Study Could Lead to Gene Editing Therapy for Inherited Blood Disorders

Rare Daily Staff

A study that determined how naturally-occurring gene mutations can counter the effects of inherited blood diseases has opened the potential to use gene editing to treat patients with sickle cell disease, thalassemia, and other disorders.

University of South Wales, Sydney-led researchers used CRISPR gene editing to introduce beneficial natural mutations into blood cells to boost their production of fetal hemoglobin. They say their study solved a 50-year-old mystery about how these beneficial mutations carried by a small percentage of people alter the expression of genes.

The Australian team’s results were first presented at an international conference at Asilomar, California in 2016 and a race between UNSW and other labs ensued with the UNSW-led study being published in Nature Genetics.

“Our new approach can be seen as a forerunner to ‘organic gene therapy’ for a range of common inherited blood disorders including beta thalassemia and sickle cell anemia,” said Merlin Crossley, study leader and UNSW deputy vice-chancellor, academic. “It is organic because no new DNA is introduced into the cells; rather we engineer in naturally occurring, benign mutations that are known to be beneficial to people with these conditions.”

Crossley said the approach should prove to be safe and effective but will require more research for it to be turned into effective treatments.

People with thalassemia or sickle cell anemia have defective adult hemoglobin, a molecule that transports oxygen from the lungs throughout the body. Patients with these conditions require life-long treatment with blood transfusions and medications.

But some people with these diseases have reduced symptoms because they also carry mutations that activates the gene that produces fetal hemoglobin, which compensates for their damaged adult hemoglobin.

The fetal hemoglobin gene is naturally silenced after birth and researchers have for 50 years sought to discover how it is switched off with the hopes of finding a way to turn it back on.

The researchers identified two genes—BCL11A and ZBTB7A—that switch off the fetal hemoglobin gene by binding directly to it. They also discovered the beneficial mutations work by disrupting the two sites where these two genes bind.

The findings provide insight into how globin genes are regulated, but also provides a path to developing therapies for these conditions using CRISPR to target precise changes in the genome.

“Our study, which is the culmination of many years of work, solves that mystery,” said Crossley

April 2, 2018
Photo: Merlin Crossley, study leader and UNSW deputy vice-chancellor, academic