The Experts below are selected from a list of 327 Experts worldwide ranked by ideXlab platform
Caroline Claude - One of the best experts on this subject based on the ideXlab platform.
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inhalable delivery of aav based mrp4 abcc4 Silencing RNA prevents monocrotaline induced pulmonary hypertension
Molecular therapy. Methods & clinical development, 2015Co-Authors: Caroline Claude, Nathalie Mougenot, Julia Bechaux, Lahouaria Hadri, Damian Brockschnieder, Michel Clergue, Fabrice AtassiAbstract:The ATP-binding cassette transporter MRP4 (encoded by ABCC4) regulates membrane cyclic nucleotides concentrations in arterial cells including smooth muscle cells. MRP4/ABCC4 deficient mice display a reduction in smooth muscle cells proliferation and a prevention of pulmonary hypertension in response to hypoxia. We aimed to study gene transfer of a MRP4/ABCC4 Silencing RNA via intratracheal delivery of aerosolized adeno-associated virus 1 (AAV1.shMRP4 or AAV1.control) in a monocrotaline-induced model of pulmonary hypertension in rats. Gene transfer was performed at the time of monocrotaline administration and the effect on the development of pulmonary vascular remodeling was assessed 35 days later. AAV1.shMRP4 dose-dependently reduced right ventricular systolic pressure and hypertrophy with a significant reduction with the higher doses (i.e., >1011 DRP/animal) as compared to AAV1.control. The higher dose of AAV1.shMRP4 was also associated with a significant reduction in distal pulmonary arteries remodeling. AAV1.shMRP4 was finally associated with a reduction in the expression of ANF, a marker of cardiac hypertrophy. Collectively, these results support a therapeutic potential for downregulation of MRP4 for the treatment of pulmonary artery hypertension.
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abstract 18751 inhalable delivery of aav based mrp4 abcc4 Silencing RNA attenuates monocrotaline induced pulmonary hypertension
Circulation, 2014Co-Authors: Caroline Claude, Nathalie Mougenot, Julia Bechaux, Michel Clergue, Fabrice Atassi, Annemarie Lompre, Jeansebastien HulotAbstract:The ATP-binding cassette transporter MRP4 (encoded by ABCC4) functions as a plasma membrane efflux pump to extrude cyclic nucleotides from various cell types. MRP4 regulates membrane cyclic nucleotides concentrations in arterial cells including smooth muscle cells (SMCs). In previous experiments, we have shown that MRP4 Silencing inhibits SMCs proliferation in vitro. Concordantly, MRP4/ABCC4 deficient mice display a reduction in SMCs proliferation and a prevention of pulmonary hypertension in response to hypoxia. We here aimed to study gene transfer of a MRP4/ABCC4 Silencing RNA via intratracheal delivery (using a MicroSprayer® Aerosolizer) of aerosolized adeno-associated virus 1 (AAV1.shMRP4 or AAV1.control) in a monocrotaline-induced model of pulmonary hypertension in rats. Gene transfer was performed at the time of monocrotaline administration and the effect on the development of pulmonary vascular remodeling was assessed thirty-five days later. The efficiency of this approach to transduce the lung vasculature was firstly assessed using inhalable AAV1 carrying LacZ encoding the β-galactosidase protein (AAV1.βGal, 1x10e11 DRP/animal). X-gal staining was clearly observed in bronchial smooth muscle cells and in the intima and media of large and small vessels. We then aimed to evaluate the effect of targeted vascular gene transfer of AAV1.shMRP4 on pulmonary hemodynamics and vascular remodeling. AAV1.shMRP4 dose-dependently reduced right ventricular systolic pressure and hypertrophy with a significant reduction with the higher doses (i.e., >10e11 DRP/animal) as compared to AAV1.control. The higher dose of AAV1.shMRP4 was also associated with a significant reduction in distal pulmonary arteries remodeling. AAV1.shMRP4 was finally associated with a reduction in the expression of ANF, a marker of cardiac hypertrophy. In conclusion, we showed that localized viral gene knockout of MRP4 in pulmonary vessels help to limit pulmonary vessels remodeling in a model of monocrotaline-induced PAH in rats. Collectively, these results support a therapeutic potential for downregulation of MRP4 for the treatment of pulmonary artery hypertension.
