INNOVATIVE CRISPR genome editing has been used to inhibit the pathological morphology of red blood cells caused by sickle cell disease, offering a new therapeutic approach for the treatment of a range of blood disorders.
Sickle cell disease inhibits the ability of erythrocytes to deliver oxygen around the body, by causing genetic mutations in the beta subunit of haemoglobin molecules. Fetal haemoglobin, however, lacks the beta subunit and is instead made up of the gamma subunit. This means that the mutations caused by sickle cell disease do not take effect until after birth when postnatal haemoglobin becomes more prominent in thw cells and fetal haemoglobin declines.
“Our approach to gene editing is informed by the known benefits of hereditary persistence of fetal haemoglobin,” explained Dr Mitchell J. Weiss, Head of Hematology Department, St Jude Children’s Research Hospital, Memphis, Tennessee, USA. “It has been known for some time that individuals with genetic mutations that persistently elevate fetal haemoglobin are resistant to the symptoms of sickle cell disease and beta-thalassaemia, genetic forms of severe anaemia that are common in many regions of the world. We have found a way to use CRISPR gene editing to produce similar benefits.”
The research team used genome editing to inhibit the switching from gamma to beta subunits that takes place in postnatal haemoglobin. As a result, they were able to ensure that stem cells taken from patients with sickle cell disease maintained enough haemoglobin made up of the gamma subunit to ensure healthy erythrocytes were able to inhibit the ability of sickle cell disease to cause hypoxia.
“Our work has identified a potential DNA target for genome editing-mediated therapy and offers proof-of-principle for a possible approach to treat sickle cell and beta-thalassaemia,” Dr Weiss said. “We have been able to snip that DNA target using CRISPR, remove a short segment in a ‘control section’ of DNA that stimulates gamma-to-beta switching, and join the ends back up to produce sustained elevation of fetal haemoglobin levels in adult red blood cells.” The researchers now seek to further refine the gene editing process and minimise potentially harmful ‘off-target’ mutations before beginning human clinical trials with this new therapeutic approach.