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Fasudil, a clinically safe ROCK inhibitor, decreases disease burden in a Cbl/Cbl-b deficiency-driven murine model of myeloproliferative disorders.

ABSTRACT: Mutations in Cbl or Cbl-b gene occur in 10% of myeloproliferative disorder (MPD) patients and are associated with poor prognosis. Hematopoietic Cbl/Cbl-b double knockout (DKO) leads to a disease in mice phenotypically similar to human MPDs. The aim of this study was to evaluate the anti-MPD activity of a clinically safe drug, Fasudil, identified in an in vitro kinase inhibitor as an inhibitor of proliferation of DKO mouse hematopoietic stem/progenitor cells (HSPCs).Fasudil exhibited relatively selective anti-proliferative activity against Cbl/Cbl-b DKO vs. control murine bone marrow HSPCs. We established a mouse model with uniform time of MPD onset by transplanting Cbl/Cbl-b DKO HSPCs into busulfan-conditioned NOD/SCID/gamma chain-deficient mice. Four weeks post-transplant, mice were treated with 100 mg/kg fasudil (13 mice) or water (control, 8 mice) daily by oral gavage, followed by blood cell count every 2 weeks.By 2 weeks of treatment, total white cell and monocyte counts were significantly lower in mice treated with fasudil. We observed a trend towards improved survival in fasudil-treated mice that did not reach statistical significance. Notably, prolonged survival beyond 27 weeks was observed in two fasudil-treated mice, nearly twice the 16-week average life-span in the Cbl/Cbl-b DKO MPD model.Our results suggest a therapeutic potential for fasudil, a clinically safe drug with promising results in vascular diseases, in the treatment of MPDs or other mutant Cbl-driven myeloid disorders.

SUBMITTER: William BM

PROVIDER: S-EPMC5555218 | biostudies-other | 2016 May

REPOSITORIES: biostudies-other

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Fasudil decreases lesion burden in a murine model of cerebral cavernous malformation disease.

Project description:Cerebral cavernous malformations (CCMs) are characterized by grossly dilated capillaries, associated with vascular leak and hemorrhage, and occur in sporadic or inherited (autosomal-dominant) forms with mutations in 1 of 3 gene loci (CCM 1, 2 or 3). We previously reported that the CCM1 protein (KRIT1) localizes to endothelial cell-cell junctions and loss of KRIT1 leads to junctional instability associated with activation of RhoA and its effector Rho kinase. Although Rho kinase inhibition has been proposed as potential therapy for CCM, there has been no demonstration of a therapeutic effect on CCM lesion genesis in vivo.Our recently generated a model of CCM1 disease (Ccm1(+/-)Msh2(-/-)) was treated with the Rho kinase inhibitor fasudil (100 mg/kg/day administered in drinking water from weaning to 5 months of age), or placebo, and blindly assessed CCM lesion burden by systematic survey of animals' brains. For comparison, we also assessed therapeutic effect in previously described Ccm2(+/-)Trp53(-/-) mice treated with the same dose and duration of fasudil and placebo.Fasudil-treated Ccm1(+/-)Msh2(-/-) mice had a significantly decreased prevalence of CCM lesions compared with placebo controls. Lesions in treated animals were smaller and less likely associated with hemorrhage, inflammation, and endothelial proliferation and exhibited decreased expression of Rho kinase activation biomarkers. A therapeutic effect was also documented in Ccm2(+/-)Trp53(-/-) mice.This represents the first report of therapeutic benefit of pharmacological therapy in development and progression of CCMs and indicates that Rho kinase activation is a critical step in CCM lesion genesis and maturation.

| S-EPMC3265629 | biostudies-literature

Rapidly fatal myeloproliferative disorders in mice with deletion of Casitas B-cell lymphoma (Cbl) and Cbl-b in hematopoietic stem cells.

Project description:Casitas B-cell lymphoma (Cbl)-family E3 ubiquitin ligases are negative regulators of tyrosine kinase signaling. Recent work has revealed a critical role of Cbl in the maintenance of hematopoietic stem cell (HSC) homeostasis, and mutations in CBL have been identified in myeloid malignancies. Here we show that, in contrast to Cbl or Cbl-b single-deficient mice, concurrent loss of Cbl and Cbl-b in the HSC compartment leads to an early-onset lethal myeloproliferative disease in mice. Cbl, Cbl-b double-deficient bone marrow cells are hypersensitive to cytokines, and show altered biochemical response to thrombopoietin. Thus, Cbl and Cbl-b play redundant but essential roles in HSC regulation, whose breakdown leads to hematological abnormalities that phenocopy crucial aspects of mutant Cbl-driven human myeloid malignancies.

| S-EPMC2941297 | biostudies-other

Use of CBL exon 8 and 9 mutations in diagnosis of myeloproliferative neoplasms and myelodysplastic/myeloproliferative disorders: an analysis of 636 cases.

