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The MAPT gene encodes Tau protein, a member of the large family of microtubule-associated proteins. Tau forms large insoluble aggregates that are toxic to neurons in several neurological disorders, and neurofibrillary Tau tangles represent a key pathological hallmark of Alzheimer's disease (AD) and other tauopathies. Lowering Tau expression levels constitutes a potential treatment for AD but the mechanisms that regulate Tau expression at the transcriptional or translational level are not well understood. Natural antisense transcripts (NATs) are a particular class of long non-coding RNAs (lncRNAs) that can regulate expression of their overlapping protein-coding genes at the epigenetic, transcriptional, or translational level. We and others identified a long non-coding RNA associated with the MAPT gene, named MAPT antisense 1 (MAPT-AS1). We confirmed that MAPT-AS1 is expressed in neurons in human post mortem brain tissue. To study the role of MAPT-AS1 on MAPT expression regulation, we modulated the expression of this lncRNA in human neuroblastoma cell lines and in human induced pluripotent stem cell (iPSC) derived neurons. In contrast to previous reports, we observed no changes on MAPT mRNA or Tau protein levels upon modulation of MAPT-AS1 levels in these cellular models. Our data suggest that MAPT-AS1 does not regulate Tau expression levels in human neurons in vitro. Thus, MAPT-AS1 does not represent a valuable therapeutic target to lower Tau expression in patients affected by tauopathies including AD., Competing Interests: CdY is an employee of Janssen Pharmaceutica, pharmaceutical companies of Johnson&Johnson. In connection with such employment, CdY receives salary, benefits, and stock-based compensations including stock options, restricted stock and other stock-related grants. CdY and SMM hold patents covering methods to modify Tau expression. BDS is scientific founder of Augustine Therapeutics and Muna Therapeutics, two biotech companies that do not work on Tau. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2025 Policarpo et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Bedaquiline (BDQ), by targeting the electron transport chain and having a long half-life, is a good candidate to simplify leprosy treatment. Our objectives were to (i) determine the minimal effective dose (MED) of BDQ administered orally, (ii) evaluate the benefit of combining two inhibitors of the respiratory chain, BDQ administered orally and clofazimine (CFZ)) and (iii) evaluate the benefit of an intramuscular injectable long-acting formulation of BDQ (intramuscular BDQ, BDQ-LA IM), in a murine model of leprosy., Methodology/principal Findings: To determine the MED of BDQ administered orally and the benefit of adding CFZ, 100 four-week-old female nude mice were inoculated in the footpads with 5x103 bacilli of M. leprae strain THAI53. Mice were randomly allocated into: 1 untreated group, 5 groups treated with BDQ administered orally (0.10 to 25 mg/kg), 3 groups treated with CFZ 20 mg/kg alone or combined with BDQ administered orally 0.10 or 0.33 mg/kg, and 1 group treated with rifampicin (RIF) 10 mg/kg. Mice were treated 5 days a week during 24 weeks. To evaluate the benefit of the BDQ-LA IM, 340 four-week-old female swiss mice were inoculated in the footpads with 5x103 to 5x101 bacilli (or 5x100 for the untreated control group) of M. leprae strain THAI53. Mice were randomly allocated into the following 11 groups treated with a single dose (SD) or 3 doses (3D) 24h after the inoculation: 1 untreated group, 2 treated with RIF 10 mg/kg SD or 3D, 8 treated with BDQ administered orally or BDQ-LA IM 2 or 20 mg/kg, SD or 3D. Twelve months later, mice were sacrificed and M. leprae bacilli enumerated in the footpad. All the footpads became negative with BDQ at 3.3 mg/kg. The MED of BDQ administered orally against M. leprae in this model is therefore 3.3 mg/kg. The combination of CFZ and BDQ 10-fold lower than this MED did not significantly increase the bactericidal activity of CFZ. The BDQ-LA IM displayed similar or lower bactericidal activity than the BDQ administered orally., Conclusion: We demonstrated that the MED of BDQ administered orally against M. leprae was 3.3 mg/kg in mice and BDQ did not add significantly to the efficacy of CFZ at the doses tested. BDQ-LA IM was similar or less active than BDQ administered orally at equivalent dosing and frequency but should be tested at higher dosing in order to reach equivalent exposure in further experiments., Competing Interests: We have read the journal’s policy and the authors of this manuscript have the following competing interests: NL is an employee of Janssen and KA has retired from Janssen; they