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Background: Anti-obesity medications are recommended for patients who do not achieve and maintain weight loss despite lifestyle interventions. S-309309 is a novel oral inhibitor of monoacylglycerol O-acyltransferase 2 being developed as a treatment for obesity. Objective: The objective of the study was to investigate the safety, clinical pharmacology, pharmacokinetics and pharmacodynamic biomarker of S-309309. Methods: A phase I, single-center, two-part, randomized, double-blind, placebo-controlled study of S-309309 following oral administration of a single-ascending dose (part 1) and a multiple dose (part 2) in healthy adults with or without obesity was conducted. We also assessed the effect of food on the pharmacokinetics of S-309309 and the effect of S-309309 on electrocardiogram parameters, the pharmacokinetics of midazolam (a cytochrome P450 3A substrate), and the pharmacodynamic biomarker of monoacylglycerol O-acyltransferase 2 inhibition. Results: In part 1 (N = 50), a single-ascending dose of S-309309 in healthy adults demonstrated dose proportionality and comparable exposure of S-309309 between the fasted and fed states. In part 2 (N = 24), no clinically meaningful difference was observed in the pharmacokinetics of multiple doses between healthy adults with or without obesity. S-309309 did not affect the pharmacokinetics of the cytochrome P450 3A substrate. The pharmacodynamic biomarker of monoacylglycerol O-acyltransferase 2 inhibition, dicarboxylic acid (18:1), was significantly increased after S-309309 administration in healthy adults with or without obesity. Overall, S-309309 demonstrated acceptable safety and tolerability without any serious adverse events or discontinuations because of adverse events, and did not have a clinically relevant effect on the heart rate or cardiac conduction. An effect on the placebo-corrected change-from-baseline corrected QT interval, corrected for heart rate using the Fridericia method, exceeding 10 ms can be excluded. Conclusions: S-309309 was well tolerated as single-dose (up to 300 mg) and multiple-dose (50 mg once daily for 14 days) oral administration. The pharmacokinetic characteristics remained unaffected by obesity and food intake. S-309309 did not affect the pharmacokinetics of the cytochrome P450 3A substrate. Overall, S-309309 had an acceptable safety profile and favorable pharmacokinetic and pharmacodynamic characteristics. Clinical Trial Registration: NCT05247970, date of registration: 8 February, 2022. [ABSTRACT FROM AUTHOR]

We assessed S-268019-b, a recombinant spike protein vaccine with a squalene-based adjuvant, for superiority in its immunogenicity over ChAdOx1 nCoV-19 vaccine among adults in Japan. In this multicenter, randomized, observer-blinded, phase 3 study, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)–naïve participants (aged ≥ 18 years, without prior infection or vaccination against SARS-CoV-2) were randomized (1:1) to receive either S-268019-b or ChAdOx1 nCoV-19 as two intramuscular injections given 28 days apart. Participants who provided consent for a booster administration received S-268019-b at Day 211. The primary endpoint was SARS-CoV-2 neutralizing antibody (NAb) titer on Day 57; the key secondary endpoint was the seroconversion rate for SARS-CoV-2 NAb titer on Day 57. Other endpoints included anti–SARS-CoV-2 S-protein immunoglobulin (Ig)G antibody titer and safety. The demographic and baseline characteristics were generally comparable between S-268019-b (n = 611) and ChAdOx1 nCoV-19 (n = 610) groups. S-268019-b showed superior immunogenicity over ChAdOx1 nCoV-19, based on their geometric mean titers (GMTs) and GMT ratios of SARS-CoV-2 NAb on Day 57 by cytopathic effect assay (GMT [95% confidence interval {CI}] 19.92 [18.68, 21.23] versus 3.63 [3.41, 3.87]; GMT ratio [95% CI] 5.48 [5.01, 6.00], respectively; two-sided p-values < 0.0001). Additionally, NAb measured using a cell viability assay also showed similar results (GMT [95% CI] 183.25 [168.04, 199.84] versus 24.79 [22.77, 27.00]; GMT ratio [95% CI] 7.39 [6.55, 8.35] for S-268019-b versus ChAdOx1 nCoV-19, respectively; p < 0.0001). The GMT of anti–SARS-CoV-2 S-protein IgG antibody was 370.05 for S-268019-b versus 77.92 for ChAdOx1 nCoV-19 on Day 57 (GMT ratio [95% CI] 4.75 [4.34, 5.20]). Notably, immune responses were durable through the end of the study. S-268019-b elicited T-helper 1 skewed T-cell response, comparable to that of ChAdOx1 nCoV-19. After the first dose, the incidence of solicited systemic treatment-related adverse events (TRAEs) was higher in the ChAdOx1 nCoV-19 group, but after the second dose, the incidence was higher in the S-268019-b group. Headache, fatigue, and myalgia were the most commonly reported solicited systemic TRAEs, while pain at the injection site was the most frequently reported solicited local TRAE following both doses in both groups. No serious treatment-related adverse serious TRAEs events were reported in the two groups. S-268019-b was more immunogenic than ChAdOx1 nCoV-19 vaccine and was well tolerated (jRCT2051210151). [ABSTRACT FROM AUTHOR]

