Abstract
Accumulation of tau protein is a key pathology of age-related neurodegenerative diseases such as Alzheimer's disease and progressive supranuclear palsy. Those diseases are collectively ...termed tauopathies. Tau pathology is associated with axonal degeneration because tau binds to microtubules (MTs), a component of axon and regulates their stability. The acetylation state of MTs contributes to stability and histone deacetylase 6 (HDAC6) is a major regulator of MT acetylation status, suggesting that pharmacological HDAC6 inhibition could improve axonal function and may slow the progression of tauopathy. Here we characterize
N
-(1R,2R)-2-{3-5-(difluoromethyl)-1,3,4-oxadiazol-2-yl-5-oxo-5H,6H,7H-pyrrolo3,4-bpyridin-6-yl}cyclohexyl-2,2,3,3,3-pentafluoropropanamide (T-518), a novel, potent, highly selective HDAC6 inhibitor with clinically favorable pharmacodynamics. T-518 shows potent inhibitory activity against HDAC6 and superior selectivity over other HDACs compared with the known HDAC6 inhibitors in the enzyme and cellular assays. T-518 showed brain penetration in an oral dose and blocked HDAC6-dependent tubulin deacetylation at Lys40 in mouse hippocampus. A 2-week treatment restored impaired axonal transport and novel object recognition in the P301S tau Tg mouse, tauopathy model, while a 3-month treatment also decreased RIPA-insoluble tau accumulation. Pharmaceutical inhibition of HDAC6 is a potential therapeutic strategy for tauopathy, and T-518 is a particularly promising drug candidate.
A 45-year-old man with steroid-dependent ulcerative pancolitis was hospitalized with frequent diarrhea, abdominal pain and distension 3 months after induction of golimumab, a tumor necrosis ...factor-alpha antagonist. Computed tomography showed wall thickening from the stomach to the colon and massive ascites. Peripheral blood test revealed eosinophilia. A large number of eosinophils were observed in the ascites fluid. Although esophagogastroduodenoscopy showed no abnormal findings and colonoscopy showed ulcerative colitis with a Mayo endoscopic subscore of 1, eosinophil infiltration was histologically observed. Based on these findings, we diagnosed him with eosinophilic gastroenteritis and started prednisolone. Consequently, his eosinophil counts and abdominal symptoms dramatically improved.
Transferrin receptor (TfR)-mediated transcytosis is an attractive pathway for delivering large-molecule therapeutics to the central nervous system across the blood-brain barrier. Despite the clinical ...success of some drugs conjugated with TfR-binder, the desired drug profile for efficient TfR-mediated delivery to the targeted compartment within the brain, especially considering the species-related differences, has not been fully elucidated. To provide a prospective direction in the TfR-mediated drug delivery system, we developed an advanced physiologically based pharmacokinetic (PBPK) model. The model addresses TfR-mediated trans- and intracellular disposition of anti-TfR antibodies from brain capillary blood, endothelial cells, extracellular fluid (ECF), and eventually to brain parenchymal cells (BPCs), which correspond to pharmacological target sites of interest. The PBPK model is applicable in rats, monkeys, and human TfR knock-in (hTfR-KI) mice with satisfactory prediction accuracy through model calibration using the brain and plasma PK data of anti-TfR monoclonal antibodies, including their fused protein, with diverse binding affinity to TfR (TfR-Kd). The sensitivity analysis to determine drug properties required for the optimal brain delivery revealed 1) a bell-shaped relationship between TfR-Kd and brain exposure; 2) a minimum species difference between monkeys and hTfR-KI mice in the optimal TfR-Kd range, but not with rats; 3) a low TfR-Kd range to be preferably targeted for BPCs compared with ECF; and 4) an increase in brain exposure when using the pH-sensitive antibody. This may advance model-informed drug development, improve molecular design optimization, and provide precise human dose projection of drugs leveraging TfR-mediated shuttle technology into the brain.
