Using the gene-editing technique CRISPR, a UNSW Sydney-led team of scientists has introduced a beneficial natural mutation into blood cells, switching on production of foetal haemoglobin. This advance could eventually lead to a cure for sickle cell anaemia and other blood disorders.
Sickle Cell Anaemia
Cells in tissues need a constant, steady supply of oxygen to function properly. Normally, haemoglobin in red blood cells picks up oxygen in the lungs and transports it around the body. Red blood cells that contain normal haemoglobin are disc-shaped, like a doughnut without a hole. This disc shape enables the cells to be flexible, ensuring they can move freely through large and small blood vessels to deliver their precious oxygen cargo.
People with sickle cell anaemia have damaged adult haemoglobin, the vital molecule that picks up oxygen in the lungs and transports it around the body. The haemoglobin can form stiff rods within the red cell, changing it into a crescent, or sickle shape. These sickle-shaped cells are inflexible and tend to adhere to the walls of blood vessels, causing blockages and thereby a reduced supply of oxygen to the tissues. Sickle cell anaemia necessitates life-long treatment with blood transfusions and medication.
Some people with sickle cell anaemia also carry a beneficial natural mutation called British-198. These individuals experience reduced symptoms, because the mutation switches on the foetal haemoglobin gene that is normally turned off after birth. The extra foetal haemoglobin in their blood, which has a very strong affinity for oxygen, does the work of the defective adult haemoglobin.
Mutations affecting adult haemoglobin production are among the most common of all genetic variations, with about 5 per cent of the world’s population carrying a defective gene.
“With CRISPR gene-editing we can now precisely cut and alter single genes within our vast genome,” says study senior author and UNSW molecular biologist Professor Merlin Crossley.
“Our laboratory has shown that introducing the beneficial mutation British-198 into blood cells using this technology substantially boosts their production of foetal haemoglobin. Because this mutation already exists in nature and is benign, this ‘organic gene therapy’ approach should be effective and safe to use to treat, and possibly cure, serious blood disorders. However, more research is still needed before it can be tested in people,” he says.
The beneficial British-198 mutation, was first identified in a large British family in 1974. It involves a change in just a single letter of the genetic code. Carriers of this mutation have foetal haemoglobin levels as high as 20% of total haemoglobin, while most people’s foetal haemoglobin levels fall to about 1 per cent of total haemoglobin after birth.
The researchers also discovered how this British-198 mutation works. They found it creates a new binding site for a protein called KLF1 that turns blood genes on.
“To turn the new gene editing approach into a therapy for blood disorders, the British-198 mutation would have to be introduced into blood-forming stem cells from the patient. A large number of stem cells would have to be edited in order to repopulate the patients’ blood with genetically enhanced cells,” says Professor Crossley.
The study by scientists from UNSW, the Japanese Red Cross Society and the RIKEN BioResource Centre in Japan, is published in the journal Blood.
Image: Blood smear illustrating sickle cell anaemia. Stained with Giemsa. Note the distinctive “sickle” shape, and “target cells” with concentric rings of red stain. Courtesy of Wikimedia Commons.