PROSTACYCLIN-SECRETING CELLS AS THERAPY FOR PULMONARY ARTERY HYPERTENSION
Richard Af Dixon
Texas Heart Institute, Box 20345, Mc 3-116, Houston, Tx 77225-0345
Grant 5RC1HL100807-02 from National Heart, Lung, And Blood Institute
Abstract: This application addresses broad Challenge Area (04) Clinical Research and specific Challenge Topic, 04-HL-110 Treatment of Pulmonary Hypertension and Right Heart Failure. PROJECT SUMMARY/ Pulmonary arterial hypertension (PAH) is an incurable, devastating disease with a high mortality rate. Characterized by progressive increases in pulmonary arterial pressure and pulmonary vascular resistance, PAH ultimately leads to right heart failure and death. Current therapies improve hemodynamic measures but have significant drawbacks, including variable patient responses and continued deterioration in patient status. Because vasoconstriction of the pulmonary vessels characterizes the pathology of PAH, intravenous therapy with the potent vasodilator prostacyclin is often used in patients with PAH. However, this therapy is expensive and tethers the patient to a cumbersome delivery system comprising a continuous-infusion pump with an indwelling catheter. Developing a cell-based therapy that replenishes prostacyclin levels would overcome existing flaws in the treatment of patients with PAH and help stimulate development of this novel technology for other cardiovascular diseases. Our broad, long-term challenge is to develop a cell-based therapy using prostacyclin-secreting transfected cells to treat patients with PAH. Our immediate objectives for this proposal are to develop genetically engineered cells that stably overexpress prostacyclin (Specific Aim 1) and study their therapeutic potential in animal models (Specific Aim 2). For Specific Aim 1, we plan to create and characterize rat and human transgenic cell lines overexpressing a recently developed novel fusion protein (COX-1-10aa-PGIS) that continuously produces and releases prostacyclin. For Specific Aim 2, we will study the efficacy of the genetically engineered rat and human cell lines in treating PAH in animal models. We will use the well-established rat model of monocrotaline- induced PAH to examine the effects of COX-1-10aa-PGIS-overexpressing cells on survival and right ventricular systolic pressure and the right ventricular and left ventricular weight ratio, which are the most significant measures of PAH. In addition to efficacy, we will examine cell trafficking in rats by studying the tissue localization of fluorescently labeled prostacyclin-overexpressing transfected cells. Once we establish the efficacy of our cell lines in rats, we will study them in a large animal model that more closely resembles the human anatomy. In the pig model of shunt- induced PAH, we will similarly examine the in vivo distribution of fluorescently labeled transfected cells and monitor pulmonary pressures (via right heart catheterization) as an indicator of efficacy in treating PAH. We believe our work will provide the preclinical foundation to move this novel cell-based therapy for PAH forward into clinical trials. Pulmonary arterial hypertension is a rare but fatal disease, and current therapies are not curative and are associated with significant drawbacks. As part of a cell-based therapy approach, the objective of the current proposal is to develop and test in animal models genetically engineered rat and human cells that stably overexpress prostacyclin, a potent vasodilator that is reduced in patients with pulmonary arterial hypertension. These studies should provide sufficient preclinical data to allow this innovative cell therapy to move forward into clinical trials and help usher in a new era in the treatment of this devastating disease
