Beta thalassemia is a rare, inherited blood disorder that causes severe anemia and damage to organs. Another type of genetic blood disease, hemoglobinopathies, includes sickle cell disease (SCD). About 70,000 Americans and millions around the world are affected by SCD. Red blood cells carry a protein called hemoglobin, which transports oxygen from the lungs to the rest of the body. People with SCD have an abnormal form of hemoglobin that causes red blood cells to take on a crescent (sickle) shape instead of being round. Because of their irregular shape, sickle cells cannot easily move through blood vessels, and they slow blood flow to limbs and organs. This blockage causes pain and organ damage, and it can lead to infection. No widely available cure exists for either disease.
Both beta thalassemia and SCD are caused by gene defects that lead to abnormal forms of hemoglobin. In both disorders, a gene necessary to produce of a type of hemoglobin called fetal hemoglobin is turned off. Fetal hemoglobin is thought to prevent cells from becoming sickle-shaped and blocking blood flow in SCD, and fetal hemoglobin can replace deficient hemoglobin in beta thalassemia. The investigators are developing a drug that increases production of fetal hemoglobin to treat these diseases. The project’s goal is to continue preparing the drug for testing in human clinical trials.
The beta thalassemias and hemoglobinopathies are types of genetic diseases with early mortality caused by molecular mutations affecting the beta globin chain of adult hemoglobin A. Reactivating expression of developmentally silenced fetal globin genes, which can functionally substitute for deficient beta globin in beta thalassemia and inhibit sickling in the sickle syndromes, is one accepted approach to therapy. Short chain fatty acids (SCFAs) stimulate fetal globin gene expression in experimental models, including patients’ cultured cells, transgenic mice and baboons. In clinical trials, prototype SCFA therapeutics have induced fetal globin and improved total hemoglobin levels, demonstrating proof-of-concept. However, the prototype drugs are metabolized rapidly, necessitating prolonged IV infusion or large oral doses, and their administration must be limited for antiproliferative effects on erythroid cells. An orally active SCFA compound with a more favorable pharmacokinetics (PK) profile and proliferative actions is needed for many patients.
With NIH support, the investigators have evaluated two libraries of SCFA candidates for stimulation of fetal globin production and identified a few compounds that also prolong erythroid cell survival and increase cell proliferation through alteration of Bcl-family proteins. This activity is particularly important in beta thalassemia, as thalassemic erythroid cells undergo rapid apoptosis early during cell development. One SCFA (sodium ST20) with these dual beneficial actions has favorable oral PK in baboons and an acceptable safety profile. Accordingly, sodium ST20 was selected for clinical development. Good Manufacturing Practice (GMP) synthesis, formulation, mutagenicity testing and preclinical toxicology studies in two species have been performed on sodium ST20. At a pre-Investigational New Drug (IND) meeting, two standard safety pharmacology studies were requested by the Food and Drug Administration before initiating human clinical trials of ST20.
The goal of this project is to conduct two preclinical studies required for an IND for sodium ST20 for potential treatment of beta thalassemia and sickle cell disease.
Boston University School of Medicine
Susan P. Perrine, M.D.
Public Health Impact
NIH investment would allow translation of basic science to be brought into clinical trials in three patient populations (beta thalassemia, sickle cell anemia, and potentially myelodysplastic syndromes). These disorders are not a focus of large pharmaceutical companies, primarily because of their orphan status in the United States.
The investigator successfully filed an IND application using NIH Rapid Access to Intervention Development program data (now known as the BrIDGs program). Seven clinical trials have been conducted, including Phase II trials in patients with beta thalassemia and sickle cell anemia.
- Formulation development
- Bioanalytical method development
- IND-directed toxicology
Short-Term Toxicity Study of ST-20 (NSC-741804) by Oral Gavage in Sprague-Dawley Rats • Toxicology & Pathology • May 10, 2011