The oxygen-carrying hemoglobin protein (Hemoglobin A or HbA) is a tetrameric molecule, comprising two paired alpha-chain/beta-chain protein dimers. Beta-thalassemia is caused by mutations that result in insufficient production of the beta-globin protein, whereas sickle cell disease is caused by a point mutation in the beta-globin protein that causes the hemoglobin tetramers to form rigid polymers that deform the red blood cell, causing early cell death, abnormal adhesion to blood vessels and resulting widespread organ damage. HbA is the adult form of hemoglobin, produced mostly after birth. At earlier developmental stages, fetal forms of hemoglobin (HbF) are expressed. Importantly, these fetal globin proteins can replace the abnormal adult beta-globin proteins found in sickle cell disease and compensate for the absence of adult beta-globin proteins in beta-thalassemia. Although fetal globin expression stops shortly after birth, the drug PB-04 can reactivate expression of the fetal-stage beta-globin gene. This activation may lead to production of sufficient levels of HbF to mitigate the beta-hemoglobinopathies. The goal of this project is to repurpose this drug, currently in use in the European Union and Canada for another indication, for treatment of the hemoglobin disorders beta-thalassemia and sickle cell disease. The TRND team formalized and initiated a comprehensive preclinical project plan with a primary focus on beta-thalassemia as the first indication. The team has begun pharmacology and efficacy studies to recapitulate key data generated by the collaborator, with further studies planned to support filing an Investigational New Drug (IND) application with the U.S. Food and Drug Administration.
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