Project description:We analyzed 636 patients with diverse myeloproliferative neoplasms or myelodysplastic/myeloproliferative neoplasms for mutations of the Casitas B-cell lymphoma gene (CBL(mut)) in exons 8 and 9 and performed correlations to other genetic alterations. CBL(mut) were detected in 63 of 636 (9.9%) of these selected patients. CBL(mut) were more frequent in myelodysplastic/myeloproliferative neoplasms than myeloproliferative neoplasms (51 of 328, 15.5% vs. 12 of 291, 4.1%; P<0.001). Frequency was 48 of 278 (17.3%) in chronic myelomonocytic leukemia and 3 of 33 (9.1%) in unclassifiable myelodysplastic/myeloproliferative neoplasms. CBL(mut) was not detected in polycythemia vera, primary myelofibrosis, essential thrombocythemia, or refractory anemia with ring sideroblasts and marked thrombocytosis. CBL(mut) were underrepresented in JAK2(V617F) mutated as compared to JAK2V617(wt) cases (P<0.001), and mutually exclusive of JAK2exon12(mut) and MPLW515(mut). CBL(mut) were associated with monosomy 7 (P=0.008) and TET2(mut) (P=0.003). In chronic myelomonocytic leukemia, CBL(mut) had no significant impact on survival outcomes. Therefore, CBL(mut) are frequent in chronic myelomonocytic leukemia, absent in classical myeloproliferative neoplasms, and are only exceptionally found in coincidence with JAK-STAT pathway activating mutations.

| S-EPMC3685285 | biostudies-literature

Compassionate Use of the ROCK Inhibitor Fasudil in Three Patients With Amyotrophic Lateral Sclerosis.

Project description:The Rho kinase (ROCK) inhibitor Fasudil is a promising drug for a disease-modifying therapy of amyotrophic lateral sclerosis (ALS). In preclinical models, Fasudil was shown to increase motor neuron survival, inhibit axonal degeneration, enhance axonal regeneration and modulate microglial function in vitro and in vivo. It prolonged survival and improved motor function of SOD1-G93A-mice. Recently, a phase IIa clinical trial has been commenced to investigate the safety, tolerability, and efficacy of Fasudil in ALS patients at an early stage of disease (ROCK-ALS trial, NCT03792490, Eudra-CT-Nr.: 2017-003676-31). Although Fasudil has been approved in Japan for many years for the treatment of vasospasms following subarachnoid hemorrhage and is known to have a favorable side effect profile in these patients, there is no data on its use in human patients with ALS or any other neurodegenerative conditions. Here, we report the first three cases of compassionate use of Fasudil in patients with ALS. Between May 2017 and February 2019, one male (66 years old) and two female (62 and 68 years old) subjects with probable or definite ALS according to the El Escorial criteria (one of the females having a pathogenic SOD1 mutation) were administered Fasudil 30 mg intravenously twice daily over 45 min on 20 consecutive working days. Blood pressure, heart rate and routine laboratory tests were constantly controlled. All three subjects tolerated the Fasudil infusions well without any obvious side effects. Interestingly, the slow vital capacity showed a significant increase in one of the patients. Taken together, we report here the first compassionate use of the ROCK inhibitor Fasudil in three ALS patients, which was well-tolerated.

| S-EPMC7083210 | biostudies-literature

Myeloproliferative disorders: A retrospective cohort study.

Project description:ObjectivesThis study was aimed to identify the number, shape and distribution of megakaryocytes and to recognize blast cells and its location.Further, to identify presence of fibrosis or increased microvascularity.Also,study correlation between histological findings.MethodsA retrospective was conducted between January 2016 to December 2018 at al-mouwasat university hospital. A total of 44 cases of myeloproliferative disorders using H&E and IHC stains were studied.Chi-square test was performed with descriptive statistics.ResultsMost of our patients were men younger than 75 years of age. 40 was the most prevalent as a median number of megakaryocytes in bone marrow biopsy with normal shape and diffuse pattern, most of biopsies were fibrotic, paratrabecular pattern and absent of hemosiderin deposits that correlate significantly to women patients.Minimal blast cells were more common with diffuse pattern.ConclusionBone marrow biopsy is a useful investigation in myeloproliferative disorders. Evaluation of megakaryopoiesis, fibrosis, and localization of blasts are possible on a bone marrow biopsy.

| S-EPMC8361036 | biostudies-literature

Mental Disorders, Musculoskeletal Disorders and Income-Driven Patterns: Evidence from the Global Burden of Disease Study 2017.

