Named for the shape of patients’ red blood cells (RBCs), sickle cell disease is cause by a mutant form of hemoglobin makes RBCs become crescent-shaped and rigid, rather than round and pliant like normal RBCs. Circulating “sickled” RBCs stick together and impede blood flow. Since oxygen carried by any RBC is essential for life, oxygen deficiencies associated with SCD damage tissues and cause anemia, infection, and bouts of intense pain called vaso-occlusive crises. Current treatments cannot prevent these episodes or long-term organ damage that is even seen in infants and children with SCD. Patients typically do not live beyond their early 50s, with pulmonary dysfunction the most common cause of death.
LJI’s Joel Linden, Ph.D., is an expert on a group of anti-inflammatory cell surface proteins called adenosine receptors. Linden previously explored how the small molecule adenosine, which activates these receptors, protects tissues in the heart from damage due to low blood flow. Realizing that SCD patients also exhibit low blood flow, Linden reasoned that treatments that would activate adenosine receptors might ameliorate pain associated with that condition.
Linden began testing his theory in mouse models of SCD about four years ago and found that treatment with adenosine-like compounds countered the damaging effects of the disease. He was aware of an existing FDA-approved adenosine-like drug was already been approved for another use, meaning it was safe in humans and could probably gain rapid approval if proven effective in clinical trials as a treatment for sickle cell disease.
As a result, he and collaborators at Rady Children’s Hospital-San Diego are now in the midst of a phase 2 clinical trial of an adenosine-based anti-inflammatory agent as treatment for SCD’s severest pain symptoms.
In parallel, Linden’s lab is examining tissue damage that occurs after blood flow blockage in SCD is relieved. At that point, rapid restoration of normal blood flow can actually damage tissues (a condition called ischemia reperfusion injury), in part because it mobilizes immune cells known as natural killer T cells (NKTs), which mistake the body’s normal tissue for foreign invaders. Over a patient’s lifetime, multiple cycles of inappropriate NKT cell activation gradually worsen SCD lesions and potentially shorten that individual’s lifespan.
Linden thinks that many of the anti-inflammatory effects of adenosine are actually due to their ability to inhibit NKT cells. Thus, he is pursuing two new SCD treatments based on activation of adenosine and is seeking new opportunities to develop novel therapeutic approaches through adenosine receptors.