Natural regulatory mutations elevate the fetal globin gene via disruption of BCL11A or ZBTB7A binding

A ‘natural’ gene therapy for blood disorders

25 April 2019

By reproducing naturally occurring mutations that elevate the production of foetal haemoglobin, a new CRISPR-based gene therapy could help treat inherited blood disorders such as sickle cell disease and β-thalassemia.

The mutations are found in patients with a benign condition called ‘hereditary persistence of foetal haemoglobin’, or HPFH, in which the γ-globin that is normally switched off after birth remains active.

A team led by scientists at the University of New South Wales identified two repressor proteins that normally bind part of the γ-globin gene at specific sites where mutations responsible for HPFH occur.

Using CRISPR gene-editing technology, they introduced HPFH-associated mutations into blood-forming cells and saw elevated expression of the γ-globin gene.

This finding helps clarify how these mutations prevent gene silencing, and it highlights a potential way to reactivate foetal haemoglobin production using genetic changes known to be safe in people.

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References

1. Nature Genetics 50, 498–503 (2018). doi: 10.1038/s41588-018-0085-0