Gene Editing: A New Horizon in Sickle Cell Disease Treatment

A gene-editing trial deploying CRISPR shows promise for curing sickle cell disease.

By Ellie Purinton

Imagine if you had episodes of intense pain that could occur at any moment; if you knew that you would likely not live beyond your fifties. This is the experience of individuals with sickle cell disease. 

Sickle cell disease is a rare blood cell disorder that causes low life expectancy, strokes, and infections. The only cure for the disease, which mostly affects African Americans, consists of a blood and bone marrow transplant. However, this treatment is only available to about one in five patients, because a close DNA match is needed. For other individuals, the only option is medication to reduce the symptoms. But there may be new hope for those with the disease, as one small clinical trial published in August showed promising results for using gene editing to cure individuals. 

This study was published in The New England Journal of Medicine. Researchers from the University of Chicago and St. Jude Children’s Research Hospital used CRISPR/Cas-9 to alter the DNA of the stem cells. CRISPR/Cas-9 is a sort of molecular scissor in which an enzyme cuts DNA at a specific location and enables new DNA sequences to be added; this technique eliminates the need for a donor transplant. Researchers edited the part of red blood cell DNA that codes for hemoglobin, a protein that carries oxygen and is abnormally hard and sticky in individuals with sickle cell disease. 

When babies are in the womb, they have fetal hemoglobin instead of adult hemoglobin. Fetal hemoglobin is structured differently and is not mutated in those with sickle cell disease. When an individual is born, a gene switches the fetal hemoglobin to adult hemoglobin. This is the point where sickle cell symptoms begin the hemoglobin being produced has an abnormal component. In editing the stem cell DNA, researchers focused on the group of genes that code for hemoglobin, or the “globin locus,” to produce fetal hemoglobin in adult blood cells.

“This is the first time that anybody has edited the globin locus,” says Akshay Sharma, one of the first authors of the paper and a pediatric hematologist at St. Jude’s. “We know not only that these patients benefited from it, but also we showed a proof of concept that editing at the global locus can increase fetal hemoglobin.” 

The treatment was accomplished by infusing patients once with their own modified red blood cells. This phase 1 and 2 clinical trial, sponsored by Novartis Pharmaceuticals, began in 2019. Three individuals with severe sickle cell disease received the genetically modified cells and were followed for six to 18 months. All three of the participants experienced a reduction in the occurrence of sickle cell symptoms, and they all had improved levels of red blood cells. 

A new approach using a new tool

Previously, researchers have used gene editing to directly target the gene that causes fetal hemoglobin to switch to adult hemoglobin. However, they discovered that this method resulted in a lower production of blood cells, which could potentially have negative side effects. 

This time, they took a cue from a condition known as hereditary persistence of fetal hemoglobin, or HPFH. HPFH is known to be completely harmless, and individuals with this condition have hemoglobin mutations that increase the amount of fetal hemoglobin in adult red blood cells. So, by editing genes in a similar manner, researchers have reduced the possibility of negative side effects. In targeting hemoglobin genes that repress fetal hemoglobin, Sharma and other researchers were able to increase the amount of healthy red blood cells in a more natural way than targeting the gene that switches fetal to adult hemoglobin.

 “We in transplant are excited about this therapy- we will do double duties of curing someone of their sickle cell disease, as well as reducing the toxic side effects from a transplant,” says Kathryn Leung, a pediatric hematologist specializing in sickle cell disease and the clinical director of Emory’s Bone and Marrow Transplant Research Center. However, this development is not an immediate cure-all for the disease. “We may still be about a decade off from gene editing becoming the regular therapy for sickle cell,” says Leung.

Choosing future research paths

The hemoglobin locus is complex, and it is comprised of many different genes, not just the ones that were edited in this trial. How these genes contribute exactly to sickle cell disease is still being explored.

“To be honest, we don’t know which the best strategy is to edit and which one of these genes should be turned on the most,” says Sharma. However, the success of this trial is a step in the right direction to cure the 80% of individuals with sickle cells who do not qualify for a transplant. 

Next, Sharma and other researchers are turning to other sites of the globin locus. In the next few months, they are planning on developing another clinical trial to edit a different site that increases fetal hemoglobin. 

As researchers experiment more with editing the globin locus, they get closer to fixing the mutation. “All these things that we are trying to do are surrogates,” says Sharma. “The best thing would be we just fix the mutation itself, which is easier said than done. Editing the hemoglobin locus opens the avenue that hopefully someday we will be able to fix the sickle mutation itself.”