Solution to 50-Year-Old Mystery Could Lead to Gene Therapy For Common Blood Disorders


Source: University of New South Wales

Summary: In a landmark study, researchers have used CRISPR gene editing to introduce beneficial natural mutations into blood cells to boost their production of foetal haemoglobin.


Sickle cell anaemia and beta thalassemia are the most common single-gene genetic disorders in the world, affecting millions of people. These debilitating inherited diseases are highly prevalent in regions where malaria was present, now or in the past, including South East Asia, southern China and India, Africa and the Middle East. They are also found in other countries, such as Australia and the United States, due to migrations of populations over time. The globin genes are perhaps the best understood of any human genes, with world famous scientists and some of the most competitive labs around the globe having worked in these conditions. In a landmark study, researchers from the UNSW have used CRISPR gene editing to introduce beneficial natural mutations into blood cells to boost their production of foetal haemoglobin. This could lead to new therapies for sickle cell anaemia and other blood disorders. The study findings were published in the journal Nature Genetics.

CRISPR

UNSW Sydney scientist Professor Merlin Crossley. Credit: UNSW

People with thalassemia or sickle cell anaemia have defective adult haemoglobin – the vital molecule that picks up oxygen in the lungs and transports it around the body – and require life-long treatment with blood transfusions and medications. The foetal haemoglobin gene is naturally silenced after birth. For 50 years, researchers have been competing furiously to find out how it is switched off, so it can be turned back on. The team found that two genes, called BCL11A and ZBTB7A, switch off the foetal haemoglobin gene by binding directly to it. And the beneficial mutations work by disrupting the two sites where these two genes bind. The research solves a 50-year-old mystery about how these mutations – which are naturally carried by a small percentage of people – operate and alter the expression of human genes.

Prof. Crossly said, “This landmark finding not only contributes to our appreciation of how these globin genes are regulated. It means we can now shift our focus to developing therapies for these genetic diseases using CRISPR to target precise changes in the genome.”


More Information: Natural regulatory mutations elevate the fetal globin gene via disruption of BCL11A or ZBTB7A binding, Nature Genetics (2018). nature.com/articles/doi:10.1038/s41588-018-0085-0


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