Background: A reported clinical pharmacokinetics and safety study of suspension formulation of ensitrelvir, a therapeutic agent used in severe acute respiratory syndrome coronavirus 2 infection, demonstrated favorable pharmacokinetics and was well tolerated in healthy male Japanese and White participants. Understanding the safety and pharmacokinetic features of ensitrelvir (using the formulation approved for clinical use) in various populations, and the effect of food, is crucial for optimal clinical use. Objectives: The objectives of this study were to (1) assess the safety, tolerability, and pharmacokinetics of ensitrelvir following multiple-dose administration of ensitrelvir tablets in populations with different races, ages, and sex; and (2) assess the effect of food on the pharmacokinetics of ensitrelvir tablets in the fasted or fed state. Methods: A phase 1, multicenter, double-blinded, randomized, placebo-controlled study was conducted to evaluate the safety and pharmacokinetics of once-daily ensitrelvir tablets at loading/maintenance doses of 375/125 mg or 750/250 mg for 5 days in healthy Japanese females, Japanese elderly (only 375/125 mg), and White male and female participants. An open-label, two-group, two-period crossover study was also conducted to estimate the effect of food on the pharmacokinetics of ensitrelvir at single dose of 375 mg. The nature, frequency, and severity of treatment-emergent adverse events were evaluated and recorded in safety assessments in both studies. Results: The maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) were similar within these populations. The geometric mean half-life of ensitrelvir following multiple-dose administration was 48.7–58.9 h across all cohorts. The Cmax and AUC increased in a dose-proportional manner in Japanese female participants, and increased in a less than dose-proportional manner in White participants. Furthermore, there was no clear relationship between the dose and geometric mean half-life of ensitrelvir. The plasma concentration at 24 h (C24) after an initial dose of 375/125 mg exceeded the target plasma concentration (6.09 µg/mL) in all populations. Regarding the effect of food on the pharmacokinetics of ensitrelvir, although time to Cmax in the fed state was delayed, there was no clinically meaningful difference in the exposure levels (Cmax and AUC) of ensitrelvir between the fasted and fed states. Most treatment-emergent adverse events were mild in nature and had resolved. Conclusion: Ensitrelvir (375/125 mg and 750/250 mg tablet formulation) was well tolerated, without any major safety concerns. The pharmacokinetics of ensitrelvir between all populations in the study were similar and C24 exceeded the target plasma concentration at 375/125 mg. These results suggest that ensitrelvir can be effectively administered with no necessity for dose adjustment for age, sex, and race without food restriction. Clinical Trial Registration: Japan Registry of Clinical Trials identifier: jRCT2031210202, registered on 16 July 2021. [ABSTRACT FROM AUTHOR]

Aim: This phase 1 study assessed the pharmacokinetics, safety, and tolerability of zuranolone in Japanese and White healthy adults, and Japanese healthy elderly subjects. Methods: This single‐center study consisted of three parts. In Part A (randomized, double‐blind), the safety, tolerability, and pharmacokinetics of single dose and 7‐day consecutive multiple doses of zuranolone 10, 20, and 30 mg and placebo were assessed in 36 Japanese adults, 24 White adults, and 12 Japanese elderly (aged 65–75 years) subjects. In Part B (randomized, open‐label, crossover), the effect of food intake on the pharmacokinetics and safety of single‐dose zuranolone 30 mg was evaluated in 12 Japanese adults. In Part C (randomized, double‐blind, crossover), the effects of single‐dose zuranolone 10 and 30 mg and placebo on electroencephalography parameters were evaluated in eight Japanese adults. Results: Single and multiple doses of zuranolone were safe and well tolerated in all subjects. Linear pharmacokinetics were observed in the studied dose range. Time to steady‐state plasma concentration was within 72 h for Japanese and White adults. Pharmacokinetic profiles were comparable between Japanese and White adults and between Japanese adults and Japanese elderly subjects. Plasma exposures of zuranolone were greater in the fed versus fasted state. Single‐dose zuranolone 30 mg increased low‐beta electroencephalography power. Conclusion: In healthy Japanese subjects, zuranolone was well tolerated; pharmacokinetic profile was unaffected by ethnicity or age; plasma exposures were greater in the fed state. The increased low‐beta electroencephalography power with the 30‐mg dose is consistent with γ‐aminobutyric acid receptor type A activation by zuranolone. [ABSTRACT FROM AUTHOR]