Fabrice Atassi - One of the best experts on this subject based on the ideXlab platform.
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inhalable delivery of aav based mrp4 abcc4 Silencing RNA prevents monocrotaline induced pulmonary hypertension
Molecular therapy. Methods & clinical development, 2015Co-Authors: Caroline Claude, Nathalie Mougenot, Julia Bechaux, Lahouaria Hadri, Damian Brockschnieder, Michel Clergue, Fabrice AtassiAbstract:The ATP-binding cassette transporter MRP4 (encoded by ABCC4) regulates membrane cyclic nucleotides concentrations in arterial cells including smooth muscle cells. MRP4/ABCC4 deficient mice display a reduction in smooth muscle cells proliferation and a prevention of pulmonary hypertension in response to hypoxia. We aimed to study gene transfer of a MRP4/ABCC4 Silencing RNA via intratracheal delivery of aerosolized adeno-associated virus 1 (AAV1.shMRP4 or AAV1.control) in a monocrotaline-induced model of pulmonary hypertension in rats. Gene transfer was performed at the time of monocrotaline administration and the effect on the development of pulmonary vascular remodeling was assessed 35 days later. AAV1.shMRP4 dose-dependently reduced right ventricular systolic pressure and hypertrophy with a significant reduction with the higher doses (i.e., >1011 DRP/animal) as compared to AAV1.control. The higher dose of AAV1.shMRP4 was also associated with a significant reduction in distal pulmonary arteries remodeling. AAV1.shMRP4 was finally associated with a reduction in the expression of ANF, a marker of cardiac hypertrophy. Collectively, these results support a therapeutic potential for downregulation of MRP4 for the treatment of pulmonary artery hypertension.
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abstract 18751 inhalable delivery of aav based mrp4 abcc4 Silencing RNA attenuates monocrotaline induced pulmonary hypertension
Circulation, 2014Co-Authors: Caroline Claude, Nathalie Mougenot, Julia Bechaux, Michel Clergue, Fabrice Atassi, Annemarie Lompre, Jeansebastien HulotAbstract:The ATP-binding cassette transporter MRP4 (encoded by ABCC4) functions as a plasma membrane efflux pump to extrude cyclic nucleotides from various cell types. MRP4 regulates membrane cyclic nucleotides concentrations in arterial cells including smooth muscle cells (SMCs). In previous experiments, we have shown that MRP4 Silencing inhibits SMCs proliferation in vitro. Concordantly, MRP4/ABCC4 deficient mice display a reduction in SMCs proliferation and a prevention of pulmonary hypertension in response to hypoxia. We here aimed to study gene transfer of a MRP4/ABCC4 Silencing RNA via intratracheal delivery (using a MicroSprayer® Aerosolizer) of aerosolized adeno-associated virus 1 (AAV1.shMRP4 or AAV1.control) in a monocrotaline-induced model of pulmonary hypertension in rats. Gene transfer was performed at the time of monocrotaline administration and the effect on the development of pulmonary vascular remodeling was assessed thirty-five days later. The efficiency of this approach to transduce the lung vasculature was firstly assessed using inhalable AAV1 carrying LacZ encoding the β-galactosidase protein (AAV1.βGal, 1x10e11 DRP/animal). X-gal staining was clearly observed in bronchial smooth muscle cells and in the intima and media of large and small vessels. We then aimed to evaluate the effect of targeted vascular gene transfer of AAV1.shMRP4 on pulmonary hemodynamics and vascular remodeling. AAV1.shMRP4 dose-dependently reduced right ventricular systolic pressure and hypertrophy with a significant reduction with the higher doses (i.e., >10e11 DRP/animal) as compared to AAV1.control. The higher dose of AAV1.shMRP4 was also associated with a significant reduction in distal pulmonary arteries remodeling. AAV1.shMRP4 was finally associated with a reduction in the expression of ANF, a marker of cardiac hypertrophy. In conclusion, we showed that localized viral gene knockout of MRP4 in pulmonary vessels help to limit pulmonary vessels remodeling in a model of monocrotaline-induced PAH in rats. Collectively, these results support a therapeutic potential for downregulation of MRP4 for the treatment of pulmonary artery hypertension.
