restoring SBDS protein resynthesis and function both in hematological and non-hematological SDS cells. Besides confirming that ataluren can efficiently induce SBDS protein re-expression in SDS cells, the authors found that another analogue, namely NV848, can restore full-length SBDS protein synthesis as well, showing very low toxicity in zebrafish. Furthermore, NV848 can improve myeloid differentiation in bone marrow hematopoietic progenitors, enhancing neutrophil maturation and reducing the number of dysplastic granulocytes in vitro. Therefore, these findings broaden the possibilities of developing novel therapeutic options in terms of nonsense mutation suppression for SDS. Eventually, this study may act as a proof of concept for the development of similar approaches for other IBMFS caused by nonsense mutations.

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Mercuri, Eugenio, Ros Quinlivan, and Sylvie Tuffery-Giraud. "Early Diagnosis and Treatment – The Use of Ataluren in the Effective Management of Duchenne Muscular Dystrophy." European Neurological Review 13, no. 1 (2018): 31. http://dx.doi.org/10.17925/enr.2018.13.1.31.

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The understanding of the natural history of Duchenne muscular dystrophy (DMD) is increasing rapidly and new treatments are emerging that have the potential to substantially improve the prognosis for patients with this disabling and life-shortening disease. For many, however, there is a long delay between the appearance of symptoms and DMD diagnosis, which reduces the possibility of successful treatment. DMD results from mutations in the large dystrophin gene of which one-third are de novo mutations and two-thirds are inherited from a female carrier. Roughly 75% of mutations are large rearrangements and 25% are point mutations. Certain deletions and nonsense mutations can be treated whereas many other mutations cannot currently be treated. This emphasises the need for early genetic testing to identify the mutation, guide treatment and inform genetic counselling. Treatments for DMD include corticosteroids and more recently, ataluren has been approved in Europe, the first disease-modifying therapy for treating DMD caused by nonsense mutations. The use of ataluren in DMD is supported by positive results from phase IIb and phase III studies in which the treatment produced marked improvements in the 6-minute walk test, timed function tests such as the 10 m walk/run test and the 4-stair ascent/descent test compared with placebo. In these trials, ataluren was well tolerated and adverse event profiles were similar to placebo. As such disease-modifying treatments become more widely available, the outlook for children with DMD will improve but physicians must be aware of the disease, rapidly initiate testing where it is suspected and promptly begin appropriate treatment.

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Wang, Bingjing, Zhaohui Yang, Becky K. Brisson, Huisheng Feng, Zhiqian Zhang, Ellen M. Welch, Stuart W. Peltz, Elisabeth R. Barton, Robert H. Brown, and H. Lee Sweeney. "Membrane blebbing as an assessment of functional rescue of dysferlin-deficient human myotubes via nonsense suppression." Journal of Applied Physiology 109, no. 3 (September 2010): 901–5. http://dx.doi.org/10.1152/japplphysiol.01366.2009.

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Mutations that result in the loss of the protein dysferlin result in defective muscle membrane repair and cause either a form of limb girdle muscular dystrophy (type 2B) or Miyoshi myopathy. Most patients are compound heterozygotes, often carrying one allele with a nonsense mutation. Using dysferlin-deficient mouse and human myocytes, we demonstrated that membrane blebbing in skeletal muscle myotubes in response to hypotonic shock requires dysferlin. Based on this, we developed an in vitro assay to assess rescue of dysferlin function in skeletal muscle myotubes. This blebbing assay may be useful for drug discovery/validation for dysferlin deficiency. With this assay, we demonstrate that the nonsense suppression drug, ataluren (PTC124), is able to induce read-through of the premature stop codon in a patient with a R1905X mutation in dysferlin and produce sufficient functional dysferlin (∼15% of normal levels) to rescue myotube membrane blebbing. Thus ataluren is a potential therapeutic for dysferlin-deficient patients harboring nonsense mutations.

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&NA;. "Ataluren a no nonsense approach to cystic fibrosis." Inpharma Weekly &NA;, no. 1653 (August 2008): 7. http://dx.doi.org/10.2165/00128413-200816530-00011.

