Translarna (ataluren)

Interestingly, AMPD3 can be an effective therapeutic target for NF1-associated diseases. Together, our study suggests that ataluren can be considered a therapeutic agent for some NF1NS/+ patients and contributes to expanding insights into NF1 therapy.

After screening food and drug administration (FDA)-approved drugs, bortezomib and ataluren are found to effectively inhibit TREM2 expression in TAMs, indicating a potential therapeutic strategy against TREM2. This study elucidates the mechanism by which TREM2 shapes the immunosuppressive microenvironment and promotes tumorigenesis, highlighting TREM2 as a target for cancer immunotherapy.

Herein, we introduce two Pt complexes, ataluren monosubstituted platinum(IV) (SPA, formula: c,c,t,-[Pt(NH3)2Cl2(OH)(C15H8FN2O3)], where C15H8FN2O3 = ataluren) and ataluren bisubstituted platinum(IV) complex (DPA, formula: c,c,t,-[Pt(NH3)2Cl2(C15H8FN2O3)2], where C15H8FN2O3 = ataluren), which effectively suppress ribosome biogenesis by inhibiting 47s pre-RNA expression. Notably, in clinically relevant models, including orthotopic hepatic tumor-bearing mice and patient-derived bladder cancer organoids, DPA outperforms cisplatin significantly, with the added benefit of oral administration, enhancing clinical feasibility. To our knowledge, DPA emerges as the pioneering Pt(IV) agent targeting the ribosome, providing new insights for designing next-generation metal-based therapeutics.

To test ataluren's potential applicability in nonsense mutation NF1 patients, we evaluated its therapeutic effects using three treatment regimens in a previously established NF1 patient-derived (c.2041C > T; p.Arg681X) nonsense mutation mouse model. Collectively, our experiments indicate that: i) ataluren appeared to slow the growth of neurofibromas and alleviate some paralysis phenotypes, ii) female Nf1-nonsense mutation mice manifested more severe paralysis and neurofibroma phenotypes than male mice, iii) ataluren doses with apparent effectiveness were lower in female mice than in male mice, and iv) age factors also influenced ataluren's effectiveness.

P3, N=270, Enrolling by invitation, PTC Therapeutics | Trial completion date: Apr 2024 --> Apr 2025 | Trial primary completion date: Apr 2024 --> Apr 2025

P3, N=270, Enrolling by invitation, PTC Therapeutics | Trial completion date: Dec 2023 --> Apr 2024 | Trial primary completion date: Dec 2023 --> Apr 2024

The identification of the novel BMPR1A variant enriched the genotype-phenotype spectrum of BMPR1A. Meanwhile, our finding also provided support for future PTC-targeting therapy for BMPR1A-mediated JPS and CRC.

Ataluren also restored full-length SBDS synthesis in primary osteoblasts, suggesting that its beneficial role may go beyond the myeloid compartment. Altogether, our results strengthened the rationale for a Phase I/II clinical trial of ataluren in SDS patients who harbour the nonsense mutation.

PTC124 could reverse TT-10 (a YAP signaling activator)-mediated HO-1-u-1 cell proliferation. (4) PTC124 can rescue nonsense mutation of NOTCH1 and FAT1 to repress HNSCC cell proliferation.

We differentiated Nf1-3X-FLAG mES cells into cortical neurons in vitro, treated the cells with ataluren, and demonstrated that ataluren can promote readthrough of the nonsense mutation at codon 683 of Nf1 mRNA in neural cells. The resulting full-length protein is able to reduce the cellular level of hyperactive phosphorylated ERK (pERK), a RAS effector normally suppressed by the NF1 protein.