Michel Clergue - One of the best experts on this subject based on the ideXlab platform.
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inhalable delivery of aav based mrp4 abcc4 Silencing RNA prevents monocrotaline induced pulmonary hypertension
Molecular therapy. Methods & clinical development, 2015Co-Authors: Caroline Claude, Nathalie Mougenot, Julia Bechaux, Lahouaria Hadri, Damian Brockschnieder, Michel Clergue, Fabrice AtassiAbstract:The ATP-binding cassette transporter MRP4 (encoded by ABCC4) regulates membrane cyclic nucleotides concentrations in arterial cells including smooth muscle cells. MRP4/ABCC4 deficient mice display a reduction in smooth muscle cells proliferation and a prevention of pulmonary hypertension in response to hypoxia. We aimed to study gene transfer of a MRP4/ABCC4 Silencing RNA via intratracheal delivery of aerosolized adeno-associated virus 1 (AAV1.shMRP4 or AAV1.control) in a monocrotaline-induced model of pulmonary hypertension in rats. Gene transfer was performed at the time of monocrotaline administration and the effect on the development of pulmonary vascular remodeling was assessed 35 days later. AAV1.shMRP4 dose-dependently reduced right ventricular systolic pressure and hypertrophy with a significant reduction with the higher doses (i.e., >1011 DRP/animal) as compared to AAV1.control. The higher dose of AAV1.shMRP4 was also associated with a significant reduction in distal pulmonary arteries remodeling. AAV1.shMRP4 was finally associated with a reduction in the expression of ANF, a marker of cardiac hypertrophy. Collectively, these results support a therapeutic potential for downregulation of MRP4 for the treatment of pulmonary artery hypertension.
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abstract 18751 inhalable delivery of aav based mrp4 abcc4 Silencing RNA attenuates monocrotaline induced pulmonary hypertension
Circulation, 2014Co-Authors: Caroline Claude, Nathalie Mougenot, Julia Bechaux, Michel Clergue, Fabrice Atassi, Annemarie Lompre, Jeansebastien HulotAbstract:The ATP-binding cassette transporter MRP4 (encoded by ABCC4) functions as a plasma membrane efflux pump to extrude cyclic nucleotides from various cell types. MRP4 regulates membrane cyclic nucleotides concentrations in arterial cells including smooth muscle cells (SMCs). In previous experiments, we have shown that MRP4 Silencing inhibits SMCs proliferation in vitro. Concordantly, MRP4/ABCC4 deficient mice display a reduction in SMCs proliferation and a prevention of pulmonary hypertension in response to hypoxia. We here aimed to study gene transfer of a MRP4/ABCC4 Silencing RNA via intratracheal delivery (using a MicroSprayer® Aerosolizer) of aerosolized adeno-associated virus 1 (AAV1.shMRP4 or AAV1.control) in a monocrotaline-induced model of pulmonary hypertension in rats. Gene transfer was performed at the time of monocrotaline administration and the effect on the development of pulmonary vascular remodeling was assessed thirty-five days later. The efficiency of this approach to transduce the lung vasculature was firstly assessed using inhalable AAV1 carrying LacZ encoding the β-galactosidase protein (AAV1.βGal, 1x10e11 DRP/animal). X-gal staining was clearly observed in bronchial smooth muscle cells and in the intima and media of large and small vessels. We then aimed to evaluate the effect of targeted vascular gene transfer of AAV1.shMRP4 on pulmonary hemodynamics and vascular remodeling. AAV1.shMRP4 dose-dependently reduced right ventricular systolic pressure and hypertrophy with a significant reduction with the higher doses (i.e., >10e11 DRP/animal) as compared to AAV1.control. The higher dose of AAV1.shMRP4 was also associated with a significant reduction in distal pulmonary arteries remodeling. AAV1.shMRP4 was finally associated with a reduction in the expression of ANF, a marker of cardiac hypertrophy. In conclusion, we showed that localized viral gene knockout of MRP4 in pulmonary vessels help to limit pulmonary vessels remodeling in a model of monocrotaline-induced PAH in rats. Collectively, these results support a therapeutic potential for downregulation of MRP4 for the treatment of pulmonary artery hypertension.