participated to the methodology design and writing of the manuscript. AA, AC, VJ, NV have no conflict of interest to declare except funding aforementioned., (Copyright: © 2023 Chauffour et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: We aimed to provide regional data on clinical symptoms, medical resource utilization (MRU), and risk factors for increased MRU in hospitalized respiratory syncytial virus (RSV)-infected Belgian pediatric population., Methods: This prospective, multicenter study enrolled RSV (+) hospitalized children (aged ≤5y) during the 2013-2015 RSV seasons. RSV was diagnosed within 24h of hospitalization. Disease severity of RSV (+) patients was assessed until discharge or up to maximum six days using a Physical Examination Score (PES) and a derived score based on ability to feed, dyspnea and respiratory effort (PES3). MRU (concomitant medications, length of hospitalization [LOH], and oxygen supplementation) was evaluated. Kaplan-Meier survival analysis was performed to compare MRU by age and presence of risk factors for severe disease. Association between baseline covariates and MRU was analyzed using Cox regression models., Results: In total, 75 children were included, Median (range) age was 4 (0-41) months, risk factors were present in 18.7%, and early hospitalization (≤3 days of symptom onset) was observed in 57.3% of patients. Cough (100%), feeding problems (82.2%), nasal discharge (87.8%), and rales and rhonchi (82.2%) were frequently observed. Median (range) LOH and oxygen supplementation was 5 (2-7) and 3 (1-7) days. Oxygen supplementation, bronchodilators, and antibiotics were administered to 58.7%, 64.0%, and 41.3% of the patients, respectively. Age <3 months and baseline total PES3 score were associated with probability and the duration of receiving oxygen supplementation. LOH was not associated with any covariate., Conclusion: RSV is associated with high disease burden and MRU in hospitalized children. Oxygen supplementation but not length of hospitalization was associated with very young age and the PES3 score. These results warrant further assessment of the PES3 score as a predictor for the probability of receiving and length of oxygen supplementation in RSV hospitalized children., Registration: NCT02133092., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: YV, RF, JB, and GI are employees of Janssen Pharmaceutica NV and may own stock in Johnson & Johnson. MP, AR, EK, FV, KS, MR, AV, WL, and KG have no conflict of interest.

Flubendazole (FBZ) is highly efficacious against filarial nematodes after parenteral administration and presents a promising macrofilaricidal drug candidate for the elimination of onchocerciasis and other filariae. In the present study the efficacy of a newly developed bioavailable amorphous solid dispersion (ASD) oral formulation of FBZ was investigated in the Litomosoides sigmodontis jird model. FBZ was administered to chronically infected, microfilariae-positive jirds by single (40mg/kg), repeated (2, 6 or 15mg/kg for 5 or 10 days) oral (OR) doses or single subcutaneous (SC) injections (2 or 10mg/kg). Jirds treated with 5 SC injections at 10mg/kg served as positive controls, with untreated animals used as negative controls. After OR doses, FBZ is rapidly absorbed and cleared and the exposures increased dose proportionally. SC administered FBZ was slowly released from the injection site and plasma levels remained constant up to necropsy eight weeks after treatment end. Increasing single SC doses caused less than dose-proportional exposures. At necropsy, all animals receiving 1x or 5x 10mg/kg SC FBZ had cleared all adult worms and the 1x 2mg/kg SC treatment had reduced the adult worm burden by 98%. 10x 15mg/kg OR FBZ reduced the adult worm burden by 95%, whereas 1x 40mg/kg and 5x 15mg/kg OR reduced the worm burden by 85 and 84%, respectively. Microfilaremia was completely cleared at necropsy in all animals of the SC treatment regimens, while all oral FBZ treatment regimens reduced the microfilaremia by >90% in a dose and duration dependent manner. In accordance, embryograms from female worms revealed a FBZ dose and duration dependent inhibition of embryogenesis. Histological analysis of the remaining female adult worms showed that FBZ had damaged the body wall, intestine and most prominently the uterus and uterine content. Results of this study demonstrate that single and repeated SC injections and repeated oral administrations of FBZ have an excellent macrofilaricidal effect., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests by LQ, SLD, FT, BB, ME as paid employment by Janssen (developed flubendazole), patent applications for flubendazole. MPH and AH received funding for this study by Janssen.