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•A PBPK model for TfR-mediated drug delivery into the brain was developed.•The model describes a bell-shaped relationship between TfR-Kd and brain exposure.•The optimal TfR-Kd range would be close between monkeys and hTfR-KI mice.•A low TfR-Kd range would be required when targeting BPCs compared with ECF.•A pH-sensitive TfRmAb would be more efficient to target BPCs than ECF.
Ovarian cancer has the highest mortality rate among gynecological cancers. Gene mutations are involved in the carcinogenesis, metastasis, and therapeutic response in ovarian cancer. However, the ...variety and proportion of gene mutation is not fully analyzed in Japanese ovarian cancer patients, especially, in those with recurrent tumors. In the present study, RNA-sequencing was performed for 32 clinical ovarian specimens obtained from 24 Japanese patients (24 primary cancer specimens and 8 recurrent specimens paired with corresponding primary cancer specimens). Mutations in 24 primary specimens were analyzed by comparing the sequence data mapped on RefSeq genes with those in the public online databases BRCA Exchange, COSMIC, ClinVar, and cBioportal. Mutations were observed in TP53 in 16 specimens (67%), BRCA1 in 9 (38%), BRCA2 in 13 (54%), ARID1A in 3 (13%), PIK3CA in 2 (8%), KRAS in 1 (4%), PTEN in 1 (4%), and CTNNB1 in 1 (4%), excluding synonymous mutations. Among those identified muations, 13 of 14 mutations in TP53, 10 of 11 mutations of BRCA1, 10 of 23 mutation positions of BRCA2, none of 7 mutations of ARID1A, 1 mutation of PIK3CA, and 1 mutation of CTNNB1 were consistent with those reported in the public online databases; however, the other mutations identified were novel. Comparison between matched-paired specimens of primary and recurrent tumors revealed the changes of mutational status in expressed RNAs. RNA-sequencing-based mutation analysis will be useful to reveal ethnic differences of gene mutations in ovarian cancer and to understand the contribution of gene mutations to recurrence.
Purpose
TAK-831 is a highly selective and potent inhibitor of D-amino acid oxidase (DAAO) currently under clinical development for schizophrenia. In this study, a mechanistic multilayer quantitative ...model that parsimoniously connects pharmacokinetics (PK), target occupancy (TO) and D-serine concentrations as a pharmacodynamic (PD) readout was established in mice.
Methods
PK, TO and PD time-profiles were obtained in mice and analyzed by mechanistic binding kinetics model connected with an indirect response model in a step wise fashion. Brain distribution was investigated to elucidate a possible mechanism driving the hysteresis between PK and TO.
Results
The observed nonlinear PK/TO/PD relationship was well captured by mechanistic modeling framework within a wide dose range of TAK-831 in mice. Remarkably different brain distribution was observed between target and reference regions, suggesting that the target-mediated slow binding kinetics rather than slow penetration through the blood brain barrier caused the observed distinct kinetics between PK and TO.
Conclusion
A quantitative mechanistic model for concentration- and time-dependent nonlinear PK/TO/PD relationship was established for TAK-831 in mice with accounting for possible rate-determining process. The established mechanistic modeling framework will provide a quantitative means for multilayer biomarker-assisted clinical development in multiple central nervous system indications.
Gaucher disease (GD), the most common lysosomal storage disorders, is caused by GBA gene mutations resulting in glycosphingolipids accumulations in various tissues, such as the brain. While ...suppressing glycosphingolipid accumulation is the central strategy for treating peripheral symptoms of GD, there is no effective treatment for the central nervous system symptoms. As glycosphingolipid biosynthesis starts from ceramide glycosylation by glucosylceramide synthase (GCS), inhibiting GCS in the brain is a promising strategy for neurological GD. Herein, we discovered T‐036, a potent and brain‐penetrant GCS inhibitor with a unique chemical structure and binding property. T‐036 does not harbor an aliphatic amine moiety and has a noncompetitive inhibition mode to the substrates, unlike other known inhibitors. T‐036 exhibited sufficient exposure and a significant reduction of glucosylsphingolipids in the plasma and brain of the GD mouse model. Therefore, T‐036 could be a promising lead molecule for treating central nervous system symptoms of GD.
