Sickle Cell Disease is a disorder caused by a single mutation that results in the production of Hemoglobin S. It is an autosomal dominant disease as it is not on a sex chromosome. If both parents possess the abnormal gene and each pass a copy to his/her offspring the child has sickle cell disease. Thus, if the child of such a parent gets only one copy of the abnormal gene he/she will have sickle cell trait rather than the disease. The trait is a very mild condition that only expresses itself under limited conditions. The disease, on the other hand, is a harsh one that is characterized by severe vaso-occlusive and debilitating pain, chronic hemolytic anemia, end-organ disease, and early death.

Treatments for the disease consist of stem cell transplantation which is limited by the availability of matched donors, the risk of graft versus host disease (GVHD), and the complications of immunosuppressive therapy and graft rejection which can be fatal.

A new type of therapy designed to reactivate fetal hemoglobin production has been developed. The treatment is exagamglogene autotemcel (exa-cell) which accomplishes the reactivation just mentioned through a complicated series of steps I won’t describe here. Elevated levels of fetal hemoglobin are associated with reduced morbidity and mortality from both sickle cell disease and ß-thalassemia (reported in the same issue of the NEJM). Exa-cell was shown to be beneficial in both disorders.

Fetal hemoglobin is the main oxygen carrier protein in the human fetus. Hemoglobin F is found in fetal red blood cells and is involved in transporting oxygen from the mother’s bloodstream to organs and tissues in the fetus. It is produced at around six weeks of pregnancy and the levels remain high after birth until the baby is roughly 2–4 months old. Hemoglobin F has a different composition from adult forms of hemoglobin, allowing it to bind (or attach to) oxygen more strongly; this in turn enables the developing fetus to retrieve oxygen from the mother’s bloodstream, which occurs through the placenta found in the mother’s uterus.

In the newborn, levels of hemoglobin F gradually decrease and reach adult levels (less than 1% of total hemoglobin) usually within the first year, as adult forms of hemoglobin begin to be produced. Diseases such as ß-thalassemias, which affect components of the adult hemoglobin, can delay this process, and cause hemoglobin F levels to be higher than normal. In sickle cell anemia, increasing the production of hemoglobin F has been used as a treatment to relieve some of the symptoms.

The May 9 issue of the New England Journal of Medicine contains Exagamglogene Autotemcel for Severe Sickle Cell Disease. The mechanism and use of exa-cell is beyond the scope of an article written for laymen or many physicians for that matter. The current report is a phase 3, single-group, open-label study of exa-cel in patients 12 to 35 years of age with sickle cell disease who had had at least two severe vaso-occlusive crises in each of the 2 years before screening. The primary end point was freedom from severe vaso-occlusive crises for at least 12 consecutive months. A key secondary end point was freedom from inpatient hospitalization for severe vaso-occlusive crises for at least 12 consecutive months. The safety of exa-cel was also assessed.

Treatment with exa-cel eliminated vaso-occlusive crises in 97% of patients with sickle cell disease for a period of 12 months or more. The safety profile of exa-cel was generally consistent with that of myeloablative busulfan conditioning (part of the exa-cl treatment) and autologous hematopoietic stem-cell transplantation. No cancers occurred. Although all the patients had adverse events, in most patients these events were considered by the investigators to be related to the busulfan-based conditioning regimen and occurred within the first six months after the exa-cel infusion. There were no cases of GVHD or myelodysplasia.

A longer term study is underway to determine both the long term efficiency and safety of the treatment. This approach sickle cell disease is a new example of our advances in applied genomics. More such medical applications are sure to follow that use these techniques to ameliorate diseases that up to now have evaded our attempts to control them.

If only we could come up with interventions that would improve our behavior and social interactions which appear not to have changed since the Paleolithic age our lives would be better than our best medical science can achieve. But that’s another story. The paper mentioned here is below.