Inherited disorders which decrease production or alter structure of the 2-chain of hemoglobin A (2-thalassemias or sickle cell disease) are among the most common monogenic diseases in the world, afflicting millions worldwide, and are designated by WHO as a global health burden. Fetal hemoglobin (HbF: 12, 32) is another type of hemoglobin which is present in all humans, but is normally suppressed in infancy to levels below 2%. Decades of biochemical, clinical, and epidemiologic research have shown that any incremental increase in HbF reduces the severity of sickle cell disease, or reduces the life-threatening anemia of 2-thalassemia. Pharmacologic augmentation of fetal hemoglobin (3-globin chain) production, to replace the defective or missing 2-globin chains, is established as a therapeutic modality. A small panel of therapeutic agents of different chemical classes can induce HbF experimentally, and a few have been tested clinically. Classes of agents shown to induce HbF in sickle cell disease and beta-thalassemia include: cytotoxic chemotherapeutic agents (such as hydroxyurea (HU), 5-azacytidine, and decitabine), short chain fatty acids (SCFAs) and derivatives (SCFADs), and some HDAC inhibitors. Some have shown proof-of-principle in reducing hospitalizations and transfusion dependency, but, except for HU, require parenteral administration or large doses, or are cytotoxic and mutagenic, and have not proven suitable for broad application. Further, any new chemical entities require costly toxicology and development costs for FDA approval. We recently developed and utilized a novel high-throughput screening program to interrogate a chemical library of drugs which are already FDA-approved for other conditions, and identified a select panel of novel, and previously unrecognized potent HbF-inducing drugs some of which have benign safety profiles. The activity was validated in a secondary gene assays, erythroid cell culture, and in a pilot study in baboons. This proposal is to confirm and compare the efficacy of 3 candidate HbF-inducers in a nonhuman primate model which has been predictive of subsequent human responses for other drugs. This will allow selection of a therapeutic for rapid clinical application. Our Aims include: Aim I: To determine comparative in vivo activity of the candidate therapeutics in anemic nonhuman primates. Aim II: To prepare a medicinal formulation of the selected therapeutic
Public Health Relevance: This proposal will evaluate three therapeutics for a new medical use in an animal model that simulates sickle cell disease and beta thalassemia, serious blood diseases worldwide. The therapeutics are already approved for other conditions. Upon completion of the proposed studies, the most potent agent can be tested in the patient populations, and a new therapy can be rapidly applied to patient care.
Thesaurus Terms: 2'-Deoxy-5-Azacytidine;21+ Years Old;4-Amino-1-Beta-D-Ribofuranosyl-1,3,5-Triazin-2(1h)-One;5 Azc;5-Ac;5-Aza-2'deoxycytidine/Decitabine;5-Aza-2-Deoxycytidine;5-Aza-Cytidine;5-Azacytidine;5-Azadeoxycytidine;5-Deoxyazacytidine;Azc;Adult;Adult Human;Affect;Anemia;Animal Model;Animal Models And Related Studies;Assay;Azacitidine;Azacytidine;B-Thalassemia;Baboons;Benign;Bioassay;Biochemical;Biologic Assays;Biological Assay;Blood Diseases;Cell Culture Techniques;Chemicals;Clinical;Decitabine;Deoxyazacytidine;Dependency;Dependency (Psychology);Development;Dezocitidine;Disease;Disorder;Dose;Drug Formulations;Drugs;Epidemiologic Research;Epidemiologic Studies;Epidemiological Studies;Epidemiology Research;Erythroid Cells;Fda Approved;Fetal Hemoglobin;Formulation;Genes;Genetic Alteration;Genetic Change;Genetic Condition;Genetic Diseases;Genetic Defect;Globin;Hdac Agent;Hdac Inhibitor;Hb Ss Disease;Hbss Disease;Hematologic Diseases;Hematological Disease;Hematological Disorder;Hemoglobin;Hemoglobin A;Hemoglobin F;Hemoglobin S Disease;Hemoglobin Sickle Cell Disease;Hemoglobin Sickle Cell Disorder;Hereditary Disease;High Throughput Assay;Histone Deacetylase Inhibitor;Hospitalization;Human;Hydroxycarbamid;Hydroxycarbamide;Inborn Genetic Diseases;Inherited Disorder;Libraries;Life;Man (Taxonomy);Medical;Medication;Modality;Modeling;Modern Man;Molecular Disease;Mutation;Oral;Papio;Papios;Patient Care;Patient Care Delivery;Pharmaceutic Preparations;Pharmaceutical Preparations;Pilot Projects;Production;Promoter;Promoters (Genetics);Promotor;Promotor (Genetics);Reporter;Safety;Savanna Baboons;Severities;Short-Chain Fatty Acids;Sickle Cell;Sickle Cell Anemia;Simulate;Staging;Structure;Syndrome;Trnsf;Testing;Thalassemia;Therapeutic;Therapeutic Agents;Toxicology;Transfusion;Volatile Fatty Acids;Adult Human (21+);Adulthood;Beta Thalassemia;Blood Disorder;Cell Culture;Chemical Library;Chemotherapeutic Agent;Clinical Applicability;Clinical Application;Comparative;Comparative Efficacy;Compare Efficacy;Cost;Cytotoxic;Developmental;Disease/Disorder;Drepanocyte;Drug/Agent;Emotional Dependency;Epidemiologic Investigation;Fetal Globin;Genetic Disorder;Genome Mutation;Global Health;Hereditary Disorder;High Throughput Screening;Hydroxy-Urea;Hydroxyurea;In Vivo;Inborn Error;Infancy;Infantile;Ladakamycin;Model Organism;Non-Human Primate;Nonhuman Primate;Novel;P-Globin;P-Thalassemia;Patient Population;Pilot Study;Pre-Clinical;Preclinical;Programs;Response;Safety Testing;Sickle Rbc;Sickle Cell Disease;Sickle Disease;Sickle Erythrocyte;Sickle Red Blood Cell;Sicklemia;Sickling;Small Molecule Libraries;Success;Therapeutic Target
