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Study brings sickle-cell gene therapy one step closer

12 September 2016
Appeared in BioNews 868

A genetically engineered virus that triggers the production of an alternative form of haemoglobin has reversed the symptoms of sickle cell disease in mice.

Researchers believe that they have jumped the final hurdle and will now gain approval for a clinical gene therapy trial that could begin early next year.

Sickle cell disease is caused by a mutation in the gene that makes haemoglobin, the protein that carries oxygen in red blood cells, causing the cells to become stiff and sickle-shaped. This leads to anaemia as well as pain and tissue damage.

However, it was discovered in the 1980s that people with a second mutation – in the BCL11A gene – are unaffected by sickle cell disease. It turns out BCL11A acts as a switch, turning off the fetal haemoglobin that is used to get oxygen via maternal blood in the placenta, and turning on adult (beta) haemoglobin. Only adult haemoglobin is affected by the sickle cell mutation, and people are able to function normally with fetal haemoglobin in their blood.

Using this insight, researchers at the Dana-Farber/Boston Children's Cancer and Blood Disorders Center in Boston, Massachusetts, genetically engineered a harmless virus to create blood stem cells that had their BCL11A gene suppressed. The blood cells produced 80 percent fetal haemoglobin – well in excess of the 50 percent they were hoping for and which would avoid sickle cell symptoms. When they transplanted these modified cells back into mice with sickle cell disease, it reversed their symptoms.

They performed the same gene therapy technique on blood from four sickle cell patients and achieved the same level of fetal haemoglobin.

'The tendency for a red blood cell to sickle is proportional to how much non-sickling versus sickling hemoglobin it has,' said Dr David Williams, president of Dana-Farber/Boston Children's Center the senior author of the study, which was published in the Journal of Clinical Investigation. 'BCL11A represses fetal hemoglobin, which does not lead to sickling, and also activates beta hemoglobin, which is affected by the sickle-cell mutation. So when you knock BCL11A down, you simultaneously increase fetal hemoglobin and repress sickling hemoglobin, which is why we think this is the best approach to gene therapy in sickle cell disease.'

The team first tried silencing the BCL11A gene in mice red blood cells in 2011, but they discovered that switching off the gene had a secondary effect of preventing blood stem cells from grafting onto bone marrow (see BioNews 629). In this new study they inserted the virus into precursor blood cells, which avoided this problem.

Following this successful study, the team expect to get approval from the US Food and Drug Administration next month to begin a clinical trial for sickle cell gene therapy in early 2017. They also believe that this approach could be beneficial for other blood diseases, such as beta-thalassaemia.

BCL11A-based gene therapy for sickle cell disease passes key preclinical test
Eurekalert (press release) |  6 September 2016
Gene Therapy for Sickle Cell Aces Vital Preclinical Test
Genetic Engineering and Biotechnology News |  7 September 2016
Gene therapy for sickle cell disease passes key preclinical test
Harvard Gazette |  6 September 2016
Gene therapy for sickle cell moves closer as scientists clear unexpected obstacle
STAT |  7 September 2016
Lineage-specific BCL11A knockdown circumvents toxicities and reverses sickle phenotype
Journal of Clinical Investigation |  6 September 2016
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