Suppression of glycosphingolipids accumulations by inhibition of glucosylceramide synthase (GCS) is considered a promising therapeutic approach for Gaucher disease. However, there is no effective treatment for the central nervous system symptoms today. Here, we report discovery of a novel GCS inhibitor T‐036, which is potent, orally effective, and brain‐penetrant. T‐036 does not harbor an aliphatic amine moiety and has a non‐competitive, inhibitory binding mode to the substrates unlike other known inhibitors. T‐036 exhibited significant reduction of glycosphingolipids in the disease mouse model. Therefore, T‐036 could be a promising lead molecule for treating central nervous system symptoms of GD.
Low-frequency noise may create specific perceptions, which might cause various health effects. The present study aimed to identify exposure–response relationships between low-frequency noise and ...perceptions by re-analysing an experimental study. We investigated the predominant perceptions of ‘feeling bothered’ and ‘feeling of pressure and/or vibration’ using multivariate logistic regression analysis. A significant interaction between 1/3 octave-band sound pressure level and frequency was indicated for ‘feeling bothered’ but not ‘feeling of pressure and/or vibration’, suggesting that the ‘feeling of pressure and/or vibration’ does not originate in cochlear. A mathematical model indicating resonance at approximately 50 Hz fitted the results well. A frequency weighting derived from the mathematical model could be applied to broad-band low-frequency noise to evaluate the perception and health effects. However, further investigations on the weighting for the perception are necessary because the results were obtained only from the existing study.
Direct-acting antiviral (DAA) therapy carries a potential risk of inducing hepatitis B virus (HBV) reactivation. However, the HBV kinetics during and after DAA therapy in patients co-infected with ...hepatitis C virus (HCV) and HBV remain unknown. We retrospectively evaluated the HBV kinetics during and after sofosbuvir/ribavirin therapy in four HBV inactive carriers co-infected with HCV. HCV was eradicated in all patients. Changes in HBV-DNA levels during treatment differed among patients. The hepatitis B surface antigen (HBsAg) levels uniformly decreased (mean -0.530 logIU/mL) by the end of treatment and returned to near the baseline in all patients. Sofosbuvir/ribavirin therapy thus demonstrated a suppressive effect on HBsAg.
Mutations in the GBA gene, encoding glucocerebrosidase (GCase), are linked to Gaucher disease (GD) and are the most common risk factors for Parkinson’s disease (PD). The glucosylsphingosine (GlcSph) ...in cerebrospinal fluid (CSF) is used as a pharmacodynamic marker for GCase functionalizing therapy in GD patients. Its isobaric structural isomer, galactosylsphingosine (GalSph, psychosine), is also used as a diagnostic blood marker in Krabbe disease (KD) which is caused by a deficiency in β-galactocerebrosidase (GALC). However, there are no reports of GlcSph quantification in the CSF of GBA-PD patients and normal healthy humans due to low concentrations. In this study, we successfully quantified GlcSph in healthy human CSF using a highly sensitive LC-MS/MS method with separation of GalSph. The lower limit of quantitation (LLOQ) was 0.1 pg/mL. Additionally, GlcSph and GalSph concentrations in the plasma and brain were determined using different LC-MS/MS methods. The mean concentrations of GlcSph and GalSph in normal human CSF were 1.07 and 9.44 pg/mL, respectively. The GalSph level in the CSF and brain was higher than that of GlcSph, whereas plasma GalSph was lower than GlcSph. Because GCase and GALC are expressed in the brain and the peripheral tissues, GlcSph and GalSph in CSF would be a good surrogate of concentration change in the brain by targeted therapies. This method measures normal levels of GlcSph and GalSph in healthy human CSF without accumulation of sphingolipids, and confirms whether abnormal CSF concentrations can be reduced to normal levels by therapy.
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•A sensitive method for glucosylsphingosine and galactosylsphingosine quantification.•The method was applied for the CSF of normal healthy humans.•The balance of two sphigolipids was compared among CSF, plasma and brain samples.
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