Keywords: 20-Norcrotalanan-11, 15-dione, 14, 19-dihydro-12, 13-dihydroxy-, (13alpha, 14alpha)-; Address; Adipocytes; Adipose Cell; Adipose tissue; Affect; Allogenic; Anatomic; Anatomical Sciences; Anatomy; Animal Model; Animal Models and Related Studies; Arachidonic Acids; Area; Autologous; Blood Pressure, High; Body Tissues; Bone Marrow Blood-Deriving Cell; Bone Marrow Blood-Forming Cell; Bone Marrow Cells; CD34; CD34 gene; Cardiac Catheterization Procedures; Cardiovascular Diseases; Catheterization, Cardiac; Cell Line; Cell Lines, Strains; Cell Therapy; CellLine; Cells; Cessation of life; Chimera Protein; Chimeric Proteins; Clinical; Clinical Research; Clinical Study; Clinical Trials; Clinical Trials, Unspecified; Common Rat Strains; Communities; Continuous Infusion; Data; Death; Deterioration; Development; Diagnosis; Disease; Disorder; Engineering; Engineerings; Enzymes; Family suidae; Fat Cells; Fatty Tissue; Foundations; Fusion Protein; HPCA1; Heart Catheterization; Heart Catheterization Pocedure; Heart failure; Human; Human Cell Line; Human, General; Hypertension; IV drip; Implantable Catheters; In-Dwelling Catheters; Individual; Indwelling Catheter; Infusion Pumps; Infusors; Insertion of catheter into heart chamber; Intravenous; Intravenous Drip; Intravenous Infusion; Label; Left; Lipocytes; Lung; Mammals, Mice; Mammals, Rats; Man (Taxonomy); Man, Modern; Mature Lipocyte; Mature fat cell; Measures; Medical; Methods; Mice; Modeling; Monitor; Monocrotaline; Mortality; Mortality Vital Statistics; Murine; Mus; Pathology; Patients; Perfusion Pumps; Pigs; Population; Pressure; Pressure- physical agent; Prostacyclins; Prostaglandins I; Publishing; Pulmonary Artery; Pulmonary Hypertension; Pulmonary Vascular Resistance; Pulmonary artery structure; Pulmonary vessels; Rat; Rattus; Reproducibility; Respiratory System, Lung; SCID; Science of Anatomy; Severe Combined Immunodeficiency; Severe Combined Immunodeficiency Syndrome; Severe Combined Immunologic Deficiency; Shunt; Shunt Device; Suidae; Swine; System; System, LOINC Axis 4; Systolic Pressure; Testing; Therapeutic; Therapeutic Studies; Therapy Research; Therapy, Cell; Tissues; Transgenic Organisms; Treatment Efficacy; Vascular Hypertensive Disease; Vascular Hypertensive Disorder; Vascular constriction (function); Vasoconstriction; Vasodilating Agent; Vasodilator Agents; Vasodilator Drugs; Vasodilators; Venous Reservoirs; Ventricular; Weight; Work; ing; adipose; anatomy; base; cardiac failure; cardiovascular disorder; cell type; cell-based therapy; clinical investigation; combined T and B cell inborn immunodeficiency; cultured cell line; disease/disorder; drip infusion; genetically modified cells; hemodynamics; hyperpiesia; hyperpiesis; hypertensive disease; improved; in vivo; indexing; innovate; innovation; innovative; intravenous administration; model organism; new technology; novel; overexpression; porcine; pre-clinical; preclinical; precursor cell; pressure; pulmonary; pulmonary arterial hypertension; response; shunts; suid; therapeutic efficacy; therapeutically effective; trafficking; transgenic; vein infusion; white adipose tissue; yellow adipose tissue
Relevance: Pulmonary arterial hypertension is a rare but fatal disease, and current therapies are not curative and are associated with significant drawbacks. As part of a cell-based therapy approach, the objective of the current proposal is to develop and test in animal models genetically engineered rat and human cells that stably overexpress prostacyclin, a potent vasodilator that is reduced in patients with pulmonary arterial hypertension. These studies should provide sufficient preclinical data to allow this innovative cell therapy to move forward into clinical trials and help usher in a new era in the treatment of this devastating disease
Project start date: 2009-09-30
Project end date: 2011-08-31
Budget start date: 1-SEP-2010
Budget end date: 31-AUG-2011
PFA/PA: RFA-OD-09-003
5RC1HL100807-02 (2010): $500000
Sponsored Links Excellgen http://Excellgen.com
Grants awarded to Richard Af Dixon
