Next Generation Therapeutics for Hemoglobinopathies

DESCRIPTION (provided by applicant): Sickle cell disease and 2-thalassemias are mankind's most common hereditary monogenic diseases, comprise a major global health burden, and cost the US healthcare system gt 1 billion annually. Patients have chronic disabling morbidity and early mortality. Fetal hemoglobin (HbF: a2,g2) is another endogenous type of hemoglobin normally present in all humans, but is normally suppressed in infancy to low levels. Pharmacologic augmentation of fetal hemoglobin is established asan effective therapeutic strategy, as decades of research have shown that any incremental increase in HbF and F-cells reduce the severity of sickle cell disease or the severe anemia of the b-thalassemias. Hydroxyurea (HU) is the sole FDA-approved drug fortreatment of sickle cell disease, its beneficial effects are due primarily to its ability to increase HbF, and not all patients respond favorably. Additional therapeutics, which can be used alone or in combination with HU, would benefit a serious unmet medical need. A confounding issue in evaluating new therapies in the globin disorders is the wide variability in patients' basal HbF levels, related to different geneti modifier profiles which alter baseline HbF levels and affect therapeutic responses. Frommolecular modeling studies and a high-throughput screening program of a library of drugs which are FDA-approved for other medical conditions, we discovered previously unrecognized, highly potent, HbF-inducing drugs in reporter gene assays and confirmed their activity in erythroid cells cultured from normal subjects. This proposal is to determine which of three therapeutic candidates is most potent in erythroid cells cultured from genotyped sickle cell patients with different genetic modifier profiles and baseline HbF levels, in order to select optimal agent(s) fo evaluation in clinical trials. Our aims include: Aim I: To determine the comparative in vitro activity of 3 candidate therapeutics in erythroid progenitors from genotyped sickle cell patients with different genetic modifier profiles and HbF levels and to select the optimal drug for clinical testing Aim II: To develop a medicinal formulation of the most active therapeutic for rapid evaluation in clinical trials in the patient population PUBLIC HEALTH RELEVANCE: This proposal will evaluate 3 safe oral therapeutics for a new medical use in hemoglobin diseases, serious blood diseases which confer life-long morbidity and early mortality, an annual US healthcare burden of gt 1 Billion, and high childhood mortality internationally. The candidate therapeutics are already approved for other medical conditions, or in late-stage testing. Upon completion of the proposed studies on patients' cells in culture, the most potent agent can be tested in the patient populations, and a new therapy can be expediently applied to their medical care.