Sickle cell disease reversed in mice

The blood condition sickle cell disease may be reversed by turning off a single gene, according to scientists in the USA. By inactivating a single gene in red blood cells the researchers were able to alleviate symptoms of the disease in mice, offering the hope of a potential new treatment for humans.

Before birth, babies produce a special form of haemoglobin - the protein in red blood cells that fixes oxygen, enabling its transport around the body - which allows them to obtain oxygen from the mother via the placenta. Shortly after birth a switch occurs and the baby will start to produce adult rather than fetal haemoglobin. It is at this point that sickle cell disease can come to light, leading to symptoms including anaemia, pain and organ damage. The condition is potentially lethal.

Sickle cell disease is caused by a genetic mutation in adult haemoglobin that affects approximately 1 in 5000 people, and is more common in people of African origin. In sickle cell disease the mutated haemoglobin causes red blood cells to form rigid sickle shapes that mean they do not flow through small blood vessels as well as they should.

A team of researchers at Harvard Medical School and Howard Hughes Medical Institute in Boston, USA, previously identified the gene BCL11A as being important for the switch from producing fetal to adult haemoglobin. BCL11A is one of the molecular switches that help to stop production of fetal haemoglobin not long after birth, allowing production of the adult form to take over.

For their latest study, published in the journal Science, the researchers found that inactivating BCL11A in developing red blood cells caused adult mice to start producing fetal haemoglobin. This finding was replicated in two different mouse models of human sickle cell disease, and in both instances the mice started producing red blood cells with no 'sickling'. Up to 85 percent of red blood cells carried fetal haemoglobin, reversing the clinical symptoms of the disease.

'We knew from previous clinical studies that the body needs to produce cells containing only 15 to 20 percent fetal haemoglobin to reverse disease', said Professor Stuart Orkin, the leader of the research team. 'With these results, we know now we have a target that, if we can develop ways to inactivate or silence it clinically, could be very beneficial to people with sickle cell'.

Currently, the most effective treatment option for sickle cell disease is a bone marrow transplant. However, this requires a compatible donor and can lead to complications associated with transplantation. Another option is the drug hydroxyurea, however scientists do not currently understand how or why it works, and it is not effective in all patients.

By reversing the symptoms of sickle cell disease in mice, this study has identified the potential for future drugs targeting BCL11A. However, Professor Alex Felice, a haematologist and molecular genetics expert at the University of Malta, has warned that success in animal models does not guarantee success in humans. He told ScienceNOW that in humans 'BCL11A is expressed in other blood cell types' meaning that silencing it could be problematic.