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Peltz, Stuart W., Manal Morsy, Ellen M. Welch, and Allan Jacobson. "Ataluren as an Agent for Therapeutic Nonsense Suppression." Annual Review of Medicine 64, no. 1 (January 14, 2013): 407–25. http://dx.doi.org/10.1146/annurev-med-120611-144851.

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Loudon, John A. "Ataluren: A ‘no-nonsense’ approach for pulmonary diseases." Pulmonary Pharmacology & Therapeutics 26, no. 3 (June 2013): 398–99. http://dx.doi.org/10.1016/j.pupt.2013.01.007.

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Bushby, Katharine, Richard Finkel, Brenda Wong, Richard Barohn, Craig Campbell, Giacomo P. Comi, Anne M. Connolly, et al. "Ataluren treatment of patients with nonsense mutation dystrophinopathy." Muscle & Nerve 50, no. 4 (September 22, 2014): 477–87. http://dx.doi.org/10.1002/mus.24332.

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Kong, Ronald, Oscar L. Laskin, Diksha Kaushik, Fengbin Jin, Jiyuan Ma, Joseph McIntosh, Marcio Souza, and Neil Almstead. "Ataluren Pharmacokinetics in Healthy Japanese and Caucasian Subjects." Clinical Pharmacology in Drug Development 8, no. 2 (January 10, 2019): 172–78. http://dx.doi.org/10.1002/cpdd.645.

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Kent, Emma, and Thomas Paling. "VP16 A NICE Way To Manage Managed Access: Case Study In Muscular Dystrophy." International Journal of Technology Assessment in Health Care 35, S1 (2019): 79. http://dx.doi.org/10.1017/s0266462319002939.

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IntroductionManaged access arrangements (MAAs) represent a way of enabling patient access to promising treatments while collecting real world data to inform future health technology evaluations (HTE) and commissioning decisions. In July 2016, the National Institute for Health and Care Excellence (NICE) recommended Ataluren for treating Duchenne Muscular Dystrophy within a MAA. NICE is uniquely placed to oversee the implementation and monitoring of this MAA in collaboration with multiple stakeholders to ensure the final outputs meet the needs of a future HTE.MethodsNICE assembled an Ataluren Managed Access Oversight Committee (MAOC) consisting of representatives from the manufacturer, patient organisations, commissioning body and treatment centres. This group were to meet every six months under the chairmanship of NICE with the primary function of reviewing the progress of data collection and identifying operational challenges in implementing the terms of the arrangement.ResultsThe Ataluren MAOC has convened four times since the MAA commenced and these discussions identified a number of important actions. Data completeness was a concern and prompted stakeholders to collaborate on implementing measures to circumvent this, to ensure data quality for future HTE. Lack of awareness and understanding of the MAA in the patient community was highlighted and resulted in the production of lay information. A review of the statistical analysis plan resulted in the need for an agreement amendment. To ensure an audit trail and appropriate critique, NICE produced an amendment process to define and justify amendments made during the agreement term.ConclusionsMAOC meetings play an important role in monitoring the progress of MAAs and have ensured that implementation issues are identified promptly and resolved with input from key stakeholders. This process allows NICE to coordinate the work of stakeholders to facilitate the success of the MAA, and will be adopted in future NICE MAAs in ultra-rare diseases.

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Drake, Kylie M., Benjamin J. Dunmore, Lauren N. McNelly, Nicholas W. Morrell, and Micheala A. Aldred. "Correction of NonsenseBMPR2andSMAD9Mutations by Ataluren in Pulmonary Arterial Hypertension." American Journal of Respiratory Cell and Molecular Biology 49, no. 3 (September 2013): 403–9. http://dx.doi.org/10.1165/rcmb.2013-0100oc.

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Wilschanski, M., L. L. Miller, D. Shoseyov, H. Blau, J. Rivlin, M. Aviram, M. Cohen, et al. "Chronic ataluren (PTC124) treatment of nonsense mutation cystic fibrosis." European Respiratory Journal 38, no. 1 (January 13, 2011): 59–69. http://dx.doi.org/10.1183/09031936.00120910.

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Hall, Adam, Lok Wan Liu, Richard Macaulay, and Sean Walsh. "OP127 Sugar And Spice And All Things NICE - Managed Access Agreements." International Journal of Technology Assessment in Health Care 35, S1 (2019): 28–29. http://dx.doi.org/10.1017/s0266462319001582.

