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Could the solution for sickle cell disease lie with gene editing? New research, not yet in humans, suggests that a novel gene-editing strategy holds promise for people with this and other serious inborn disorders of hemoglobin, the oxygen-carrying molecules in red blood cells.
The results are so promising that the study team at Fred Hutchinson Cancer Research Center hopes that gene editing could even prove to be a cure, they said. The term “gene editing” refers to technologies that can be used to make precise modifications to the genome.
The ongoing research is led by Dr. Olivier Humbert, a staff scientist in the lab of Dr. Hans-Peter Kiem at Fred Hutch. The team used a novel gene-editing approach to increase blood stem cells’ production of the type of hemoglobin that is found in high levels in fetuses and infants. This is important because having more fetal hemoglobin in red blood cells can compensate for the dangerous problems associated with the defective or missing form of adult hemoglobin that is a hallmark of the inborn hemoglobin disorders collectively called hemoglobinopathies: sickle cell disease and beta thalassemias.
About 300,000 children worldwide are born each year with sickle cell disease, the most well-known hemoglobin disorder, and sickle cell is a leading cause of child death in many African nations. This genetic disorder causes people’s red blood cells to deform, a change that leads to episodes of excruciating pain, stroke and organ failure. The only cure currently available is bone marrow transplant, which is out of reach of many patients and associated with significant side effects.
Humbert presented the team’s findings last Friday during the annual meeting of the American Society of Gene & Cell Therapy. His talk was one of just four of the meeting’s nearly 1,000 research abstracts to be featured in the Presidential Symposium, the conference’s most prominent venue.
Working with an advanced laboratory model, Humbert and colleagues used the gene-editing strategy known as CRISPR to remove cells’ normal genetic mechanism for turning down the production of fetal hemoglobin. In his talk, Humbert showed that the team’s approach efficiently made the key genetic tweak and that high percentages of the modified cells survived over time in the bone marrow and blood.
Most thrilling to the researchers was the evidence they found that the procedure might prove to help people with hemoglobinopathies. “Most importantly, when we measured fetal hemoglobin levels, it was in the therapeutic range,” Humbert said.
“These levels, we hope, would be curative” — an exciting prospect for the team, added Kiem, who holds the Endowed Chair for Cell and Gene Therapy at Fred Hutch.
The team’s work also incorporated a recent discovery in the Kiem Lab: that a tiny fraction of blood stem cells is exclusively responsible for repopulating the entire blood and immune system after a patient receives a bone marrow transplant. Using this novel procedure, Humbert and colleagues showed that editing the genome of this small fraction of blood stem cells led to results that were similar to what they observed from editing at least 10 times as many cells.
The impact on the field would be dramatic, Kiem said, if this targeted and much more efficient gene-editing approach can be successfully translated into humans. “It will likely also improve the feasibility and safety of gene therapy and therefore, hopefully, make genome editing and gene therapy a more realistic treatment option and available to more patients,” he said.
This research provides an important proof-of-concept in advance of clinical trials of other gene-editing approaches for hemoglobinopathies, which are expected to begin enrolling patients in late 2018 or early 2019, Humbert said. The goal of these impending trials, led by other investigators, is also to increase levels of fetal hemoglobin in patients’ red blood cells, although they will use a different target to do this.
The Fred Hutch team hopes to translate its approach into a clinical trial of their own, and they are in discussions with potential industry partners to help with this next step, Humbert said. The researchers continue to refine their approach and will monitor their lab models for at least two years to see how long-lasting the effects of the gene therapy are.
“Persistence is key,” Humbert said. “We hope this will be a one-time therapy, for the life of the patient.”
At the recent meeting, Humbert’s talk was one of eight from Kiem’s group and his collaborators in Fred Hutch’s Stem Cell and Gene Therapy Program, which Kiem directs.