Aim: To evaluate the efficacy and safety of an oral, once‐daily, 14‐day treatment course of zuranolone in Japanese patients with major depressive disorder (MDD). Methods: This multicenter, randomized, double‐blind, placebo‐controlled study randomized eligible patients (1:1:1) to receive oral zuranolone 20 mg, zuranolone 30 mg, or placebo once daily for 14 days (treatment‐period), followed by two 6‐week follow‐up periods. The primary endpoint was change from baseline in the 17‐item Hamilton Depression Rating Scale (HAMD‐17) total score on Day 15. Results: Overall, 250 patients (enrolled: 07/07/2020–05/26/2021) were randomized to receive placebo (n = 83), zuranolone 20 mg (n = 85), or zuranolone 30 mg (n = 82). The demographic and baseline characteristics were balanced between groups. The adjusted mean (standard error) change from baseline in the HAMD‐17 total score on Day 15 was −6.22 (0.62), −8.14 (0.62), and − 8.31 (0.63) in the placebo, zuranolone 20‐mg, and zuranolone 30‐mg groups, respectively. Significant differences in the adjusted mean (95% confidence interval [CI]) for zuranolone 20 mg versus placebo (−1.92; [−3.65, −0.19]; P = 0.0296) and zuranolone 30 mg versus placebo (−2.09; [−3.83, −0.35]; P = 0.0190) groups were observed on Day 15, and also as early as Day 3. A nonsignificant yet distinct drug‐placebo separation was observed during follow‐up. Somnolence (placebo [3.7%], zuranolone 20 mg [10.6%], and zuranolone 30 mg [20.7%]) and dizziness (3.7%, 9.4%, and 9.8%, respectively) were more common with zuranolone. Conclusion: Oral zuranolone was safe and demonstrated significant improvements in depressive symptoms, as assessed by HAMD‐17 total score change from baseline over 14 days in Japanese patients with MDD. [ABSTRACT FROM AUTHOR]

Drug‐drug interaction potentials of ensitrelvir, a novel oral inhibitor of 3C‐like protease of severe acute respiratory syndrome coronavirus 2, for drug transporters were evaluated by in vitro and clinical studies. The target drug transporters assessed were P‐glycoprotein (P‐gp), breast cancer resistance protein (BCRP), organic anion transporting polypeptide (OATP) 1B1, OATP1B3, organic anion transporter (OAT) 1, OAT3, organic cation transporter (OCT) 1, OCT2, and multidrug and toxin extrusion 1 and 2K. In vitro study revealed that ensitrelvir is a substrate for P‐gp and BCRP and inhibits P‐gp, BCRP, OATP1B1, OATP1B3, OCT1, and OAT3. Based on these results, a clinical drug‐drug interaction study to evaluate the effect of ensitrelvir on the pharmacokinetics of P‐gp, BCRP, OATP1B1, OATP1B3, and OCT1 substrates was conducted with a cocktail approach using digoxin (P‐gp substrate), rosuvastatin (BCRP, OATP1B1, and OATP1B3 substrate), and metformin (OCT1 substrate). The cocktail was administered first, and after the washout period, the cocktail was coadministered with 500 mg of ensitrelvir. No treatment‐emergent adverse events were observed. Pharmacokinetic analyses demonstrated that the ratios (90% confidence intervals) of "cocktail with ensitrelvir" to "cocktail without ensitrelvir" for maximum plasma concentration and area under the plasma concentration–time curve were, respectively, 2.17 (1.72‐2.73) and 1.31 (1.13‐1.52) for digoxin, 1.97 (1.73‐2.25) and 1.65 (1.47‐1.84) for rosuvastatin, and 1.03 (0.91‐1.16) and 1.02 (0.94‐1.11) for metformin. The results indicate that the exposure levels of digoxin and rosuvastatin increased when coadministered with ensitrelvir, but those of metformin were not changed. In conclusion, ensitrelvir has an impact on the exposure levels of P‐gp, BCRP, OATP1B1, and OATP1B3 substrates. [ABSTRACT FROM AUTHOR]