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IntroductionThe National Institute for Health and Care Excellence (NICE) has increasingly agreed to reimburse innovative products with high levels of uncertainty as part of managed access agreements (MAAs) while additional data are collected, through the new Cancer Drugs Fund (CDF) or highly specialized technology (HST) pathways. This research aimed to review the data collection stipulations of current MAAs.MethodsWe reviewed all current MAAs entered into between NHS England and manufacturers as of 29 October 2018 and key data were extracted.ResultsTwenty-two MAAs were identified (19 through the CDF; three through HST). All MAAs involved an observational data collection component. The source of observational data collection was existing NHS databases (19/22 MAAs: 86.5 percent), existing independent registries (one MAA: 4.5 percent [ataluren]); bespoke MAA registry maintained by manufacturer (1/22 MAA: 4.5 percent [asfotase alfa]), and registries developed as a part of regulatory approval and maintained by the manufacturer (1/22 MAA: 4.5 percent [elosulfase alfa]). Only eight MAAs (asfotase alfa, ataluren, elosulfase alfa, brentuximab vedotin, venetoclax, ibrutinib, daratumumab, and pembrolizumab) had observational data collection as the primary method of data collection. Additionally, 17/22 MAAs (77 percent; all from the CDF) also required ongoing data collection from clinical trials as a key component of the data collection arrangement.ConclusionsThis research identified observational data collection as a requirement in all MAAs, which is primarily through existing registries (except ataluren, which required development of a bespoke registry), while ongoing trial data collection was limited to the CDF. The relatively low cost of using existing registries to fulfil data requirements, with the ability to achieve reimbursement whilst still collecting data from ongoing RCTs, make MAAs an attractive proposition for manufacturers. NICE reportedly plan to increase use of MAAs, with ongoing NICE consultation for changes in the appraisal process potentially allowing expansion to include all indications, which would mean increased opportunities to explore innovative MAAs to support access in the future.

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Loudon, John A. "Ataluren-time for a 'no–nonsense' approach to haematological malignancies." Hematology and Leukemia 1, no. 1 (2013): 2. http://dx.doi.org/10.7243/2052-434x-1-2.

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Loudon, John A. "Ataluren: Time for a ‘No-Nonsense’ Approach to Heart Diseases." Cardiovascular Drugs and Therapy 27, no. 2 (January 6, 2013): 181–82. http://dx.doi.org/10.1007/s10557-012-6435-8.

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Blaschek, Astrid, Martin Rodrigues, Lena Ille, Mohammed Idriess, Therese Well, Birgit Warken, Christine Müller, et al. "Is Exercise-Induced Fatigue a Problem in Children with Duchenne Muscular Dystrophy?" Neuropediatrics 51, no. 05 (May 5, 2020): 342–48. http://dx.doi.org/10.1055/s-0040-1708859.

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Abstract Objective Duchenne muscular dystrophy (DMD) is a devastating X-linked muscular disorder. The number of studies investigating new therapeutic approaches is substantially increasing. This study aims to investigate the impact and diagnostic value of exercise-induced fatigue in DMD, which has been proposed as a suitable outcome parameter in other conditions like spinal muscular atrophy. Patients and Methods A cohort of 55 DMD patients (49 of them treated with steroids and 9 with ataluren) underwent a total of 241 6MWT (mean 4.4 tests/patient) which were retrospectively analyzed. Exercise-induced fatigue was assessed by the ratio between the distance achieved in the sixth minute and the distance in the second minute of the 6MWT. In previous studies a quotient above 1 was defined as a sign of fatigue. Results The average fatigue quotient in the whole cohort of patients was 1.0. In a further analysis no impact of age, steroid therapy, ataluren therapy, overall disability, and distance in the 6-minute walk test (6MWT) on fatigue in DMD patients could be shown. Conclusion Our data show that fatigue does not play a relevant role in DMD. Analysis of fatigue is not a useful outcome parameter in DMD studies. For this reason we suggest the 2MWT, which is better accepted by the patients, as an alternative to the commonly 6MWT.

