ORLANDO, Fla. – At the 61st American Society of Hematology (ASH) annual meeting late-breaking abstracts session on Tuesday, researchers from Boston Children’s Hospital reported that three adult patients who had received an autologous transplant of gene-edited hematopoietic stem cells lacking BCL11A produced high levels of functional hemoglobin and had reduced disease symptoms for at least eight months after transplantation. 

Adverse events were in line with those expected for an autologous stem cell transplant, which is a highly toxic procedure. 

The hemoglobin protein, which carries oxygen in red blood cells, is made up of four subunits whose composition changes after birth. Fetal hemoglobin is made up of two alpha and two gamma chains each.  

After birth, gamma chains are gradually replaced by beta chains. In individuals with hemoglobinopathies, who have mutations in their beta chains, that is where the trouble begins. In SCD in particular, mutations in the beta chain lead to misshapen “sickled” red blood cells that can no longer easily pass through small blood vessels. That leads to a multitude of follow-on complications, the most troubling of which are vascular occlusive events (VOEs) and pain crises. 

The goal of targeting BCL11A is to turn back time and induce cells to once more produce gamma chains, which enables the production of functional hemoglobin. BCL11A represses the production of gamma chains and enhances the production of beta chains.  

BCL11A is in the sights of several biopharma companies, including Bluebird Bio Inc., which has licensed the work reported in the late-breaking abstract plenary session, and Sangamo Biosciences Inc.  

It is not, however, the only repressor of fetal hemoglobin. Another such repressor, ZBTB7A, was described recently.  

A poster presented at the ASH meeting identified several new gene variants that were associated with increased expression levels of fetal hemoglobin in healthy individuals. 

And researchers from Syros Pharmaceuticals Inc. reported that NFIX also functions to repress fetal hemoglobin, and that knocking down NFIX in cell culture led to levels of fetal hemoglobin expression that were “consistent with a clinical cure.” 

Jeffrey Shearstone, director of molecular and cellular biology, Syros

Syros is developing small molecules rather than gene therapies to affect gene expression, but Jeffrey Shearstone told BioWorld that while “gene therapy will probably be successful” for sickle cell disease, “a small molecule that could do the same thing… would really increase accessibility to patients.” Shearstone is director of molecular and cellular biology at Syros.   

For one, a gene therapy will be expensive. Medical pricing in the U.S. is half mystery, half disaster. And with the cost of a complication-free stem cell transplant already at around a half million dollars, and transplants where complications arise easily reaching twice that, even an expensive gene therapy is likely to be cost-effective. But an oral medication could put treatment within reach for patients who cannot afford gene therapy. 

Likewise, as long as stem cell transplant remains the risky, involved procedure that it currently is, “the first line of defense might be an oral therapeutic,” Shearstone said, especially for individuals with less severe clinical disease. 

Disease severity for patients with the same mutation is “markedly different, and the disease severity can change within the same patient over time,” Williams said. 

Of the approximately 100,000 individuals with SCD in the U.S., 10% to 20% have severe disease that necessitates repeat hospitalizations, and another 50% to 60% have repeat complications. For those with less severe disease, though, oral therapies may be an attractive alternative to stem cell transplants, which have risks including infertility and even death.  

Additionally, Shearstone said that “the other place where a small molecule will fit [is] patients who undergo gene editing whose response diminishes over time.”  

So far, there has been no evidence of BCL11A repression waning. But the longevity of gene therapy approaches is “part of what we are studying,” Williams said.  

The clinical and research efforts currently underway will add to an already rapidly growing armamentarium against sickle cell disease. Three drugs have been approved in recent years, joining hydroxyurea, which was the only option until 2017. 

On the first day of the annual meeting, ASH and the FDA released new recommendations for clinical trial endpoints to evaluate new SCD therapies. 

Press conference moderator Robert Brodsky, professor of medicine and the director of the division of hematology at Johns Hopkins School of Medicine, said the clinical landscape of targets and treatment types remains to be determined. “I imagine several [options] are going to fit into the paradigm,” he said. “The exciting thing is that there are now multiple ways of going at this previously incurable disease.” 

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