Millions of people worldwide suffer from inherited nonmalignant blood disorders like sickle cell disease and thalassemia. The culprit: genetic defects in their blood stem cells.
With a new four-year $3.5 million grant, researchers at Fred Hutchinson Cancer Research Center are working toward a safer form of a longstanding treatment for these patients.
Today, the only cure for sickle cell disease is a bone marrow transplant. During these procedures, patients first undergo chemotherapy and/or radiation to destroy their diseased bone marrow. Healthy, blood-forming stem cells are then given directly into the patient’s bloodstream.
Scientists are now exploring whether gene editing can also fix those underlying defects. But this approach still requires strong doses of chemotherapy or radiation to help clear the way for the engineered cells to engraft, or take root.
In both cases, these so-called “conditioning” regimens can cause severe toxicities. Their nonspecific nature can wreak havoc on healthy organs and tissues.
With its new grant from the National Institutes of Health, the Fred Hutch team aims to minimize those toxicities. Drs. Hans-Peter Kiem and Roland Walter will explore ways to precisely deliver powerful radioactive particles to blood and marrow cells while sparing other nonblood cells and tissues.
“For the fields of transplantation and gene therapy, these conditioning regimens are a fundamental issue,” said Kiem, who holds the Stephanus Family Endowed Chair for Cell and Gene Therapy at Fred Hutch. “It’s critical that we get these cells to engraft with the least amount of toxicity.”
To do that, they want to trade the traditional, nontargeted preparative treatments for something far more precise. Their research will involve a particular radioactive particle called astatine-211, which is known as an “alpha emitter” because of the type of radiation it produces.
“Alpha emitters are ideal for the precise delivery of potent amounts of radiation,” Walter said. That’s because they can deliver a high dose of energy over a short distance; the damage is deposited locally to the targeted cells while minimizing damage to surrounding, nontargeted cells.
Walter plans on fashioning a delivery vehicle for astatine-211 out of antibodies. These specialized immune proteins can home in on a specific surface marker on blood stem cells. He will engineer several antibodies and test the candidates in mice. Kiem then will take the most promising of these into the final steps of testing needed before they can be used in human patients.
Kiem noted that other Fred Hutch scientists, like Dr. Brenda Sandmaier, are testing a similar approach with alpha emitters for cancer patients in clinical trials.
“We have spent decades improving conditioning regimens for transplant patients, and we’re now on the leading edge of doing the same for gene therapy and genome editing,” he said. “The ultimate goal is to make these gene therapies safer and translate this work into patients.”
Jake Siegel is a former staff writer at Fred Hutchinson Cancer Center. Previously, he covered health topics at UW Medicine and technology at Microsoft. He has an M.A. from the Missouri School of Journalism.