Rivella Laboratory Research Overview

We are focusing on the treatment of beta-thalassemia, alpha-thalassemia, and sickle cell anemia, which represent the most common hemoglobinopathies caused, respectively, by deficient production or alteration of the hemoglobin chain subunits. We are also developing genetic tools to target different forms of congenital dyserythropoiesis, sideroblastic anemias, bone marrow failures, severe combined immunodeficiencies and leukodystrophies. Our approaches are based on achieving therapeutic levels of corrective genes following gene transfer ex vivo or in vivo and introducing genetically modified cells into the bone marrow with minimal conditioning.

We have shown that two different forms of monoferric transferrin are functionally distinct in regulating hepcidin and erythropoietin (EPO) responsiveness. These discoveries may also lead to novel translational applications for the treatment of ineffective erythropoiesis in beta-thalassemia. We have also shown that hepatic peptide hepcidin, which controls iron absorption, has an important role in the progressive iron overload observed in beta-thalassemia, which is the most salient and ultimately fatal complication. We have shown that in beta-thalassemia, ineffective erythropoiesis represses hepcidin, leading to iron overload.

Therefore, we hypothesized that increased expression of hepcidin reduces iron burden in beta-thalassemia. In fact, we showed that increased levels of hepcidin prevent iron overload, improve red cell production and ameliorate anemia in animals affected by beta-thalassemia. In addition, we have shown that this approach can be utilized to prevent iron overload in hemochromatosis and normalize the hematocrit in polycythemia vera.

In patients affected by beta-thalassemia there is an excessive production of immature erythroid cells. Our study suggests that erythropoiesis in beta-thalassemia is characterized by enhanced expression of genes that promote survival and cell proliferation. We are now studying the role of these proteins in this disorder and characterizing new therapeutics that modulate erythropoiesis. For instance, we showed that use of JAK2 inhibitors is effective in reversing splenomegaly, while modulation of the TGFbeta pathway improves anemia in beta-thalassemia. We are further characterizing these and other pathways that are deregulated in this disorder.

Hepcidin, through interleukin-6 and other cytokines, might be upregulated in many inflammatory disorders, including anemia of inflammation and some forms of cancer. High levels of hepcidin limit iron absorption and sequester iron in the macrophages, leading to reduced red cell production and anemia. Many inflammatory cytokines impair erythroid proliferation. We are actively investigating this process, focusing on the role of interleukin-6, tumor necrosis factor, interferon-gamma, and other cytokines in a variety of cells, such as macrophages and other immune cells.