Beta thalassemia is a rare, inherited blood disorder that causes severe anemia and damage to organs. The only current treatment is blood transfusions, and patients often must have many of these procedures. Repeated transfusions can cause too much iron to build up in the body. Patients with beta thalassemia also have reduced levels of a hormone called hepcidin, which helps the body use iron properly. A buildup of iron from transfusions combined with low levels of hepcidin can cause "iron overload," which can damage the heart, liver and other tissues. The goal of this project is to produce a treatment that increases levels of hepcidin and lowers the damaging effects of iron in patients with beta thalassemia.
Patients with beta thalassemia suffer from anemia, which is often severe, and iron overload, which causes damage to the heart, liver and endocrine tissues. Current treatment of beta thalassemia consists of blood transfusions to correct the anemia and chelation agents to remove iron from the body. Although this therapeutic approach can prevent premature death in childhood or early adulthood, it does not modify the underlying disease process. These treatments do not provide consistent, long-term benefits for patients and can confer significant toxicity.
Beta thalassemia causes defects in red blood cell production by bone marrow as well as reduced red blood cell survival time. These factors contribute to the development of anemia and lead to reductions in the iron regulatory hormone hepcidin. Low hepcidin levels allow too much iron to be absorbed from the diet, resulting in severe iron overload. Excess iron in the developing red blood cells contributes to the failure of cell production. These events create a vicious cycle in which too much iron contributes to low red blood cell production, which in turn increases the amount of iron that can cause cellular damage.
Increasing the amount of hepcidin activity in the body is one approach to breaking the cycle of excess iron and red blood cell destruction in beta thalassemia. Increasing hepcidin can restrict the flow of iron to the developing red blood cell, reducing cell damage and death and improving the production of these cells. The increased hepcidin levels also can restrict the amount of iron absorbed from the diet and prevent the development of iron overload.
The investigator is developing minihepcidins, which are novel peptides that possess the biological activities of hepcidin and can be used to increase hepcidin activity. Studies in animal models of beta thalassemia have found that treatment with a minihepcidin can reduce red blood cell damage and rapidly decrease severity of anemia. If similar effects are seen in patients, minihepcidins could become a new type of disease-modifying agent for the treatment of beta thalassemia.
Merganser Biotech LLC, Newtown Square, Pennsylvania
Brian MacDonald, Ph.D.
Public Health Impact
A disease-modifying therapy such as minihepcidin could transform the treatment of beta thalassemia by reducing or eliminating the need for transfusions and chelation therapy. It may also provide consistent, long-term improvements in the quality of life of these patients as a result of reducing the level of anemia.
During the course of the project, the lead collaborators at Merganser Biotech successfully raised private funding. This enabled them to take full control of the project and continue the remaining preclinical development with internal resources. The collaborators filed an Investigational New Drug (IND) application, which was cleared by the Food and Drug Administration, allowing clinical trials to begin.
- Formulation development
- Pharmacokinetic/absorption, distribution, metabolism, and excretion (PK/ADME) studies
- IND-directed toxicology