This document is a correction notice for an article titled "Immune response and protective efficacy of the SARS-CoV-2 recombinant spike protein vaccine S-268019-b in mice" published in Scientific Reports. The correction addresses an error in Figure 6 of the original article, where panel (e) was omitted. The corrected figure and accompanying legend are provided in the notice. The original article has been updated to reflect this correction. [Extracted from the article]

Background: Management of drug–drug interactions (DDIs) for ensitrelvir, a novel 3-chymotrypsin-like protease inhibitor of SARS-CoV-2 infection is crucial. A previous clinical DDI study of ensitrelvir with midazolam, a clinical index cytochrome P450 (CYP) 3A substrate, demonstrated that ensitrelvir given for 5 days orally with a loading/maintenance dose of 750/250 mg acted as a strong CYP3A inhibitor. Objectives: The objectives of this study were to investigate the effect of ensitrelvir on the pharmacokinetics of CYP3A substrates, dexamethasone, prednisolone and midazolam, and to assess the pharmacokinetics, safety, and tolerability of ensitrelvir following multiple-dose administration of ensitrelvir. Methods: This was a Phase 1, multicenter, single-arm, open-label study in healthy Japanese adult participants. The effects of multiple doses of ensitrelvir in the fasted state on the pharmacokinetics of dexamethasone, prednisolone, and midazolam were investigated. Ensitrelvir was administered from Day 1 through Day 5, with a loading/maintenance dose of 750/250 mg for the dexamethasone and prednisolone cohorts whereas 375/125 mg for the midazolam cohort. Either dexamethasone, prednisolone, or midazolam was administered alone (Day − 2) or in combination with ensitrelvir (Day 5) in each of the cohorts. Additionally, dexamethasone or prednisolone was administered on Days 9 and 14. The pharmacokinetic parameters of ensitrelvir, dexamethasone, prednisolone, and midazolam were calculated based on their plasma concentration data with non-compartmental analysis. In safety assessments, the nature, frequency, and severity of treatment-emergent adverse events were evaluated and recorded. Results: The area under the concentration-time curve (AUC) ratio of dexamethasone on Day 5 was 3.47-fold compared with the corresponding values for dexamethasone alone on Day − 2 and the effect diminished over time after the last dose of ensitrelvir. No clinically meaningful effect was observed for prednisolone. The AUC ratio of midazolam was 6.77-fold with ensitrelvir 375/125 mg suggesting ensitrelvir at 375/125 mg strongly inhibits CYP3A similar to that at 750/250 mg. No new safety signals with ensitrelvir were reported during the study. Conclusion: The inhibitory effect for CYP3A was confirmed after the last dose of ensitrelvir, and the effect diminished over time. In addition, ensitrelvir at 375/125 mg showed CYP3A inhibitory potential similar to that at 750/250 mg. These findings can be used as a clinical recommendation for prescribing ensitrelvir with regard to concomitant medications. Clinical Trial Registration: Japan Registry of Clinical Trials identifier: jRCT2031210202. [ABSTRACT FROM AUTHOR]

Background This phase 2b part of a randomized phase 2/3 study assessed the efficacy and safety of ensitrelvir for mild-to-moderate coronavirus disease 2019 (COVID-19) during the Omicron epidemic. Methods Patients were randomized (1:1:1) to orally receive ensitrelvir fumaric acid 125 mg (375 mg on day 1) or 250 mg (750 mg on day 1) or placebo once daily for 5 days. The co-primary endpoints were the change from baseline in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) titer on day 4 and time-weighted average change from baseline up to 120 hours in the total score of predefined 12 COVID-19 symptoms. Safety was assessed through adverse events. Results A total of 341 patients (ensitrelvir 125-mg group: 114; ensitrelvir 250-mg group: 116; and placebo group: 111; male: 53.5–64.9%; mean age: 35.3–37.3 years) were included in the efficacy analyses. The change from baseline in SARS-CoV-2 titer on day 4 was significantly greater with both ensitrelvir doses than with placebo (differences from placebo: −0.41 log10 50% tissue-culture infectious dose/mL; P <.0001 for both). The total score of the 12 COVID-19 symptoms did not show a significant difference between the ensitrelvir groups and placebo group. The time-weighted average change from baseline up to 120 hours was significantly greater with ensitrelvir versus placebo in several subtotal scores, including acute symptoms and respiratory symptoms. Most adverse events were mild in severity. Conclusions Ensitrelvir treatment demonstrated a favorable antiviral efficacy and potential clinical benefit with an acceptable safety profile. Clinical Trials Registration Japan Registry of Clinical Trials: jRCT2031210350 (https://jrct.niph.go.jp/en-latest-detail/jRCT2031210350) [ABSTRACT FROM AUTHOR]

