Is a Genetic Cure for Sickle Cell Disease on the Horizon?

Researchers studying early results from ongoing gene therapy trials at Columbia have grown optimistic about finding a safer treatment and potential cure for sickle cell disease. Researchers in the Bone Marrow Transplantation and Cell Therapy Program, led by Markus Y. Mapara, MD, PhD, are participating in multicenter trials of two kinds of gene therapies. 

“These therapies may completely change our approach to taking care of patients with this disease,” says Dr. Mapara, professor of medicine at CUMC. 

Currently, the only potential curative option for sickle cell disease is a stem cell transplant using bone marrow or blood stem cells from related or unrelated donors. Other therapies can reduce symptoms and mortality, but they do not address the root cause of the disease. 

Columbia is one of the largest centers in the nation using stem cell transplants to treat sickle cell disease, but only a small fraction of patients have a suitably matched related sibling donor. Therefore, use of unrelated or mismatched related donors is also an option, but fraught with a higher risk of treatment-related complications, especially development of graft vs. host disease. The results at Columbia using these unrelated or mismatched transplants are very encouraging, demonstrating that these types of transplants can be performed safely although they are still associated with risks.

“It would be nice to correct the sickle cell defect with a safer approach and one that is available to all patients in case a matched sibling cannot be identified,” Dr. Mapara says. “Columbia is one of the few centers in the world which has access to two types of gene therapy trials for sickle cell disease.”

The trial of a gene therapy developed by Bluebird Bio is farthest along. The treatment takes stem cells from the patient and inserts a new gene that produces a modified hemoglobin. 

 After the engineered stem cells are transplanted back into the patient, they engraft into the bone marrow and produce new red blood cells that are less likely to sickle.

This procedure has been performed on more than 20 patients, including three at Columbia, says Dr. Mapara. “The results indeed appear to be very, very good,” resulting in increasing total hemoglobin levels, decreases in hemolysis, and apparent reduction of the number of painful vaso-occlusive crises.

The other trial also involves genetic modification of a patient’s stem cells. This approach, devised by Vertex Pharmaceuticals, uses CRISPR gene editing to disable the gene that turns off the production of fetal hemoglobin, a natural process that typically happens shortly after birth. If the therapy is successful, the patient’s stem cells will produce more red blood cells with fetal hemoglobin, which reduces sickling caused by the patient’s sickle hemoglobin.

“We know that sickle cell patients who naturally produce fetal hemoglobin have fewer painful episodes, fewer complications, and better survival, and in theory this therapy will produce similar results,” says Dr. Mapara. The first patient received this therapy at a different institution, but the Columbia program has identified the next three patients to receive the therapy and is in the process of stem cell mobilization of these individuals.

These experimental gene therapies are restricted to adolescents and adults enrolled in clinical trials, Dr. Mapara says, but could be used some day on children.

Sickle cell disease is present at birth and affects approximately 100,000 Americans. An estimated three times that many children are born with the disease worldwide each year.

“These patients are sick from the day they are born,” says Dr. Mapara. “Successful treatment would hopefully give these patients a normal life.”

More information is available at the program website, cancer.columbia.edu/bone-marrowstem-cell-transplantation