eyes streaming with tears, mouth agape in
pain. The work reflects his lifelong struggle with sickle-cell disease.
Nazaire, a 43-year-old Haitian-American, figures he’s been hospitalized
more than 300 times since he was a child.
He and other sickle-cell patients will tell
you that the worst part of the disease is
the debilitating pain. “It’s a horrifying
thing to have, because it’s extremely painful. It’s a major fight all the time,” he says.
Roughly 100,000 people in the U.S.
have sickle-cell disease, most of them
African-Americans and Latinos but also
people of Middle Eastern, Asian, Indian,
and Mediterranean descent. Compared
with the average American, they live much
shorter lives—about 40 to 60 years.
The cause of sickle-cell has been
known for a century, but the disease has
long been underserved by the medical
establishment and the pharmaceutical
industry. That may be about to change.
Its genetic origin—a single, well-studied
mutation—makes it an attractive candidate for treatment with the gene-editing
The idea is that CRISPR could correct the genetic mutation responsible for
sickle-cell so that patients’ bodies could
make normal red blood cells, alleviating
the pain and other severe symptoms associated with the disease. Researchers have
already tested the gene-editing tool on
human sickle cells in the lab and are now
working on getting the technique to clinical trials. Early results hint that sickle-cell could be among the first diseases that
CRISPR essentially cures.
Despite the lingering safety concerns
about using CRISPR in people, some
sickle-cell patients and their doctors are
already embracing it. “I would be one of
the first people to volunteer and say, ‘I want
to take part in a study,’” Nazaire says. He
first heard about CRISPR two years ago,
when he came across a You Tube video fea-
turing Jennifer Doudna and Emmanuelle
Charpentier, two of the inventors of the
technology. He’s been enthusiastic about
the idea of using CRISPR to treat sickle-
cell ever since.
Sickle-cell disease is one of the most
common genetic disorders, affecting millions of people around the world. It’s
caused by a mutation in a gene known as
HBB, which makes hemoglobin, a protein
that transports oxygen throughout the
body. Blood cells with healthy hemoglobin
are red and disc-shaped. Cells with abnormal hemoglobin are shaped like sickles
used to cut wheat, the characteristic that
gives the disease its name.
These misshapen cells are sticky and
clump together. When too many of them
build up, they create blockages in blood
vessels and cut off oxygen to nearby parts of
the body, causing severe episodes of pain.
The disease can also cause frequent infections, eye problems, and organ damage.
CRISPR Therapeutics is one of a
handful of gene-editing startups pursuing new treatments for sickle-cell. The
company’s approach involves isolating
stem cells from samples of patients’ blood.
Scientists would use CRISPR to activate
a genetic switch that would raise the levels of a fetal form of hemoglobin in red
blood cells, turning them healthy. This
fetal hemoglobin effectively counteracts
the effects of the sickle mutation. The
modified cells would then be infused back
into the patients.
Samarth Kulkarni, president of
CRISPR Therapeutics, says this is safer
than injecting the gene-editing mecha-
nism directly into the patient. That’s risky
because CRISPR can cause unintentional
or off-target edits, meaning it may cut
DNA it isn’t supposed to. Editing cells
outside the body will allow scientists to
make sure the technique works before
reintroducing the cells, he says.
Testing the method in lab experiments
using stem cells taken from sickle-cell
patients, researchers at CRISPR Thera-
peutics found that 85 percent of the cells
were successfully edited, which means
they were able to make healthy red blood
cells. Kulkarni says when the stem cells
are reintroduced into the patient, they
should be able to ameliorate all symp-
toms of sickle-cell. These stem cells are
able to travel to the bone marrow, where
they make more healthy blood cells for
the rest of the body. The healthy cells
will proliferate, and eventually, he says,
they will outnumber the sickled ones. St.
Jude Children’s Research Hospital, Editas
Medicine, and Intellia Therapeutics are
working on similar approaches.
Meanwhile, researchers at Stanford
University School of Medicine are work-
ing on a different method that aims to
directly modify the mutated HBB gene
itself using CRISPR. Researchers would
do that outside the body as well. Matthew
Porteus, an associate professor of pediat-
rics at Stanford, says his team is aiming to
begin a clinical trial by early 2019.
Porteus says not all of a patient’s origi-
nal sickle cells need to be replaced with
edited ones to effectively cure the disease.
He says if the proportion of sickle cells
is below 30 percent, patients don’t have
any symptoms. So far, his team has been
able to achieve correction rates between
40 and 70 percent. He expects corrected
blood cells to eventually surpass sickled
ones in a patient’s body. Sickle cells live
only 10 to 20 days, but normal red blood
cells last from 90 to 120 days.
The first clinical trials using CRISPR
haven’t started in the U.S. yet, but
“I would be one of the first
people to volunteer and say,
‘I want to take part in a study.’”