Development of tools to modify globin gene expression in stem cells The objective of this proposal is to develop a treatment for patients with sickle cell disease. The development of methods for treating common genetic diseases, such as sickle cell disease remains an elusive goal. Gene therapy is a technology which has the potential to overcome several of the problems in the development of a therapy for sickle cell disease. Hemoglobinopathies offer a major advantage for researchers in that their stem cells reside in the bone marrow. They are easy to access, manipulate in the laboratory and can be given back to the patient. This proposal intends to create optimized gene expression vectors that reduce mutant sickle beta-globin protein levels while increasing the expression of another normal globin gene, thus maintaining the balance of hemoglobin protein expression that is critical to the formation of normal red blood cells. These vectors will be tested in human bone marrow stem cells to determine their potential to improve hemoglobin expression.
Public Health Relevance: Patients with Sickle Cell Disease suffer from a range of many symptoms including painful sickle crises, damage to organs such as the lungs, kidneys, liver and spleen and stroke, which shorten life expectancy to the mid-40's. At present there is no curative treatment for majority of patients with this common genetic disease. Although there are a number of possible treatments currently under investigation which may reduce the disease complications or offer the potential of a cure, this proposal seeks to develop a new therapeutic approach that has demonstrated potential in models of other genetic diseases.
Thesaurus Terms: Apoplexy;Autologous;B-Globin;Back;Biological Models;Blood Precursor Cell;Blood Erythrocyte;Blood Normocyte;Body Tissues;Bone Marrow;Bone Marrow Stem Cell;Cd34;Cd34 Gene;Cgd;Cells;Cerebral Stroke;Cerebrovascular Apoplexy;Cerebrovascular Stroke;Cerebrovascular Accident;Chronic Granulomatous Disease;Clinical Protocols;Collecting Cell;Complementary Dna;Dna, Complementary;Development;Disease;Disorder;Dorsum;Ectopic Expression;Equilibrium;Erythrocytes;Erythrocytic;Fetal Hemoglobin;Fluorescence-Activated Cell Sorting;Fractionation, Fluorescence Activated Cell Sorting;Gene Expression;Gene Products, Rna;Gene Transfer Clinical;Gene Transfer Procedure;Gene-Tx;Genes;Genetic Condition;Genetic Diseases;Genetic Intervention;Globin;Goals;Granulomatous Disease, Chronic;Hpca1;Hb Ss Disease;Hbss Disease;Hematopoietic Stem Cells;Hemoglobin;Hemoglobin F;Hemoglobin S Disease;Hemoglobin Sickle Cell Disease;Hemoglobin Sickle Cell Disorder;Hemoglobinopathies;Hemoglobinopathies / Iron Metabolism;Hereditary Disease;Human;Human, General;Intervention, Genetic;Investigation;Investigators;Kidney;Laboratories;Lead;Length;Libraries;Life;Life Expectancy;Liver;Lung;Man (Taxonomy);Man, Modern;Marrow Erythrocyte;Mediating;Messenger Rna;Methods And Techniques;Methods, Other;Model System;Modeling;Models, Biologic;Molecular Biology, Gene Therapy;Molecular Disease;Mother Cells;Nih;National Institutes Of Health;National Institutes Of Health (U.S.);Organ;Other Genetics;Pain;Painful;Patients;Pb Element;Phase;Plasmids;Pre-Mrna;Progenitor Cells;Progenitor Cells, Hematopoietic;Proteins;Rna;Rna, Messenger;Rna, Messenger, Precursors;Rna, Non-Polyadenylated;Red Blood Cells;Red Cell;Red Blood Corpuscule;Red Cell Of Marrow;Reporting;Research Personnel;Researchers;Respiratory System, Lung;Reticuloendothelial System, Bone Marrow;Reticuloendothelial System, Erythrocytes;Reticuloendothelial System, Spleen;Ribonucleic Acid;Sickle Cell Anemia;Sortings, Fluorescence-Activated Cell;Specificity;Spleen;Spliceosomes;Staging;Stem Cells;Stroke;Symptoms;Techniques;Technology;Testing;Thalassemia;Therapeutic;Therapy, Dna;Time;Tissues;Trans Rna Splicing;Trans-Splicing;Transcript;Transgenes;United States National Institutes Of Health;Urinary System, Kidney;Vascular Accident, Brain;Balance;Balance Function;Base;Beta Globin;Blood Corpuscles;Body System, Hepatic;Brain Attack;Cdna;Cerebral Vascular Accident;Chronic Granulomatous Disease;Complementary Dna;Disease /Disorder;Disease/Disorder;Expression Vector;Fetal;Gene Correction;Gene Product;Gene Therapy;Gene-Corrected;Genetic Disorder;Genetic Therapy;Heavy Metal Pb;Heavy Metal Lead;Hemoglobinopathy;Hereditary Disorder;Improved;In Vivo Model;Library;Mrna;Mrna Precursor;Messenger Rna;Method Development;Model;Mutant;Novel Therapeutic Intervention;Organ System, Hepatic;P-Globin;Pre-Clinical;Preclinical;Precursor Mrna;Premrna;Prevent;Preventing;Protein Expression;Pulmonary;Renal;Sickle Cell Disease;Sickle Disease;Sicklemia;Sickling;Stroke;Therapeutic Protein;Therapeutic Transgene;Tool Development;Transgene Expression;Vector
