Oral Therapeutic for Beta-Thalassemia

Faller, Douglas

Abstract

The beta thalassemias are genetic disorders caused by molecular mutations affecting the genes for adult hemoglobin and are among the most common genetic diseases worldwide, although they comprise an orphan condition in the U.S. The beta thalassemia syndromes are characterized by excess alpha globin chains, which are toxic to the developing red blood cell and cause rapid apoptosis, resulting in severe anemia and early mortality from complications of blood transfusions, including infections and iron overload. Pharmacologic reactivation of the genes for fetal globin can compensate for the deficient beta globin chains, and this approach has been successfully demonstrated with a short chain fatty acid, arginine butyrate, given intravenously, and a derivative, sodium phenylbutyrate, which requires large drug quantities that are difficult for patient to tolerate. A more tolerable oral therapeutic which both stimulate fetal globin and erythropoiesis is needed for long-term therapy of most patients. The investigators have developed a new-generation short chain fatty acid derivative (ST7), which stimulates both fetal globin gene expression and erythropoiesis in anemic and non-anemic animal models, and enhances proliferation and survival of erythroid cells, including cultured thalassemic erythroid progenitor cells. This lead candidate is orally-bioavailable with PK profiles at low oral doses which are superior to previous short chain fatty acid therapies. The investigators propose in this application: 1) to perform the medicinal formulation required for a new IND; and 2) to refine low-dose regimens for subsequent clinical trials in humans. These are tasks required for development of ST7 as a new oral therapeutic for treatment of patients with beta thalassemia