PROSTACYCLIN-SECRETING CELLS AS THERAPY FOR PULMONARY ARTERY HYPERTENSION
Richard Af Dixon
Texas Heart Institute, Box 20345, Mc 3-116, Houston, Tx 77225-0345
Grant 1RC1HL100807-01 from National Heart, Lung, And Blood Institute
Abstract: This application addresses broad Challenge Area (04) Clinical Research and specific Challenge Topic, 04-HL-110 Treatment of Pulmonary Hypertension and Right Heart Failure. PROJECT SUMMARY/ Pulmonary arterial hypertension (PAH) is an incurable, devastating disease with a high mortality rate. Characterized by progressive increases in pulmonary arterial pressure and pulmonary vascular resistance, PAH ultimately leads to right heart failure and death. Current therapies improve hemodynamic measures but have significant drawbacks, including variable patient responses and continued deterioration in patient status. Because vasoconstriction of the pulmonary vessels characterizes the pathology of PAH, intravenous therapy with the potent vasodilator prostacyclin is often used in patients with PAH. However, this therapy is expensive and tethers the patient to a cumbersome delivery system comprising a continuous-infusion pump with an indwelling catheter. Developing a cell-based therapy that replenishes prostacyclin levels would overcome existing flaws in the treatment of patients with PAH and help stimulate development of this novel technology for other cardiovascular diseases. Our broad, long-term challenge is to develop a cell-based therapy using prostacyclin-secreting transfected cells to treat patients with PAH. Our immediate objectives for this proposal are to develop genetically engineered cells that stably overexpress prostacyclin (Specific Aim 1) and study their therapeutic potential in animal models (Specific Aim 2). For Specific Aim 1, we plan to create and characterize rat and human transgenic cell lines overexpressing a recently developed novel fusion protein (COX-1-10aa-PGIS) that continuously produces and releases prostacyclin. For Specific Aim 2, we will study the efficacy of the genetically engineered rat and human cell lines in treating PAH in animal models. We will use the well-established rat model of monocrotaline- induced PAH to examine the effects of COX-1-10aa-PGIS-overexpressing cells on survival and right ventricular systolic pressure and the right ventricular and left ventricular weight ratio, which are the most significant measures of PAH. In addition to efficacy, we will examine cell trafficking in rats by studying the tissue localization of fluorescently labeled prostacyclin-overexpressing transfected cells. Once we establish the efficacy of our cell lines in rats, we will study them in a large animal model that more closely resembles the human anatomy. In the pig model of shunt- induced PAH, we will similarly examine the in vivo distribution of fluorescently labeled transfected cells and monitor pulmonary pressures (via right heart catheterization) as an indicator of efficacy in treating PAH. We believe our work will provide the preclinical foundation to move this novel cell-based therapy for PAH forward into clinical trials. Pulmonary arterial hypertension is a rare but fatal disease, and current therapies are not curative and are associated with significant drawbacks. As part of a cell-based therapy approach, the objective of the current proposal is to develop and test in animal models genetically engineered rat and human cells that stably overexpress prostacyclin, a potent vasodilator that is reduced in patients with pulmonary arterial hypertension. These studies should provide sufficient preclinical data to allow this innovative cell therapy to move forward into clinical trials and help usher in a new era in the treatment of this devastating disease