Julia Bechaux - One of the best experts on this subject based on the ideXlab platform.
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inhalable delivery of aav based mrp4 abcc4 Silencing RNA prevents monocrotaline induced pulmonary hypertension
Molecular therapy. Methods & clinical development, 2015Co-Authors: Caroline Claude, Nathalie Mougenot, Julia Bechaux, Lahouaria Hadri, Damian Brockschnieder, Michel Clergue, Fabrice AtassiAbstract:The ATP-binding cassette transporter MRP4 (encoded by ABCC4) regulates membrane cyclic nucleotides concentrations in arterial cells including smooth muscle cells. MRP4/ABCC4 deficient mice display a reduction in smooth muscle cells proliferation and a prevention of pulmonary hypertension in response to hypoxia. We aimed to study gene transfer of a MRP4/ABCC4 Silencing RNA via intratracheal delivery of aerosolized adeno-associated virus 1 (AAV1.shMRP4 or AAV1.control) in a monocrotaline-induced model of pulmonary hypertension in rats. Gene transfer was performed at the time of monocrotaline administration and the effect on the development of pulmonary vascular remodeling was assessed 35 days later. AAV1.shMRP4 dose-dependently reduced right ventricular systolic pressure and hypertrophy with a significant reduction with the higher doses (i.e., >1011 DRP/animal) as compared to AAV1.control. The higher dose of AAV1.shMRP4 was also associated with a significant reduction in distal pulmonary arteries remodeling. AAV1.shMRP4 was finally associated with a reduction in the expression of ANF, a marker of cardiac hypertrophy. Collectively, these results support a therapeutic potential for downregulation of MRP4 for the treatment of pulmonary artery hypertension.
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abstract 18751 inhalable delivery of aav based mrp4 abcc4 Silencing RNA attenuates monocrotaline induced pulmonary hypertension
Circulation, 2014Co-Authors: Caroline Claude, Nathalie Mougenot, Julia Bechaux, Michel Clergue, Fabrice Atassi, Annemarie Lompre, Jeansebastien HulotAbstract:The ATP-binding cassette transporter MRP4 (encoded by ABCC4) functions as a plasma membrane efflux pump to extrude cyclic nucleotides from various cell types. MRP4 regulates membrane cyclic nucleotides concentrations in arterial cells including smooth muscle cells (SMCs). In previous experiments, we have shown that MRP4 Silencing inhibits SMCs proliferation in vitro. Concordantly, MRP4/ABCC4 deficient mice display a reduction in SMCs proliferation and a prevention of pulmonary hypertension in response to hypoxia. We here aimed to study gene transfer of a MRP4/ABCC4 Silencing RNA via intratracheal delivery (using a MicroSprayer® Aerosolizer) of aerosolized adeno-associated virus 1 (AAV1.shMRP4 or AAV1.control) in a monocrotaline-induced model of pulmonary hypertension in rats. Gene transfer was performed at the time of monocrotaline administration and the effect on the development of pulmonary vascular remodeling was assessed thirty-five days later. The efficiency of this approach to transduce the lung vasculature was firstly assessed using inhalable AAV1 carrying LacZ encoding the β-galactosidase protein (AAV1.βGal, 1x10e11 DRP/animal). X-gal staining was clearly observed in bronchial smooth muscle cells and in the intima and media of large and small vessels. We then aimed to evaluate the effect of targeted vascular gene transfer of AAV1.shMRP4 on pulmonary hemodynamics and vascular remodeling. AAV1.shMRP4 dose-dependently reduced right ventricular systolic pressure and hypertrophy with a significant reduction with the higher doses (i.e., >10e11 DRP/animal) as compared to AAV1.control. The higher dose of AAV1.shMRP4 was also associated with a significant reduction in distal pulmonary arteries remodeling. AAV1.shMRP4 was finally associated with a reduction in the expression of ANF, a marker of cardiac hypertrophy. In conclusion, we showed that localized viral gene knockout of MRP4 in pulmonary vessels help to limit pulmonary vessels remodeling in a model of monocrotaline-induced PAH in rats. Collectively, these results support a therapeutic potential for downregulation of MRP4 for the treatment of pulmonary artery hypertension.