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Wang, Xia, Xianghong Shan, Kevin Gregory-Evans, and Cheryl Y. Gregory-Evans. "RNA-based therapies in animal models of Leber congenital amaurosis causing blindness." Precision Clinical Medicine 3, no. 2 (March 12, 2020): 113–26. http://dx.doi.org/10.1093/pcmedi/pbaa009.

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Abstract Leber congenital amaurosis (LCA) is a severe, genetically heterogeneous recessive eye disease in which ~ 35% of gene mutations are in-frame nonsense mutations coding for loss-of-function premature termination codons (PTCs) in mRNA. Nonsense suppression therapy allows read-through of PTCs leading to production of full-length protein. A limitation of nonsense suppression is that nonsense-mediated decay (NMD) degrades PTC-containing RNA transcripts. The purpose of this study was to determine whether inhibition of NMD could improve nonsense suppression efficacy in vivo. Using a high-throughput approach in the recessive cep290 zebrafish model of LCA (cep290;Q1223X), we first tested the NMD inhibitor Amlexanox in combination with the nonsense suppression drug Ataluren. We observed reduced retinal cell death and improved visual function. With these positive data, we next investigated whether this strategy was also applicable across species in two mammalian models: Rd12 (rpe65;R44X) and Rd3 (rd3;R107X) mouse models of LCA. In the Rd12 model, cell death was reduced, RPE65 protein was produced, and in vivo visual function testing was improved. We establish for the first time that the mechanism of action of Amlexanox in Rd12 retina was through reduced UPF1 phosphorylation. In the Rd3 model, however, no beneficial effect was observed with Ataluren alone or in combination with Amlexanox. This variation in response establishes that some forms of nonsense mutation LCA can be targeted by RNA therapies, but that this needs to be verified for each genotype. The implementation of precision medicine by identifying better responders to specific drugs is essential for development of validated retinal therapies.

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Werner, C., X. Luo, G. Elfring, H. Kroger, P. Riebling, T. Ong, R. Spiegel, and S. Peltz. "Meta-analyses of Ataluren in Patients with Nonsense Mutation Duchenne Muscular Dystrophy." Neuropediatrics 48, S 01 (April 26, 2017): S1—S45. http://dx.doi.org/10.1055/s-0037-1602954.

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Muntoni, F., E. Mercuri, X. Luo, G. Elfring, C. Werner, P. Trifillis, S. W. Peltz, and C. M. McDonald. "Meta-analyses of ataluren in patients with nonsense mutation Duchenne muscular dystrophy." Neuromuscular Disorders 28 (April 2018): S12. http://dx.doi.org/10.1016/s0960-8966(18)30323-7.

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Zainal Abidin, Noreen, Iram J. Haq, Aaron I. Gardner, and Malcolm Brodlie. "Ataluren in cystic fibrosis: development, clinical studies and where are we now?" Expert Opinion on Pharmacotherapy 18, no. 13 (August 1, 2017): 1363–71. http://dx.doi.org/10.1080/14656566.2017.1359255.

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Seo, K., D. Kim, H. Lee, and J. Shin. "FP.33 Ataluren treatment in 30-week-old dysferlinopathy mouse with nonsense mutation." Neuromuscular Disorders 32 (October 2022): S112. http://dx.doi.org/10.1016/j.nmd.2022.07.293.

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Bhattacharya, Arpan, Shijie Huang, Mikel D. Ghelfi, Hong Li, Clark Fritsch, David M. Chenoweth, Barry S. Cooperman, and Yale E. Goldman. "Elucidating the mechanism and target sites of ataluren inside the protein synthesis machinery." Biophysical Journal 121, no. 3 (February 2022): 203a. http://dx.doi.org/10.1016/j.bpj.2021.11.1723.

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Reeves, Emer P., Ciara A. O’Dwyer, Danielle M. Dunlea, Mark R. Wormald, Padraig Hawkins, Mohammad Alfares, Darrell N. Kotton, Steven M. Rowe, Andrew A. Wilson, and Noel G. McElvaney. "Ataluren, a New Therapeutic for Alpha-1 Antitrypsin–Deficient Individuals with Nonsense Mutations." American Journal of Respiratory and Critical Care Medicine 198, no. 8 (October 15, 2018): 1099–102. http://dx.doi.org/10.1164/rccm.201802-0338le.