Keywords: 20-Norcrotalanan-11, 15-dione, 14, 19-dihydro-12, 13-dihydroxy-, (13alpha, 14alpha)-; Address; Adipocytes; Adipose Cell; Adipose tissue; Affect; Allogenic; Anatomic; Anatomical Sciences; Anatomy; Animal Model; Animal Models and Related Studies; Arachidonic Acids; Area; Autologous; Blood Pressure, High; Body Tissues; Bone Marrow Blood-Deriving Cell; Bone Marrow Blood-Forming Cell; Bone Marrow Cells; CD34; CD34 gene; Cardiac Catheterization Procedures; Cardiovascular Diseases; Catheterization, Cardiac; Cell Line; Cell Lines, Strains; Cell Therapy; CellLine; Cells; Cessation of life; Chimera Protein; Chimeric Proteins; Clinical; Clinical Research; Clinical Study; Clinical Trials; Clinical Trials, Unspecified; Common Rat Strains; Communities; Continuous Infusion; Data; Death; Deterioration; Development; Diagnosis; Disease; Disorder; Engineering; Engineerings; Enzymes; Family suidae; Fat Cells; Fatty Tissue; Foundations; Fusion Protein; HPCA1; Heart Catheterization; Heart Catheterization Pocedure; Heart failure; Human; Human Cell Line; Human, General; Hypertension; Hypertension, Pulmonary; IV drip; Implantable Catheters; In-Dwelling Catheters; Individual; Indwelling Catheter; Infusion Pumps; Infusors; Insertion of catheter into heart chamber; Intravenous; Intravenous Drip; Intravenous Infusion; Label; Left; Lipocytes; Lung; Mammals, Mice; Mammals, Rats; Man (Taxonomy); Man, Modern; Mature Lipocyte; Mature fat cell; Measures; Medical; Methods; Mice; Modeling; Monitor; Monocrotaline; Mortality; Mortality Vital Statistics; Murine; Mus; Pathology; Patients; Perfusion Pumps; Pigs; Population; Pressure; Pressure- physical agent; Prostacyclins; Prostaglandins I; Publishing; Pulmonary Artery; Pulmonary Hypertension; Pulmonary Vascular Resistance; Pulmonary artery structure; Pulmonary vessels; Rat; Rattus; Reproducibility; Respiratory System, Lung; SCID; Science of Anatomy; Severe Combined Immunodeficiency; Severe Combined Immunodeficiency Syndrome; Severe Combined Immunologic Deficiency; Shunt; Shunt Device; Suidae; Swine; System; System, LOINC Axis 4; Systolic Pressure; Testing; Therapeutic; Therapeutic Studies; Therapy Research; Therapy, Cell; Tissues; Transgenic Organisms; Treatment Efficacy; Vascular Hypertensive Disease; Vascular Hypertensive Disorder; Vascular Resistance, Pulmonary; Vascular constriction (function); Vasoconstriction; Vasodilating Agent; Vasodilator Agents; Vasodilator Drugs; Vasodilators; Venous Reservoirs; Ventricular; Weight; Work; ing; adipose; anatomy; base; cardiac failure; cardiovascular disorder; cell type; cell-based therapy; clinical investigation; combined T and B cell inborn immunodeficiency; cultured cell line; disease/disorder; drip infusion; genetically modified cells; hemodynamics; hyperpiesia; hyperpiesis; hypertensive disease; improved; in vivo; indexing; innovate; innovation; innovative; intravenous administration; model organism; new technology; novel; overexpression; porcine; pre-clinical; preclinical; precursor cell; pressure; public health relevance; pulmonary; pulmonary arterial hypertension; response; shunts; suid; therapeutic efficacy; therapeutically effective; trafficking; transgenic; vein infusion; white adipose tissue; yellow adipose tissue
Relevance: Pulmonary arterial hypertension is a rare but fatal disease, and current therapies are not curative and are associated with significant drawbacks. As part of a cell-based therapy approach, the objective of the current proposal is to develop and test in animal models genetically engineered rat and human cells that stably overexpress prostacyclin, a potent vasodilator that is reduced in patients with pulmonary arterial hypertension. These studies should provide sufficient preclinical data to allow this innovative cell therapy to move forward into clinical trials and help usher in a new era in the treatment of this devastating disease
Project start date: 2009-09-30
Project end date: 2011-08-31
Budget start date: 30-SEP-2009
Budget end date: 31-AUG-2010
PFA/PA: RFA-OD-09-003
1RC1HL100807-01 (2009): $500000