River blindness and lymphatic filariasis are two filarial diseases that globally affect millions of people mostly in impoverished countries. Current mass drug administration programs rely on drugs that primarily target the microfilariae, which are released from adult female worms. The female worms can live for several years, releasing millions of microfilariae throughout the course of infection. Thus, to stop transmission of infection and shorten the time to elimination of these diseases, a safe and effective drug that kills the adult stage is needed. The benzimidazole anthelmintic flubendazole (FBZ) is 100% efficacious as a macrofilaricide in experimental filarial rodent models but it must be administered subcutaneously (SC) due to its low oral bioavailability. Studies were undertaken to assess the efficacy of a new oral amorphous solid dispersion (ASD) formulation of FBZ on Brugia pahangi infected jirds (Meriones unguiculatus) and compare it to a single or multiple doses of FBZ given subcutaneously. Results showed that worm burden was not significantly decreased in animals given oral doses of ASD FBZ (0.2-15 mg/kg). Regardless, doses as low as 1.5 mg/kg caused extensive ultrastructural damage to developing embryos and microfilariae (mf). SC injections of FBZ in suspension (10 mg/kg) given for 5 days however, eliminated all worms in all animals, and a single SC injection reduced worm burden by 63% compared to the control group. In summary, oral doses of ASD formulated FBZ did not significantly reduce total worm burden but longer treatments, extended takedown times or a second dosing regimen, may decrease female fecundity and the number of mf shed by female worms., Competing Interests: I have read the journal's policy and the author of this manuscript have the following competing interests: SLD, ME, LQ, BBa and FT are employed by Janssen Pharmaceutica. JS received funding from Janssen.

The Onchocerca ochengi adult implant and Brugia malayi microfilariemic Severe-Combined Immunodeficient (SCID) mouse models are validated screens to measure macrofilaricidal and microfilaricidal activities of candidate onchocerciasis drugs. The purpose of this study was to assess whether 5 daily sub-cutaneous (s.c.) injections of standard flubendazole (FBZ) suspension (10mg/kg), a single s.c. injection (10mg/kg) or 5 daily repeated oral doses of FBZ amorphous solid dispersion (ASD) formulation (0.2, 1.5 or 15mg/kg) mediated macrofilaricidal efficacy against O. ochengi male worms implanted into SCID mice. The direct microfilaricidal activity against circulating B. malayi microfilariae of single dose FBZ ASD formulation (2 or 40 mg/kg) was also evaluated and compared against the standard microfilaricide, ivermectin (IVM). Systemic exposures of FBZ/FBZ metabolites achieved following dosing were measured by pharmacokinetic (PK) bioanalysis. At necropsy, five weeks following start of FBZ SC injections, there were significant reductions in burdens of motile O. ochengi worms following multiple injections (93%) or single injection (82%). Further, significant proportions of mice dosed following multiple injections (5/6; 83%) or single injection (6/10; 60%) were infection negative (drug-cured). In comparison, no significant reduction in recovery of motile adult O. ochengi adult worms was obtained in any multiple-oral dosage group. Single oral-dosed FBZ did not mediate any significant microfilaricidal activity against circulating B. malayi mf at 2 or 7 days compared with >80% efficacy of single dose IVM. In conclusion, multiple oral FBZ formulation doses, whilst achieving substantial bioavailability, do not emulate the efficacy delivered by the parenteral route in vivo against adult O. ochengi. PK analysis determined FBZ efficacy was related to sustained systemic drug levels rather than achievable Cmax. PK modelling predicted that oral FBZ would have to be given at low dose for up to 5 weeks in the mouse model to achieve a matching efficacious exposure profile., Competing Interests: Sophie Lachaud, Fetene Tekle, Ludo Quirynen, Marc Engelen, and Benny Baeten are paid employees of Janssen, developed flubendazole and hold patent applications for flubendazole. Joseph D. Turner and Mark J. Taylor received funding for this study by Janssen.