Mohamed E H Elsayed - One of the best experts on this subject based on the ideXlab platform.
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synergistic inhibition of aggressive breast cancer cell migration and invasion by cytoplasmic delivery of anti rhoc Silencing RNA and presentation of eppt1 peptide on smart particles
Journal of Controlled Release, 2018Co-Authors: Neha Kaushal, Sofia D Merajver, Yasemin Yuksel Durmaz, Li Wei Bao, Gopinath Tiruchinapally, Rabia A Gilani, Mohamed E H ElsayedAbstract:Abstract Overexpression of RhoC protein in breast cancer patients has been linked to increased cancer cell invasion, migration, and metastases. Suppressing RhoC expression in aggressive breast cancer cells using Silencing RNA (siRNA) molecules is a viable strategy to inhibit the metastatic spread of breast cancer. In this report, we describe the synthesis of a series of asymmetric pH-sensitive, membrane-destabilizing polymers engineered to complex anti-RhoC siRNA molecules forming “smart” nanoparticles. Using β-CD as the particle core, polyethylene glycol (PEG) chains were conjugated to the primary face via non-cleavable bonds and amphiphilic polymers incorporating hydrophobic and cationic monomers were grafted to the secondary face via acid-labile linkages. We investigated the effect of PEG molecular weight (2 & 5 kDa) on transfection capacity and serum stability of the formed particles. We evaluated the efficacy of EPPT1 peptides presented on the free tips of the PEG brush to function as a targeting ligand against underglycosylated MUC1 (uMUC1) receptors overexpressed on the surface of metastatic breast cancer cells. Results show that “smart” nanoparticles successfully delivered anti-RhoC siRNA into the cytoplasm of aggressive SUM149 and MDA-MB-231 breast cancer cells, which resulted in a dose-dependent inhibition of cell migration and invasion. Further, EPPT1-targeted nanoparticles demonstrate a synergistic inhibition of cell migration and invasion imparted via RhoC knockdown and EPPT1-mediated signaling via the uMUC1 receptor.
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smart nanoparticles enhance the cytoplasmic delivery of anti rhoc Silencing RNA and inhibit the migration and invasion of aggressive breast cancer cells
Molecular Pharmaceutics, 2015Co-Authors: Neha Kaushal, Sofia D Merajver, Yasemin Yuksel Durmaz, Lewei Bao, Mohamed E H ElsayedAbstract:Rho-GTPases are small GTP-binding proteins that contribute to the epithelial-to-mesenchymal transition by regulating several cellular processes including organization of the actin cytoskeleton, cell motility, transcription, and cell proliferation. Overexpression of RhoC-GTPases (RhoC) in breast cancer has been implicated in poor disease prognosis due to increased cancer cells invasion, migration, and motility, which warranted its consideration as a therapeutic target for inhibiting breast cancer metastasis. Using Silencing RNA (siRNA) molecules to knockdown RhoC expression is a promising approach to inhibit breast cancer metastases. However, transforming anti-RhoC siRNA molecules into a viable therapy remains a challenge due to the lack of a biocompatible carrier that can selectively deliver the RNA cargo into breast cancer cells. We report the use of a degradable, pH-sensitive, β-cyclodextrin (βCD)-based polymeric carrier that condenses anti-RhoC siRNA forming "smart" particles. These smart anti-RhoC particles were efficiently inteRNAlized, successfully escaped the endosome, and delivered the RNA cargo into the cytoplasm of SUM149 and MDA-MB-231 breast cancer cells. Our results show that anti-RhoC particles used at a low N/P ratio of 2.5/1 suppressed RhoC protein levels by 100% and 90% in SUM149 and MDA-MB-231 cells, respectively. Further, anti-RhoC particles inhibited the invasion, motility, and migration of SUM149 and MDA-MB-231 cells by 40-47%, 57-60%, and 61.5-73%, respectively. Smart particles encapsulating the scrambled siRNA sequence did not affect RhoC protein expression or the invasion, motility, and migration of SUM149 and MDA-MB-231 cells, which indicate the biocompatibility of the polymeric carrier and selectivity of the observed RhoC knockdown. These results collectively indicate the therapeutic potential of smart anti-RhoC particles in arresting the metastatic spread of breast cancer cells.