Project description:BACKGROUND:The aim of the present study was to use the extensive Global Burden ofDiseases, Injuries, and Risk Factors Study (GBD) database from 1990-2017 to evaluate the levels andtemporal correlation trends between disability adjusted life years (DALYs) attributed tomusculoskeletal (MSK) disorders, all mental disorders collectively and by mental disorder subcategory. METHODS:We utilized results of the GBD 2017 to describe the correlation patterns betweenDALYs due to MSK disorders, mental disorders and other diseases among 195 countries. Mixedmodel analysis was also applied. RESULTS:A consistent relation was reported between age-adjustedDALYs attributed to MSK and mental disorders (in total) among the 195 countries, in both sexes,for 1990 to 2017 (1990 Rho = 0.487; 2017 Rho =0.439 p < 0.05). Distinct regional and gender correlationpatterns between age-adjusted DALYs due to MSK and mental disorders were reported. Nocorrelation was reported between DALYs due to MSK and all mental disorders collectively, amongLow- or Middle-income countries. However, in High-income countries (HICs), the correlation wasstrong and consistent between 1990 and 2017 (1990 Rho = 0.735; 2017 Rho = 0.727, p < 0.05). CONCLUSIONS:The reported correlation patterns call for targeted preventive strategies andintervention policies for mental and MSK disorders internationally. Special attention is neededamong HICs.

| S-EPMC7408666 | biostudies-literature

Expression of Autophagy Genes in Myeloproliferative Disorders

Project description:Comparison of ATG gene family members in MPN pattients with normal controls

2015-03-31 | GSE38543 | GEO

Expression of Autophagy Genes in Myeloproliferative Disorders

Project description:Comparison of ATG gene family members in MPN pattients with normal controls One-Way ANOVA while contrasting ATG gene family members in 11 Normal (Control) with either 1) 13 PV samples 2) 24 ET samples or 3) 18 PMF samples

2015-03-31 | E-GEOD-38543 | biostudies-arrayexpress

Generalized Chorea and JAK2V617F Mutation-Positive Myeloproliferative Disorders.

Project description: Not available

| S-EPMC7197301 | biostudies-literature

ROCK-ALS: Protocol for a Randomized, Placebo-Controlled, Double-Blind Phase IIa Trial of Safety, Tolerability and Efficacy of the Rho Kinase (ROCK) Inhibitor Fasudil in Amyotrophic Lateral Sclerosis.

Project description:Objectives: Disease-modifying therapies for amyotrophic lateral sclerosis (ALS) are still not satisfactory. The Rho kinase (ROCK) inhibitor fasudil has demonstrated beneficial effects in cell culture and animal models of ALS. For many years, fasudil has been approved in Japan for the treatment of vasospasm in patients with subarachnoid hemorrhage with a favorable safety profile. Here we describe a clinical trial protocol to repurpose fasudil as a disease-modifying therapy for ALS patients. Methods: ROCK-ALS is a multicenter, double-blind, randomized, placebo-controlled phase IIa trial of fasudil in ALS patients (EudraCT: 2017-003676-31, NCT: 03792490). Safety and tolerability are the primary endpoints. Efficacy is a secondary endpoint and will be assessed by the change in ALSFRS-R, ALSAQ-5, slow vital capacity (SVC), ECAS, and the motor unit number index (MUNIX), as well as survival. Efficacy measures will be assessed before (baseline) and immediately after the infusion therapy as well as on days 90 and 180. Patients will receive a daily dose of either 30 or 60 mg fasudil, or placebo in two intravenous applications for a total of 20 days. Regular assessments of safety will be performed throughout the treatment period, and in the follow-up period until day 180. Additionally, we will collect biological fluids to assess target engagement and evaluate potential biomarkers for disease progression. A total of 120 patients with probable or definite ALS (revised El Escorial criteria) and within 6-18 months of the onset of weakness shall be included in 16 centers in Germany, Switzerland and France. Results and conclusions: The ROCK-ALS trial is a phase IIa trial to evaluate the ROCK-inhibitor fasudil in early-stage ALS-patients that started patient recruitment in 2019.

| S-EPMC6446974 | biostudies-literature

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