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Walsh, Sean, Ricky Tsang, Erika Turkstra, and Richard Macaulay. "VP22 Future Trends For Managed Access Agreements In The UK." International Journal of Technology Assessment in Health Care 34, S1 (2018): 164–65. http://dx.doi.org/10.1017/s0266462318003446.

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Introduction:In recent years, the National Institute for Health and Care Excellence (NICE) has increasingly agreed to reimburse innovative products with high levels of uncertainty as part of managed access agreements (MAAs) while new data are collected; namely, this has occurred through the new Cancer Drugs Fund (CDF) and highly specialized technology (HST) appraisal pathway. This research aimed to provide a review of ongoing data collection arrangements as part of MAAs agreed with NICE.Methods:We reviewed all current MAAs entered into between the National Health Service (NHS) England and manufacturers as of 24 November 2017 and extracted relevant information related to the data collection arrangements.Results:Thirteen MAAs were identified (10 through the CDF; 3 through HST). All MAAs involved an observational data collection agreement. The source of observational data collection was existing NHS databases (11 MAAs: 85 percent), existing independent registries (1 MMA: 8 percent [ataluren]); bespoke MAA registry maintained by manufacturer (1 MAA: 8 percent [asfotase alfa]), and registries developed as a requirement for regulatory approval and maintained by the manufacturer (1 MAA: 8 percent [elosulfase alfa]). Only 4 MAAs (asfotase alfa, ataluren, elosulfase alfa, and venetoclax) had observational data collection as the sole basis of the data collection agreement. The other 9 MAAs (69 percent; all from the CDF) also required on-going data collection from clinical trials as a key component of the data collection agreement.Conclusions:This research shows that current MAAs have predominantly utilized either ongoing data collection (e.g. from RCTs) or existing registries to date for which limited additional set-up administration and costs would be required. However, NICE plan to increase the use of MAAs, with ongoing NICE consultation for changes in the appraisal process to expand MAAs to include all indications. In future, manufacturers will have more opportunities to explore and leverage innovative and bespoke MAAs to help achieve access.

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Martínez-Edo, Gabriel, Maria C. Llinàs, Salvador Borrós, and David Sánchez-García. "Isothiocyanate-Functionalized Mesoporous Silica Nanoparticles as Building Blocks for the Design of Nanovehicles with Optimized Drug Release Profile." Nanomaterials 9, no. 9 (August 29, 2019): 1219. http://dx.doi.org/10.3390/nano9091219.

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A straightforward methodology for the synthesis of isothiocyanate-functionalized mesoporous silica nanoparticles (MSNs) by exposure of aminated MSNs to 1,1′-thiocarbonyldi-2(1H)-pyridone is reported. These nanoparticles are chemically stable, water tolerant, and readily react with primary amines without the formation of any by-product. This feature allows the easy modification of the surface of the nanoparticles for tuning their physical properties and the introduction of gatekeepers on the pore outlets. As a proof-of-concept, amino-isothiocyanate-functionalized MSNs have been used for the design of a nanocontainer able to release the drug Ataluren. The release profile of the drug can be easily fine-tuned with the careful choice of the capping amine.

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Tutone, Marco, Ivana Pibiri, Laura Lentini, Andrea Pace, and Anna Maria Almerico. "Deciphering the Nonsense Readthrough Mechanism of Action of Ataluren: An in Silico Compared Study." ACS Medicinal Chemistry Letters 10, no. 4 (February 7, 2019): 522–27. http://dx.doi.org/10.1021/acsmedchemlett.8b00558.

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De Boeck, K., H. G. M. Heijerman, J. C. Davies, I. Sermet-Gaudelus, L. Hjelte, E. Kerem, J. Sun, J. Mcintosh, A. Malfroot, and H. A. W. M. Tiddens. "WS13.1 Ataluren significantly reduces exacerbations in nonsense mutation cystic fibrosis patients not receiving tobramycin." Journal of Cystic Fibrosis 15 (June 2016): S20—S21. http://dx.doi.org/10.1016/s1569-1993(16)30132-1.

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