Last month, a CRISPR Therapeutics clinical trial for beta-thalassemia was approved to start treating patients in Europe.
The clinical trial is one of over a dozen that have been initiated since the advent of the CRISPR-Cas9 gene editing technique. Most of these trials are in China, working on the use of CRISPR in cancer, but there are also several underway in the U.S. Globally there are around 60,000 people born each year who have beta-thalassemia, a rare blood condition that causes low oxygen levels in the body and anemia. The CRISPR Therapeutics clinical trial uses CRISPR to turn off the gene that causes this disorder, and instead helps red blood cells produce a form of hemoglobin produced in newborns that isn’t impacted by the mutation.
“The sad thing about these diseases, beta-thalassemia and sickle cell, is that they have been neglected for a long time, so there are not many treatments,” says Samarth Kulkarni, CEO of CRISPR Therapeutics. “The CRISPR approach will be one of the few that will be a functional cure.”
Beta-thalassemia is caused when then the body doesn’t make enough of a protein called hemoglobin in its red blood cells. Hemoglobin carries oxygen through the body. When there isn’t enough hemoglobin, red blood cells don’t function properly, they don’t last as long, and they don’t deliver oxygen to all the cells of the body. This makes people with beta-thalassemia feel weak and short of breath. This condition, called anemia, can be damaging for organs in cases where it is severe.
The type of thalassemia a person has depends on the specific part of the hemoglobin protein that is affected. There are two parts: the alpha and beta halves. Beta-thalassemia occurs when the beta half isn’t made. And the range of severity depends on how much hemoglobin is made overall. Some people may have life-threatening anemia, requiring regular blood transfusions.
Since beta-thalassemia is caused by a well-characterized mutation in the beta-globin gene, it is a good candidate for CRISPR, according to Kulkarni. CRISPR-Cas9 is a gene-editing complex discovered in bacteria that can target gene sequences and insert or remove sections of DNA. Because of its accuracy, researchers have developed methods so it can be used to turn off or change the abnormal sequences that cause a genetic disorder like beta-thalassemia or sickle cell anemia.
“With CRISPR you can do many different things — you can knock down genes, you correct genes, insert genes. It turns out that knocking down genes is easier to do with a very high efficiency relative to inserting or correcting genes,” Kulkarni says.
The clinical trial will extract the bone marrow cells that create blood cells for the body. Then it will use CRISPR to turn the beta-globin gene off, allowing the bone marrow cells to produce fetal hemoglobin instead. The CRISPR-transformed bone marrow cells will then be transfused back into the patient, where fetal hemoglobin will start transporting oxygen to overcome the defective beta-globin genes, Kulikarni says.
But some researchers aren’t sure how many bone marrow cells may need to be modified for the CRISPR treatment to be effective. “It’s unclear how much eliminating the gene would be sufficient to cure all the patients,” says Stefano Rivella, a professor of pediatrics at Philadelphia Children’s Hospital who studies iron disorders and sickle cell anemia. “That to me is an interesting question because I do believe many people would benefit from deactivation of the gene.”
In the U.S., Matthew Porteus at Stanford University is leading a clinical trial for sickle-cell anemia, which is a blood disorder also impacted by the beta-globin gene. Instead of reverting the cells to fetal hemoglobin, however, Porteus is trying to transform the beta-globin gene into a functional version. CRISPR Therapeutics is also working to get approval for its own sickle-cell trial using CRISPR in the U.S. this year.
“I don’t think, as we speak, that one technology is safer or better than another,” Rivella says. Gene addition therapy, which involves insertion of effective copies of the beta-globin genes, faces similar challenges to CRISPR, Rivella says. These include changing enough cells to cure or alleviate symptoms, and only inserting or changing the gene in the correct place, he says.
Using CRISPR on cells outside the body helps increase how effective it is, says Kulikari, a method Stanford is using as well. But another difficulty faced by both gene therapy and the CRISPR trial is that there is a range of how severe beta-thalassemia is in the body. Rivella compares it to mountain climbing. “There are some people, to cure this you have to climb all the way up Kilimanjaro from the base to the peak,” he says. Patients with less severe cases start the climb partway up the mountain.
There are currently thirteen registered clinical trials listed for the use of CRISPR-edited cells. Ten are in China using CRISPR for cancer and HIV treatment. In the U.S. along with the Stanford sickle-cell trial, researchers at University of Pennsylvania are studying CRISPR for melanoma, sarcoma, and multiple myeloma.
The limiting factor for all these gene technologies is that the extraction of bone marrow and the transfusion of treated cells back into the body require lengthy procedures and hospital stays, Rivella says.
“This isn’t something that you can’t do everywhere in the near future,” Rivella says.
“The cost and the technique to do this kind of therapy is quite challenging.”
The real standard of care change will happen once there is a technique that is able to treat beta-thalassemia and sickle cell anemia without requiring bone marrow transplants, says Rivella. “I’m talking about something that’s not around the corner but I think that’s something that’s going to make a big difference.”