U.S. Department of Health and Human Services

A personalized medicine treatment plan developed after identification of a rare pathogenic mutation

After discovering a rare genetic mutation responsible for a previously unknown severe blood disorder in a 6-year old boy, researchers developed a personalized treatment plan for his newborn sibling, also born with the same blood disorder.  Doctors at first diagnosed the boy when he was 1 year of age with Diamond-Blackfan anemia (DBA).  DBA is a serious medical condition characterized by insufficient level of red blood cells, also known as anemia.  Red cells carry oxygen from the lungs to the body’s organs and tissues.  The boy was given standard therapy for DBA.  He was treated initially with blood transfusions, which provide a source of needed red cells, and then underwent a bone marrow transplant with a fully matched donor at 6 years of age.  Although the doctors hoped the bone marrow transplant would be curative, as is typically the case for people with DBA, early signs showed that the transplant was not working as expected, and unfortunately the boy subsequently did not survive due to complications of the procedure. 

Clinical scientists became aware of this 6-year old boy while they were conducting research to discover yet unknown genetic causes of DBA.  Given the unanticipated transplant outcome, the researchers were interested to learn the cause of the boy’s severe anemia, thinking it might be different from typical DBA, and that new insights might help in developing a better treatment approach for others.  An analysis of the boy’s genes did not reveal mutations known to cause DBA but did identify, for the first time, a mutation in the gene encoding the small protein hormone erythropoietin (EPO).  The genetic mutation alters one of the 160 amino acid building blocks of the EPO protein; it changes an arginine amino acid to a glutamine amino acid.  EPO normally stimulates red cell production by interacting with other proteins, called EPO receptors, on the surface of early stage (progenitor) red cells in the bone marrow and drives these cells to maturity. 

The investigators determined that although mutant EPO had slightly less attraction for the EPO receptor than normal EPO had, the EPO mutation decreased its ability to remain attached to the EPO receptor, apparently resulting in significantly diminished ability to stimulate red cell proliferation (i.e., an increase in number of cells) in culture, as compared to normal EPO.  These laboratory findings are consistent with the inability of mutant EPO to produce adequate levels of mature red cells in the young boy.

While these research findings were undergoing review for publication, the researchers learned that the parents of the 6-year old boy had a newborn child, who also had anemia.  Further testing confirmed that the newborn carried the same arginine to glutamine mutation in EPO.  Equipped with new knowledge gained from research, the clinical scientists developed a treatment strategy.  They obtained appropriate permissions to initiate a personalized medicine treatment plan consisting of injections of normal EPO produced in the laboratory, also called recombinant EPO.  Recombinant EPO is used often to increase levels of red cells in patients whose red cells have been depleted by a different condition, for example as a result of kidney disease or chemotherapy for cancer.  The researchers reasoned that recombinant normal EPO might also work for this child, by latching onto EPO receptors more productively than the child’s own EPO, and thus restore red cell production.  After 11 weeks of treatment, the child’s red cell production had increased—eliminating the need for blood transfusions.

This study underscores the benefit of research to greatly improve the life of a patient.  Additionally, this personalized medicine treatment plan potentially could help others with the same disorder.

Kim AR, Ulirsch JC, Wilmes S, Unal E, Moraga I, Karakukcu M, Yuan D, Kazerounian S, Abdulhay NJ, King DS, Gupta N, Gabriel SB, Lander ES, Patiroglu T, Ozcan A, Ozdemir MA, Garcia KC, Piehler J, Gazda HT, Klein DE, and Sankaran VG. Functional selectivity in cytokine signaling revealed through a pathogenic EPO mutation. Cell 168: 1053-1064. doi:10.1016/j.cell.2017.02.026, 2017.