Conference Coverage

Novel gene therapies show promise for sickle cell cure


Early results indicate experimental gene therapies could illicit a cure for sickle cell disease (SCD), but many barriers to access remain, namely cost, experts reported during a recent webinar sponsored by the National Heart, Lung, and Blood Institute.

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At present, allogeneic hematopoietic stem cell transplant remains the only curative therapy available for patients with SCD. Newer transplant techniques include the use of mobilized blood stem cells, where stem cells are collected from the circulation using blood cell growth factors, explained Mark Walters, MD, of UCSF Benioff Children’s Hospital Oakland in California.

The most promising experimental gene therapies currently undergoing clinical development are gene-addition and gene-editing therapies, he said. Another technique, in vivo gene editing to correct the sickle mutation, is also being investigated, but has not yet reached clinical development.

Gene-addition therapy

Gene-addition therapy is a technique where a fetal hemoglobin (HbF) or anti-sickling beta-hemoglobin gene is inserted into a hematopoietic stem cell to illicit a curative effect. In this technique, the corrective gene is harvested from a patient’s own blood stem cells.

In patients with SCD, when HbF levels are elevated, the likelihood of sickling is reduced, resulting in a milder form of disease. As a result, raising HbF levels is a therapeutic target that forms the basis of several ongoing clinical studies.

The technique involves packaging an HbF rescue gene into a viral vector and coincubating the vector with a patient’s own blood stem cells. Subsequently, the corrected stem cells are injected back into the patient to produce higher levels of HbF.

The ongoing phase 1/2 HGB-206 clinical study is evaluating this technique in patients aged 12-50 years with severe SCD in multiple centers throughout Europe and the United States.

In those treated thus far, initial results appear promising, Dr. Walters reported, with one patient experiencing a rise in Hb levels from 10.7 g/dL at 3 months to 15.0 g/dL at 15 months follow-up.

Dr. Walters also reported that some of these patients no longer exhibit any signs or symptoms of SCD, such as anemia or painful adverse events. While these initial findings are compelling, whether these benefits will be maintained is still unknown.

“While it’s too early to call this a cure, if [these results] could be extended for 5, 10, or 15 years, I think everyone would agree that this would be a cure,” he said.

This technique could be universally available, he said, since a patient’s own blood stem cells are used. Other complications, such as graft-versus-host disease (GVHD) or immune-related reactions, are negated with this form of therapy, he said.

Recent evidence has demonstrated that only about 20% of donor stem cells need to be corrected to illicit a very strong effect. This principle is now being applied in gene-editing techniques, as correcting every gene in every stem cell would be very challenging, Dr. Walters explained.

Gene editing

Another technique being investigated in SCD is gene editing, in which the fetal hemoglobin gene is “reawakened,” or other techniques are used to correct the sickle gene directly, such as CRISPR-Cas9 technology, Dr. Walters said.


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