Switching off a single gene can help treat sickle cell disease by keeping the blood forever young. The illness is caused by a mutant form of adult haemoglobin, but not by fetal haemoglobin. Targeting BCL11A, the gene responsible for the body鈥檚 switch-over from fetal to adult haemoglobin, effectively eliminates the condition in mice.
The mutant form of adult haemoglobin forms long sticky chains inside red blood cells. The cells containing these chains can clog small blood vessels, depriving organs of oxygen and causing pain. In severe cases, sickle cell disease can be fatal. Tricking the body into make fetal haemoglobin again can alleviate symptoms, though.
That鈥檚 because fetal haemoglobin does not form sticky chains. However, it is produced in the body only during development in the womb and in the six months following birth. It has a higher affinity for oxygen than adult haemoglobin, vital in allowing the developing fetus to 鈥渟teal鈥� oxygen from its mother鈥檚 blood.
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of Harvard Medical School in Boston, and colleagues, knocked out the BCL11A gene from mice belonging to a strain that normally develops a sickle cell-like condition. As adults, the mice produced over 20 times more fetal haemoglobin than normal and their blood contained almost no sickle-shaped cells. Their spleen and kidneys 鈥� organs easily damaged by the effects of the disease 鈥� were almost completely healthy.
Bound and gagged
Gene therapy to block the action of BCL11A in humans could in theory provide similar benefits. Specially designed lengths of RNA, injected into the bloodstream, could bind with the BCL11A gene and silence it. This approach, however, would be expensive and impractical on a large scale. 鈥淭he long-term goal is to have a drug that can effectively block the function of BCL11A,鈥� says Orkin. 鈥淚t鈥檚 a more challenging approach, but one that could be applied to large populations.鈥�
Other treatments designed to encourage the production of fetal haemoglobin have been suggested over the years. One drug in particular 鈥� hydroxyurea 鈥� is widely used but has many side effects including reducing the levels of white blood cells.
Orkin鈥檚 main concern with hydroxyurea, however, is that its effect on the body is not fully understood. 鈥淲e have no idea how it really works. In some patients it鈥檚 good, in others it doesn鈥檛 work at all. It鈥檚 unpredictable,鈥� he says. 鈥淥ur approach gets to the real mechanism. It actually silences the gene that leads to fetal haemoglobin being suppressed.鈥�
Journal reference: , DOI: 10.1126/science.1211053
