Sickle Cell Disease is a disorder of hemoglobin production secondary to an alteration in the hemoglobin gene on chromosome 11.  Specifically, there is a single amino acid substitution in “adult” β A -globin
(Glu6Val) stemming from a single base substitution (A→T) in the first exon of the human β A -globin gene. The abnormal nucleotide must be present in both chromosomes 11. If just one copy is  abnormal, the subject has sickle cell trait rather than the disease. The trait is mostly benign. Thus, both parents must have one abnormal copy of the hemoglobin gene for their child to have Sickle Cell Disease. On average, 25% of their offspring will have the disease, 50% will have the trait; the remaining 25% will have two copies of the normal hemoglobin gene.

Sickle-cell disease occurs when the sixth amino acid of hemoglobin, glutamic acid, is replaced by valine which changes its structure and function. Valine is hydrophobic, causing the hemoglobin to collapse on itself occasionally. The structure is not changed otherwise. When enough hemoglobin collapses on itself the red blood cells become sickle-shaped.

The disorder is mostly found in sub-Saharan  Africans and their descendents. About 43 million people have the trait; more than 3 million have the disease. The disease is a devastating one, characterized by painful crises, hemolytic anemia, and multi organ damage, especially to kidneys and bone. The abnormal hemoglobin agglutinates and causes vaso-occlusion which in turn is the cause of all the disease’s manifestations. Allogeneic hematopoietic stem-cell transplantation currently offers the only curative option for patients with severe sickle cell disease. But lack of suitable donors limits the applicability of this treatment.

Ribeil and 26 co-authors in the New England Journal of Medicine report a single patient with Sickle Cell Disease (a 13 year old boy) treated with gene therapy. They harvested stem cells from the patient and infected them with a lentivirus. “This self-inactivating lentiviral vector encodes the human HBB variant β A-T87Q . In addition to inhibiting HbS polymerization, the T87Q substitution allows for the β-globin chain of adult hemoglobin (HbA) T87Q to be differentially quantified by means of reverse-phase high-performance liquid chromatography.” [Quotation from above paper]

They then destroyed the patient’s bone marrow with intravenous busulfan. After a two day washout period the CD34+ traduced cells were infused. In other words, they gave the patient his own stem cells that had the new gene inserted into them. Blood transfusions were given until until the altered hemoglobin reached 25-30% of the total hemoglobin.

As shown above (click on the figure for a larger image), the total hemoglobin concentration was 11.8 g/dl (normal is about 14-16). About half was the altered hemoglobin HbA T87Q and about half was hemoglobin S. Thus, gene therapy did not prevent the synthesis of hemoglobin S, but it did stimulate the formation of normally functioning hemoglobin which was sufficient to prevent hemolytic anemia and vaso-occlusive disease. The patient was discharged after 50 days in hospital and has had no sickle cell symptoms in the ensuing 14 months.

Obviously, this is a formidable procedure that is fraught with possible complications and unintended consequences, none of which has yet to occur in this patient. But this technique hold almost limitless potential for therapeutic intervention in diseases which have resisted successful treatment. It’s also very expensive. The battalion of authors guarantees that a lot of money was spent on the treatment of this patient. I heard an amount as high as €600,000. This figure seems staggering until you consider the cost of caring for a patient with sickle cell disease over a 40-60 year life span. Given how frequently these patients are hospitalized, their cost of treatment, which is far from satisfactory, is in the millions.

Doubtless, as this type of therapy is refined its cost will will be lowered. How far it will take us is currently impossible to know, but it almost certainly will be a long way. A therapeutic tour de force.