Sickle cell disease is an inherited condition with several forms, all caused by mutations in the HBB gene and all affecting hemoglobin, the protein in red blood cells that carries oxygen. Symptoms are caused by “sickling” of the red blood cells, which means the cells are distorted into a sickle or crescent shape. The disease usually begins in childhood, and its symptoms include a low number of red blood cells, repeated infections and periodic pain. The most common form is called sickle cell anemia. Sickle cell disease affects approximately 100,000 Americans and occurs primarily in people of African or Mediterranean heritage. The only currently used treatment has serious side effects and does not work for some patients. These researchers are developing a new anti-sickling agent that works by binding with the defective hemoglobin that causes sickling.
Sickle cell disease is a hereditary blood disorder, affecting millions of patients worldwide. The disease occurs in about 1 in every 600 African-American births and 1 in every 1,000–1,400 Hispanic-American births. About 2 million Americans carry the sickle cell trait. Currently, cytotoxic hydroxyurea is the only FDA-approved drug that is being used clinically. However, hydroxyurea therapy is associated with various undesirable side effects, and not all patients benefit from this treatment.
Despite considerable effort, there has been little progress in the development of new antisickling agents that have efficacy and safety in vivo. In collaboration with the NHLBI Sickle Cell Disease Reference Laboratory, we have discovered a new potent and specific antisickling 5-membered aromatic scaffold, 5HMF. Results indicate that 5HMF possesses all unique properties of a potential drug candidate and clearly warrants a further preclinical evaluation.
Virginia Commonwealth University, Richmond
Donald J. Abraham, Ph.D.
Public Health Impact
Since sickle cell disease is an orphan disease, only a few companies are interested and are involved in sickle cell research. One of the major challenges in finding effective therapeutic agents for the treatment of sickle cell disease has been the lack of agents that would specifically bind with the high concentration of intracellular HbS present in patients without causing adverse effects, and 5HMF appears to have promise in satisfying this condition.
After the completion of approved studies, the Therapeutics for Rare and Neglected Diseases program adopted the project for further development.
Less than a year after signing the collaborative agreement with Dr. Abraham’s licensing partner, AesRx, TRND completed the preclinical toxicology, chemistry, manufacturing, controls and regulatory studies necessary to support an Investigational New Drug (IND) application to the FDA, and the IND was filed. Upon clearance from the FDA, 5HMF, under the new name Aes-103, was moved into Phase I clinical trials in both healthy volunteers and sickle cell disease patients. TRND established a project team that includes TRND staff; AesRx staff; and a leading sickle cell disease clinical researcher at NIH’s National Heart, Lung, and Blood Institute. After adoption of the project into the TRND portfolio, AesRx obtained a Massachusetts Life Sciences Center Accelerator Loan to support additional studies needed to complete clinical development of Aes-103.
In July 2014, the biopharmaceutical company Baxter International acquired Aes-103 for further clinical development — the first time a company has acquired a drug candidate developed in part by TRND researchers.
- Synthesis of Good Manufacturing Practice (GMP) and non-GMP material
- Formulation development
5-hydroxymethyl-2-furfural Modifies Intracellular Sickle Haemoglobin and Inhibits Sickling of Red Blood Cells • British Journal of Haematology • February 2005
Structural Basis for the Potent Antisickling Effect of a Novel Class of Five-Membered Heterocyclic Aldehydic Compounds • Journal of Medicinal Chemistry • Sept. 9, 2004