The emergence of multidrug resistant-tuberculosis (MDR-TB), defined as Mycobacterium tuberculosis strains with in vitro resistance to at least isoniazid and rifampicin, has necessitated evaluation and validation of appropriate surrogate endpoints for treatment response in drug trials for MDR-TB. The trial that has demonstrated efficacy of bedaquiline, a diarylquinoline that inhibits mycobacterial ATP synthase, possesses the requisite features to conduct this evaluation. Approval of bedaquiline for use in MDR-TB was based primarily on the results of the controlled C208 Stage II study (ClinicalTrials.gov number, NCT00449644) including 160 patients randomized 1:1 to receive bedaquiline or placebo for 24 weeks when added to an 18-24-month preferred five-drug background regimen. Since randomization in C208 Stage II was preserved until study end, the trial results allow for the investigation of the complex relationship between sustained durable outcome with either Week 8 or Week 24 culture conversion as putative surrogate endpoints. The relationship between Week 120 outcome with Week 8 or Week 24 culture conversion was investigated using a descriptive analysis and with a recently developed statistical methodology for surrogate endpoint evaluation using methods of causal inference. The results demonstrate that sputum culture conversion at 24 weeks is more reliable than sputum culture conversion at 8 weeks when assessing the outcome of adding one new drug to a MDR-TB regimen., Competing Interests: We have the following interests: Janssen funded the C208 Stage II trial. Koen Andries, Nacer Lounis, An Vandebosch and Wim Van der Elst are full-time employees of Janssen Pharmaceutica. Chrispin Kambili is employed full-time by Johnson and Johnson. Paul Meyvisch, Myriam Theeuwes and Brian Dannemann were previously employed by Janssen; all are potential stockholders of Johnson and Johnson. Paul Meyvisch is a voluntary researcher at the I-BioStat at KU Leuven and Universiteit Hasselt and is currently employed by Galapagos NV, Mechelen (Belgium). Geert Molenberghs is a full-time employee of IBioStat at UHasselt and KU Leuven, Belgium. Ariel Alonso is a full-time employee of IBioStat at KU Leuven, Belgium. Koen Andries is co-inventor and has three patents on the use of quinoline derivatives for the treatment of mycobacterial diseases (rights of which have been transferred to Johnson & Johnson): 1. WO 2004/011436 – Quinoline Derivatives and Their Use as Mycobacterial Inhibitors; 2. WO 2005/117875 – Use of Substituted Quinoline Derivatives for the Treatment of Drug Resistant Mycobaterial Diseases; 3. WO 2006/067048 – Quinoline Derivatives for the Treatment of Latent Tuberculosis. There are no further patents, products in development or marketed products to declare. This does not alter our adherence to all the PLOS ONE policies on sharing data and materials.

Bedaquiline (BDQ), an ATP synthase inhibitor, is the first drug to be approved for treatment of multi-drug resistant tuberculosis in decades. In vitro resistance to BDQ was previously shown to be due to target-based mutations. Here we report that non-target based resistance to BDQ, and cross-resistance to clofazimine (CFZ), is due to mutations in Rv0678, a transcriptional repressor of the genes encoding the MmpS5-MmpL5 efflux pump. Efflux-based resistance was identified in paired isolates from patients treated with BDQ, as well as in mice, in which it was confirmed to decrease bactericidal efficacy. The efflux inhibitors verapamil and reserpine decreased the minimum inhibitory concentrations of BDQ and CFZ in vitro, but verapamil failed to increase the bactericidal effect of BDQ in mice and was unable to reverse efflux-based resistance in vivo. Cross-resistance between BDQ and CFZ may have important clinical implications.