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SUNDAY SCIENCE: A PILL TO TREAT SICKLE CELL DISEASE? COMPOUND THAT
ACTIVATES FETAL GENE RAISES NEW HOPE  
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Robert F. Service
July 4, 2024
Science
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_ Drug strategy, shown to produce hemoglobin in lab animals, could
rival costly, risky gene therapies _

An experimental drug for sickle cell disease activates a fetal
hemoglobin gene that lets new blood cells assume a normal shape.,
Spencer Sutton/Science Source

 

Last year, the U.S. Food and Drug Administration (FDA) approved two
gene therapy procedures that can treat and, in some cases essentially
cure sickle cell disease, a genetic blood disorder that causes pain
and anemia in millions and still kills nearly 375,000 people worldwide
every year. But the groundbreaking treatments require risky
chemotherapy and cost some $2 million per person, putting them out of
reach of the vast majority of sickle cell patients. Now,
pharmaceutical researchers are reporting a potential oral drug that
restores healthy blood cells in animal models of the disease.

Unlike a one-time gene therapy whose benefits could last decades, the
new compound might have to be taken periodically for life and it
hasn’t even begun safety testing in humans. But the experimental
drug, described
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in Science, offers hope that sickle cell disease could one day be
widely and cheaply treatable with a simple pill.

“This seems promising,” says Lewis Hsu, a pediatric hematologist
at the University of Illinois, Chicago, who wasn’t involved with the
new research. However, he cautions, “there is a pipeline of sickle
cell disease [drug] treatments that work in mice and cells that
haven’t worked in people.”

Sickle cell disease is caused by a mutation in the gene responsible
for making adult hemoglobin. The change causes normally disk-shaped
red blood cells to adopt a characteristic crescent shape and to stick
together, clogging capillaries, damaging tissues and triggering
episodes of severe pain. One of the two newly approved therapies uses
an engineered virus to insert copies of a modified version of the gene
for adult hemoglobin into a patient’s own stem cells. Those
programmed cells are then returned to the person after chemotherapy
clears out existing blood stem cells.

The other approved therapy also modifies a patient’s blood stem
cells but, uses the CRISPR gene-editing system to block a gene for a
protein called BCL11A, which in adults represses the production of a
form of hemoglobin used by fetuses. During infancy this fetal
hemoglobin is normally dialed down as babies switch to making the
adult version. So, when CRISPR turns off BCL11A’s gene, it restores
production of fetal hemoglobin in the blood stem cells, helping sickle
cell patients.

But the high cost and complexity of gene therapy has made it tough to
see how either approach could work in lower income countries,
especially those in Africa, where most people with sickle cell disease
reside. “Regrettably, this therapy will not reach many patients,”
says Jay Bradner, a sickle cell expert with the biopharmaceutical
company Amgen.

Pharmaceutical companies have long been searching for drugs to switch
on fetal hemoglobin in adults. In 1998, FDA approved a drug called
hydroxyurea, which was found to modestly boost fetal hemoglobin
production. But the drug can also suppress the proliferation of bone
marrow stem cells, causing anemia and other side effects, a problem
that has upended several other would-be sickle cell drugs as well.
“The whole field has been struggling with this,” says Pamela Ting,
a hematology researcher at Novartis.

A team led by Ting and Bradner has recently been searching for
compounds that bind to a protein called cereblon, which is known to
tag other proteins for destruction by cells’ natural protein
recycling system. The original hope was they could find one that
helped cereblon tag the BCL11A protein, thereby restoring fetal
hemoglobin production. They screened a library of 2814
cereblon-binding molecules and fed those to immature red blood cells,
unearthing one, called dWIZ-1, that increased fetal hemoglobin
production.

But it unexpectedly didn’t target BCL11A, instead latching onto
another gene regulatory protein called WIZ, which wasn’t known to be
involved in controlling fetal hemoglobin levels. Further refinement of
that compound produced dWIZ-2, which the team found raised fetal
hemoglobin production in red blood cells from a baseline of 17% to
45%. The latter is at a level that would produce functional red blood
cells if it translated into humans, Bradner says. The compound also
worked when given orally to mice and in two out of three cynomolgus
monkeys, all without apparent side effects, the team reports. “This
is the first small molecule that induces fetal hemoglobin without
damaging the stem cells,” Bradner says.

Despite this promise, the compound still faces challenges. For
starters, WIZ is made in many cell types beyond red blood cells and
appears to have a role in regulating the activity of numerous genes.
“That could make it too broad an actor” to repress safely, says
Stuart Orkin, a stem cell biologist at Harvard University’s
Dana-Farber Cancer Institute and veteran sickle cell researcher not
involved in the new work.

But Bradner notes that dWIZ-2 seems to have an outsized effect in
boosting fetal hemoglobin. So, regardless of whether the Novartis
experimental compound passes muster in clinical trials, it has already
helped reveal a novel way to control which types of hemoglobin red
blood cells churn out. And that, in and of itself, could set the stage
for improved sickle cell drugs to come, Bradner suggests.

doi: 10.1126/science.z3iyub5

_BOB SERVICE is a news reporter for Science in Portland,
Oregon, covering chemistry, materials science, and energy stories._

_SCIENCE MAGAZINE. 
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Nuclear Danger Is Growing. Physicists of the World, Unite!
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Curtis T. Asplund, Zia Mian, Stewart Prager, Frank von Hippel
Bulletin of the Atomic Scientists
July 1, 2024

* Science
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* Medicine
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* genetics
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* Sickle Cell
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* blood
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* hemoglobin
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