Genome editing could cure blood disorders

Research led by the University of New South Wales (UNSW) has found that changing just a single letter of the DNA of human red blood cells in the laboratory increases their production of oxygen-carrying haemoglobin. Their study, published in the journal Nature Communications, may lead to a cure for blood disorders such as sickle cell anaemia.

People produce two different kinds of haemoglobin: foetal haemoglobin and adult haemoglobin. Lead author Professor Merlin Crossley explained, “During development in the womb, the foetal haemoglobin gene is switched on. This produces foetal haemoglobin, which has a high affinity for oxygen, allowing the baby to snatch oxygen from its mother’s blood.

“After we are born, the foetal haemoglobin gene is shut off and the adult haemoglobin gene is switched on.”

Mutations affecting adult haemoglobin are among the most common of all human genetic mutations, with about 5% of the world’s population carrying a defective adult haemoglobin gene. People who inherit mutant genes from both their parents have damaged haemoglobin and suffer from life-threatening diseases such as sickle cell anaemia and thalassaemia, which require lifelong treatment with blood transfusions and medication.

The researchers realised that a small number of people with damaged adult haemoglobin have a “good mutation” in their foetal haemoglobin gene, said Professor Crossley, which keeps the gene “switched on for the whole of their lives and reduces their symptoms significantly”. They therefore sought to introduce this single-letter, naturally occurring mutation into human red blood cells.

The team utilised genome-editing proteins known as TALENs, which can be designed to cut a gene at a specific point as well as provide the desired piece of donor DNA for insertion. Professor Crossley explained, “Breaks in DNA can be lethal to cells, so they have in-built machinery to repair any nicks as soon as possible, by grabbing any spare DNA that seems to match - much like you might darn a red sock with any spare red wool lying around.

“We exploited this effect. When our genome editing protein cuts the DNA, the cell quickly replaces it with the donor DNA that we have also provided.”

Professor Crossley said his team’s laboratory study provides “a proof of concept that changing just one letter of DNA in a gene could alleviate the symptoms of sickle cell anaemia and thalassaemia”. The technique could offer significant advantages over other approaches, such as conventional gene therapy, in which viruses are used to ferry healthy genes into a cell to replace the defective ones.

“Because the good genetic variation we introduced already exists in nature, this approach should be effective and safe,” said Professor Crossley. “However, more research is needed before it can be tested in people as a possible cure for serious blood diseases.”

Image caption: UNSW Dean of Science Professor Merlin Crossley.

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