Researchers have known what causes sickle cell disease for 70 years—a simple mutation. But the disease, which predominantly affects African-Americans and people in Sub-Saharan Africa, still can't easily be treated.
Gene editing could help. In a new study, researchers showed that it's possible to use the CRISPR-Cas9 gene editing tool to fix the mutation in a patient, and potentially permanently cure them.
In patients with the disease, mutated stem cells produce misshapen red blood cells that stick in blood vessels and lead to anemia, severe pain, and progressively damage organs such as the brain or lungs. In the U.S., if you have the disease, you're likely to live 30 fewer years than average.
In the new process, bone marrow would be extracted from a patient, and the stem cells would be edited in the lab to correct the mutation. Then the cells would be returned to the same patient, make their way back to the bone marrow, and start producing healthy blood cells.
It's a perfect test case for gene editing in medicine. "It's a very well-defined, single gene disease," says Dana Carroll of the University of Utah, one of the co-authors of the study. "The only mutation that causes it is one base pair in one position in the beta globin gene. So it's very well characterized and it's a very simple change that we need to make to reverse the disease mutation."
Because the cells are in the bone marrow, they're also easier to access then disease-causing cells in some other parts of the body. The disease also affects hundreds of thousands of people around the world, so the researchers realized that a potential treatment would have a significant impact. Another treatment that exists now is effective, but rare, because it has serious risks.
The new process doesn't have to alter every cell to work, partly because normal blood cells last longer in the bloodstream than sickle cells. Fixing as few as 2-5% of stem cells could eliminate some symptoms. To be reliably effective, the researchers hope to develop the technology so it can fix around 20% of stem cells.
In tests with mice, the researchers found that the new stem cells lasted in the body, and didn't cause some of the adverse effects that could be possible (for example, accidentally modifying cancer-causing genes).
Though sickle cell disease is hereditary, the researchers are focused on treating individual patients rather than DNA that could be passed to the next generation. It's safer—if something goes wrong, an individual patient could be treated without it affecting a large population. It also avoids ethical questions about altering the human germ line.
Some mutations may have unknown benefits. People with only one sickle cell mutation (rather than the two that cause the disease) are naturally more resistant to malaria. Other mutations may have more important benefits, and so it might not make sense to completely eliminate them.
Before the new technique can be used as a treatment, it will have to go through a long road of safety and efficacy trials. There are also practical challenges to overcome, like how to make it affordable enough to use in parts of Africa.
"The way we're doing things now would be quite expensive for each patient," Carroll says. "You have to have the resources to move the lab, the resources to set up a sterile environment, the resources to do the cellular treatment, and so forth." Eventually, he says, there may be a universal cell bank that could be used with any patient.
The process could eventually also be used in other blood diseases, from thalassemia to HIV infection.
For Carroll, who has been working on various gene editing techniques for 20 years, it's an important advance. "To see the technology come to the point where you can really see how applications to the clinic are going to be possible is quite exciting," he says.
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