Vaccines that efficiently target severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiological agent for coronavirus disease (COVID-19), are the best means for controlling viral spread. This study evaluated the efficacy of the COVID-19 vaccine S-268019-b, which comprises the recombinant full-length SARS-CoV-2 spike protein S-910823 (antigen) and A-910823 (adjuvant). In addition to eliciting both Th1-type and Th2-type cellular immune responses, two doses of S-910823 plus A-910823 induced anti-spike protein IgG antibodies and neutralizing antibodies against SARS-CoV-2. In a SARS-CoV-2 challenge test, S-910823 plus A-910823 mitigated SARS-CoV-2 infection-induced weight loss and death and inhibited viral replication in mouse lungs. S-910823 plus A-910823 promoted cytokine and chemokine at the injection site and immune cell accumulation in the draining lymph nodes. This led to the formation of germinal centers and the induction of memory B cells, antibody-secreting cells, and memory T cells. These findings provide fundamental property of S-268019-b, especially importance of A-910823 to elicit humoral and cellular immune responses. [ABSTRACT FROM AUTHOR]

Lusutrombopag is a thrombopoietin receptor agonist approved to treat thrombocytopenia in patients with chronic liver disease (CLD). This post hoc analysis of the Japanese L-PLUS 1 and global L-PLUS 2 trials aimed to clarify factors related to platelet count increase after lusutrombopag treatment. In L-PLUS 1, Pearson's correlation coefficients were used to evaluate correlations between platelet count and spleen index, thrombopoietin concentration, white blood cell (WBC) counts, and red blood cell counts (intent-to-treat [ITT] population). Associations between platelet count increase after lusutrombopag treatment and each parameter were assessed by regression analysis and mixed-effect model for repeated measures (MMRM). Associations between time-dependent changes in platelet count increase and each parameter were also examined in the L-PLUS 2 lusutrombopag ITT population by MMRM. In L-PLUS 1, the baseline platelet count was correlated with pretreatment spleen index (r = −0.23, 95% confidence interval [CI] −0.41 to −0.03) and WBC count (r = 0.26, 95% CI 0.06 to 0.43). No selected parameters were associated with the maximum platelet count increase from baseline. Patients with WBC counts below the normal range showed smaller platelet count increases after lusutrombopag treatment than patients with WBC counts within the normal range (p =.0028). In L-PLUS 2 (p =.0533), findings were similar and confirmed by larger pooled data of L-PLUS 1/L-PLUS 2 (p =.0021). This post hoc analysis revealed a possible association between baseline WBC count and platelet count increase after lusutrombopag treatment. WBC count could be a relevant factor for lusutrombopag efficacy. [ABSTRACT FROM AUTHOR]

Brain-derived neurotrophic factor (BDNF) signals through its high affinity receptor Tropomyosin receptor kinase-B (TrkB) to regulate neuronal development, synapse formation and plasticity. In rodents, genetic disruption of Bdnf and TrkB leads to weight gain and a spectrum of neurobehavioural phenotypes. Here, we functionally characterised a de novo missense variant in BDNF and seven rare variants in TrkB identified in a large cohort of people with severe, childhood-onset obesity. In cells, the E183K BDNF variant resulted in impaired processing and secretion of the mature peptide. Multiple variants in the kinase domain and one variant in the extracellular domain of TrkB led to a loss of function through multiple signalling pathways, impaired neurite outgrowth and dominantly inhibited glutamatergic synaptogenesis in hippocampal neurons. BDNF/TrkB variant carriers exhibited learning difficulties, impaired memory, hyperactivity, stereotyped and sometimes, maladaptive behaviours. In conclusion, human loss of function BDNF/TrkB variants that impair hippocampal synaptogenesis may contribute to a spectrum of neurobehavioural disorders. [ABSTRACT FROM AUTHOR]

