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The workflow of how genome editing occurs on "Your Favorite Gene" (YFG) using TALENs. (1) The target gene sequence is identified, (2) a corresponding TALEN sequence is engineered and (3) inserted into a plasmid. (4) The plasmid is inserted into the target cell where it is (5) translated to produce the functional TALEN. (6) The TALEN enters the nucleus and binds to then cleaves (cuts) the target gene sequence. Splicing a gene this way can be used to introduce an error (and turn off your target gene) or introduce a new DNA sequence into the target gene. Image Credit: Wikipedia

Genome editing could cure sickle cell anemia

Researchers have shown that changing just a single letter of the DNA of human red blood cells in the laboratory increases their production of oxygen-carrying hemoglobin - a world-first advance that could lead to a cure for sickle cell anaemia and other blood disorders.

The new genome editing technique, in which a beneficial, naturally-occurring genetic mutation is introduced into cells, works by switching on a sleeping gene that is active in the womb but turned off in most people after birth. The research was conducted at the University of New South Wales (UNSW).

"An exciting new age of genome editing is beginning, now that single genes within our vast genome can be precisely cut and repaired.

"Our 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 - inherited diseases in which people have damaged hemoglobin.

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

Merlin Crossley PhD, professor, study leader, Dean of Science at University of New South Wales, Sydney, Australia

The study, by Professor Crossley, UNSW PhD student Beeke Wienert, and colleagues, is published in the journal Nature Communications.

People produce two different kinds of hemoglobin - the vital molecule that picks up oxygen in the lungs and transports it around the body. "During development in the womb, the fetal hemoglobin gene is switched on. This produces fetal hemoglobin, which has a high affinity for oxygen, allowing the baby to snatch oxygen from its mother's blood," says Professor Crossley. "After we are born, the fetal hemoglobin gene is shut off and the adult hemoglobin gene is switched on."

Mutations affecting adult hemoglobin are among the most common of all human genetic mutations, with about five per cent of the world's population carrying a defective adult hemoglobin gene. People who inherit two mutant genes - one from their mother and one from their father - have damaged hemoglobin and suffer from life-threatening diseases such as sickle cell anaemia and thalassaemia, which require life-long treatment with blood transfusions and medication.

The researchers based their new approach on the fact that a small number of people with damaged adult hemoglobin have an additional, beneficial mutation in the fetal hemoglobin gene. "This good mutation keeps their fetal hemoglobin gene switched on for the whole of their lives, and reduces their symptoms significantly," says Professor Crossley.

The researchers introduced this single-letter mutation into human red blood cells using genome-editing proteins known as TALENs, which can be designed to cut a gene at a specific point, as well as providing the desired piece of donor DNA for insertion.

"Breaks in DNA can be lethal to cells. So cells have in-built machinery to repair any nicks as soon as possible. Any spare DNA that seems to match - might be used to repair a break. 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."

Merlin Crossley PhD

If the genome-editing technique is shown to work effectively in blood stem cells and be safe, it would 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.

The genetic changes to cells would not be inherited, making the approach very different to recent controversial Chinese research in which the DNA of human embryos was altered.

Abstract
Genetic disorders resulting from defects in the adult globin genes are among the most common inherited diseases. Symptoms worsen from birth as fetal γ-globin expression is silenced. Genome editing could permit the introduction of beneficial single-nucleotide variants to ameliorate symptoms. Here, as proof of concept, we introduce the naturally occurring Hereditary Persistance of Fetal Haemoglobin (HPFH) −175T>C point mutation associated with elevated fetal γ-globin into erythroid cell lines. We show that this mutation increases fetal globin expression through de novo recruitment of the activator TAL1 to promote chromatin looping of distal enhancers to the modified γ-globin promoter.

The research team includes researchers from UNSW, the University of Sydney, the University of Melbourne, Murdoch Childrens Research Institute, and Stanford University.

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