Sculpting A Better Life For Sickle Cell Patients

In Biologics, Clinical Trials, Cocktail Fodder, Drug Development, Drug Targets, Easily Confused, FDA, Genetics, Mechanism of Action, Monoclonal Antibodies, Orphan Disease, Orphan Drugs, Small Molecule Drugs, The WEEKLY by Emily Burke

With the recent announcement of two new biologics in Phase I studies for Sickle Cell Disease (SCD), WEEKLY takes a closer look at the treatments for this autosomal recessive disease, afflicting approximately 100,000 Americans and 25 million globally.

Sickle cell anemia is caused by an SNP in the beta globin gene, which codes for hemoglobin—an oxygen-binding protein in red blood cells (RBCs). The mutated hemoglobin still transports oxygen, but this single base change (A to T) affects the protein’s shape in a way that can have deadly consequences. Instead of existing as individual proteins, the mutated hemoglobin proteins clump together causing RBCs to form a “C” or “sickled” shape. Sickled RBCs are unable to enter branch points in the vascular system; they simply cannot fit through the narrowing blood vessels to feed the tissues of the body. Vital oxygen remains undelivered, potentially causing the restriction of blood flow to an organ, known as a vaso-occlusive crisis, leading to severe pain and damage. Individuals with two defective copies of the beta globin gene have sickle cell disease. Those with one defective beta globin gene have sickle cell trait.

There is no widely available cure for SCD at this time, aside from bone marrow transplants which can prove difficult due to the lack of closely related donors that are often affected by the hereditary disease themselves. Currently, most patients manage their disease with preventive antibiotics, pain relievers, and frequent blood transfusions. In this issue, we will discover how biotechnology may sculpt a better life for sickle cell anemia patients.


Small Molecule Drug

A common way to manage SCD today is a small molecule drug called hydroxyurea, brand name Droxia (Bristol-Myers Squibb, New York, NY). Hydroxyurea turns on the production of fetal hemoglobin in adults but the exact mechanism of action remains unknown. It appears hydroxyurea increases nitric oxide levels which causes a cascade of reactions that ultimately starts the production of gamma globin chains, necessary for fetal hemoglobin production. Patients see an increase in fetal hemoglobin and a decrease in RBC stickiness. Although hydroxyurea does not work for all patients, it is turning back the hemoglobin clock on select individuals for a better quality of life.

Monoclonal Antibody

Earlier this month, the FDA granted fast track designation to NKT Therapeutics’ (Waltham, MA) experimental drug for SCD, NKTT120. NKT Therapeutics derives its company name from the cells they target: natural killer T-cells.

High levels of invariant killer T-cells (iNKT) are activated during an immune response in SCD. Repeated vaso-occlusive events add increased inflammation to the picture, which causes the iNKT cells to wrongly perceive its own tissues as foreign and attack accordingly. NKTT120 is a monoclonal antibody that targets and wipes out iNKT cells. Encouraging results from the Phase I study are painting a prettier picture for better disease management.

Gene Therapy

bluebird bio (Cambridge, MA) is treating its first severe SCD patient with LentiGlobin BB305. This product is derived from the patient’s own hematopoietic (bone marrow) stem cells, and altered via gene therapy to produce a corrected beta globin gene. The corrected beta-T87Q-globin gene ultimately produces a non-sickling amino acid substitution which may prove to cure SCD. Initial clinical data on LentiGlobin BB305 is expected next year.


The word inflammation is derived from the Latin word “inflammo,” which means to ignite. Inflammation is the body’s attempt to remove harmful stimuli and jump start the healing process. Signs of inflammation include pain, heat, and swelling, lending itself to the Latin derivation.

Acute inflammation comes on suddenly and disappears when the outside stimuli is removed. It is associated with infectious agents, the presence of foreign objects, and burns.

Chronic inflammation is prolonged inflammation that can occur when the body itself activates the inflammatory response, such as the vaso-occlusive events of SCD. It is not easily resolved and therefore can last for significant time, inducing organ damage.


Before a baby is born, a slightly different form of the hemoglobin protein is produced, known as fetal hemoglobin. This hemoglobin has a higher affinity for oxygen. In other words, it binds oxygen more tightly. This tight oxygen binding prevents the hemoglobin from clumping together, and babies who will later develop SCD do not suffer from the symptoms during fetal development or shortly after birth.


Malaria may have shaped the propensity of SCD by the way of sickle cell trait in certain tropical regions, such as Sub-Saharan Africa. The malaria parasite spends part of its life in the RBC and causes the RBCs with defective hemoglobin to rupture prematurely, ensuring the Plasmodium parasite is unable to reproduce. Those with the sickle cell trait are still able to contract malaria, but their symptoms are generally less severe. In malaria prone areas, chances of survival actually increase in people carrying the sickle cell trait.