OBJECTIVE--Natriuretic peptides (NPs) have been characterized as vascular hormones that regulate vascular tone via guanylyl cyclase (GC), cyclic GMP (cGMP), and cGMP-dependent protein kinase (cGK). Recent clinical studies have shown that plasma NP levels were lower in subjects with the metabolic syndrome. The present study was conducted to elucidate the roles for NP/cGK cascades in energy metabolism. RESEARCH DESIGN AND METHODS--We used three types of genetically engineered mice: brain NP (BNP) transgenic (BNP-Tg), cGK-Tg, and guanylyl cyclase-A (GCA) heterozygous knockout (GCA+/-) mice and analyzed the metabolic consequences of chronic activation of NP/cGK cascades in vivo. We also examined the effect of NPs in cultured myocytes. RESULTS--BNP-Tg mice fed on high-fat diet were protected against diet-induced obesity and insulin resistance, and cGK-Tg mice had reduced body weight even on standard diet; surprisingly, giant mitochondria were densely packed in the skeletal muscle. Both mice showed an increase in muscle mitochondrial content and fat oxidation through upregulation of peroxisome proliferator-activated receptor (PPAR)-γ coactivator (PGC)-1α and PPARδ. The functional NP receptors, GCA and guanylyl cyclase-B, were downregulated by feeding a high-fat diet, while GCA+/- mice showed increases in body weight and glucose intolerance when fed a high-fat diet. NPs directly increased the expression of PGC-1α and PPARδ and mitochondrial content in cultured myocytes. CONCLUSIONS--The findings together suggest that NP/cGK cascades can promote muscle mitochondrial biogenesis and fat oxidation, as to prevent obesity and glucose intolerance. The vascular hormone, NP, would contribute to coordinated regulation of oxygen supply and consumption. Diabetes 58: 2880-2892, 2009 [ABSTRACT FROM AUTHOR]

Abstract: Anti-fibrotic and organ protective effects of brain natriuretic peptide (BNP) have been reported. In this study, effects of BNP on liver fibrosis were examined in the carbon tetrachloride (CCl4)-induced liver fibrosis model using BNP-transgenic (Tg) and wild-type (WT) mice. Twice-a-week intraperitoneal injections of CCl4 for 8weeks resulted in massive liver fibrosis, augmented transforming growth factor (TGF)-β1 and type I procollagen α1 chain (Col1a1) mRNA expression, and the hepatic stellate cell (HSC) activation in WT mice, all of which were significantly suppressed in Tg mice. These observations indicate that BNP inhibits liver fibrosis by attenuating the activation of HSCs. [Copyright &y& Elsevier]

Abstract: Induced pluripotent stem (iPS) cells were recently established from human fibroblasts. In the present study we investigated the adipogenic differentiation properties of four human iPS cell lines and compared them with those of two human embryonic stem (ES) cell lines. After 12days of embryoid body formation and an additional 10days of differentiation on Poly-l-ornithine and fibronectin- coated dishes with adipogenic differentiation medium, human iPS cells exhibited lipid accumulation and transcription of adipogenesis-related molecules such as C/EBPα, PPARγ2, leptin and aP2. These results demonstrate that human iPS cells have an adipogenic potential comparable to human ES cells. [Copyright &y& Elsevier]

Background: We previously demonstrated that vascular endothelial growth factor receptor type 2 (VEGF-R2)-positive cells induced from mouse embryonic stem (ES) cells can differentiate into both endothelial cells (ECs) and mural cells (MCs) and these vascular cells construct blood vessel structures in vitro. Recently, we have also established a method for the large-scale expansion of ECs and MCs derived from human ES cells. We examined the potential of vascular cells derived from human ES cells to contribute to vascular regeneration and to provide therapeutic benefit for the ischemic brain. Methods: Phosphate buffered saline, human peripheral blood mononuclear cells (hMNCs), ECs-, MCs-, or the mixture of ECs and MCs derived from human ES cells were intra-arterially transplanted into mice after transient middle cerebral artery occlusion (MCAo). Results: Transplanted ECs were successfully incorporated into host capillaries and MCs were distributed in the areas surrounding endothelial tubes. The cerebral blood flow and the vascular density in the ischemic striatum on day 28 after MCAo had significantly improved in ECs-, MCs- and ECs+MCstransplanted mice compared to that of mice injected with saline or transplanted with hMNCs. Moreover, compared to saline-injected or hMNC-transplanted mice, significant reduction of the infarct volume and of apoptosis as well as acceleration of neurological recovery were observed on day 28 after MCAo in the cell mixture-transplanted mice. Conclusion: Transplantation of ECs and MCs derived from undifferentiated human ES cells have a potential to contribute to therapeutic vascular regeneration and consequently reduction of infarct area after stroke. [ABSTRACT FROM AUTHOR]