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Therapeutics for Rare and Neglected Diseases

Repurposing an EU Therapeutic for Hemoglobinopathies

The most common global genetic diseases — beta-thalassemia and sickle cell disease — share a biochemical basis. Both of these disorders are caused by defects in one part (beta-globin) of hemoglobin, the protein in red blood cells that carries oxygen throughout the body. These hemoglobin disorders, called “hemoglobinopathies,” can result in moderate-to-severe anemia, with symptoms ranging from weakness and fatigue to damage to the heart, brain, lungs and other organs. These symptoms can cause chronic disabilities and early death. No drugs are approved to treat the underlying causes of these disorders. The lead collaborator has identified drug that is currently approved in the European Union to treat another condition that has the potential to treat beta-thalassemia and sickle cell disease. The goal of this project is to develop this existing drug as an effective therapy targeted at the underlying cause of both blood disorders.

Scientific Synopsis

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.

Lead Collaborator

Phoenicia Biosciences, Inc., Weston, Massachusetts

Susan Perrine, M.D.

Public Health Impact

Although both are orphan conditions in the United States, beta-thalassemia and sickle cell disease affect millions worldwide, are increasing in frequency in the U.S. and are classified by the World Health Organization as a growing global health burden. Beta-thalassemia has no approved drug therapy, and the single approved therapy for sickle cell disease is the anticancer agent hydroxyurea, which is approved only for use in adults and has undesirable side effects. Thus, there is a high-priority unmet medical need to develop a treatment specific for these diseases.

Outcomes

The TRND team formalized and initiated a comprehensive pre-clinical project plan with a primary focus on beta-thalassemia as the first indication. Cell-based and animal efficacy studies are in progress to confirm key data generated by the collaborator, with further studies planned to support filing an Investigational New Drug application with the Food and Drug Administration.

Last updated: 12-24-2016
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