Using
specialized nanoparticles, MIT engineers have developed a way to turn off
specific genes in cells of the bone marrow, which play an important role in
producing blood cells. These particles could be tailored to help treat heart
disease or to boost the yield of stem cells in patients who need stem cell
transplants, the researchers say.
This type
of genetic therapy, known as RNA interference, is usually difficult to target
to organs other than the liver, where nanoparticles would tend to accumulate.
The MIT researchers were able to modify their particles in such a way that they
would accumulate in the cells found in the bone marrow.
"If
we can get these particles to hit other organs of interest, there could be a
broader range of disease applications to explore, and one that we were really
interested in this paper was the bone marrow. The bone marrow is a site for
hematopoiesis of blood cells, and these give rise to a whole lineage of cells
that contribute to various types of diseases," says Michael Mitchell, a
former MIT postdoc and one of the lead authors of the study.
In a study
of mice, the researchers showed that they could use this approach to improve
recovery after a heart attack by inhibiting the release of bone marrow blood
cells that promote inflammation and contribute to heart disease.
Marvin
Krohn-Grimberghe, a cardiologist at the Freiburg University Heart Center in
Germany, and Maximilian Schloss, a research fellow at Massachusetts General
Hospital, are also lead authors of the paper, which appears today in Nature
Biomedical Engineering. The paper's senior authors are Daniel Anderson, a
professor of chemical engineering at MIT and a member of MIT's Koch Institute
for Integrative Cancer Research and Institute for Medical Engineering and
Science, and Matthias Nahrendorf, a professor of radiology at MGH.
Targeting
the bone marrow
RNA
interference is a strategy that could potentially be used to treat a variety of
diseases by delivering short strands of RNA that block specific genes from
being turned on in a cell. So far, the biggest obstacle to this kind of therapy
has been the difficulty in delivering it to the right part of the body. When
injected into the bloodstream, nanoparticles carrying RNA tend to accumulate in
the liver, which some biotech companies have taken advantage of to develop new
experimental treatments for liver disease.
Anderson's
lab, working with MIT Institute Professor Robert Langer, who is also an author
of the new study, has previously developed a type of polymer nanoparticles that
can deliver RNA to organs other than the liver. The particles are coated with
lipids that help stabilize them, and they can target organs such as the lungs,
heart, and spleen, depending on the particles' composition and molecular
weight.
"RNA
nanoparticles are currently FDA-approved as a liver-targeted therapy but hold
promise for many diseases, ranging from COVID-19 vaccines to drugs that can
permanently repair disease genes," Anderson says. "We believe that
engineering nanoparticles to deliver RNA to different types of cells and organs
in the body is key to reaching the broadest potential of genetic therapy."
In the new
study, the researchers set out to adapt the particles so that they could reach
the bone marrow. The bone marrow contains stem cells that produce many
different types of blood cells, through a process called hematopoiesis.
Stimulating this process could enhance the yield of hematopoietic stem cells
for stem cell transplantation, while repressing it could have beneficial
effects on patients with heart disease or other diseases.
"If
we could develop technologies that could control cellular activity in bone
marrow and the hematopoietic stem cell niche, it could be transformative for
disease applications," says Mitchell, who is now an assistant professor of
bioengineering at the University of Pennsylvania.
The
researchers began with the particles they had previously used to target the
lungs and created variants that had different arrangements of a surface coating
called polyethylene glycol (PEG). They tested 15 of these particles and found
one that was able to avoid being caught in the liver or the lungs, and that
could effectively accumulate in endothelial cells of the bone marrow. They also
showed that RNA carried by this particle could reduce the expression of a
target gene by up to 80 percent.
The researchers
tested this approach with two genes that they believed could be beneficial to
knock down. The first, SDF1, is a molecule that normally prevents hematopoietic
stem cells from leaving the bone marrow. Turning off this gene could achieve
the same effect as the drugs that doctors often use to induce hematopoietic
stem cell release in patients who need to undergo radiation treatments for
blood cancers. These stem cells are later transplanted to repopulate the
patient's blood cells.
"If
you have a way to knock down SDF1, you can cause the release of these
hematopoietic stem cells, which could be very important for a transplantation
so you can harvest more from the patient," Mitchell says.
The
researchers showed that when they used their nanoparticles to knock down SDF1,
they could boost the release of hematopoietic stem cells fivefold, which is
comparable to the levels achieved by the drugs that are now used to enhance
stem cell release. They also showed that these cells could successfully
differentiate into new blood cells when transplanted into another mouse.
"We
are very excited about the latest results," says Langer, who is also the
David H. Koch Institute Professor at MIT. "Previously we have developed
high-throughput synthesis and screening approaches to target the liver and
blood vessel cells, and now in this study, the bone marrow. We hope this will
lead to new treatments for diseases of the bone marrow like multiple myeloma
and other illnesses."
Combatting
heart disease
The second
gene that the researchers targeted for knockdown is called MCP1, a molecule
that plays a key role in heart disease. When MCP1 is released by bone marrow
cells after a heart attack, it stimulates a flood of immune cells to leave the
bone marrow and travel to the heart, where they promote inflammation and can
lead to further heart damage.
In a study
of mice, the researchers found that delivering RNA that targets MCP1 reduced
the number of immune cells that went to the heart after a heart attack. Mice
that received this treatment also showed improved healing of heart tissue
following a heart attack.
"We
now know that immune cells play such a key role in the progression of heart
attack and heart failure," Mitchell says. "If we could develop
therapeutic strategies to stop immune cells that originate from bone marrow
from getting into the heart, it could be a new means of treating heart attack.
This is one of the first demonstrations of a nucleic-acid-based approach of
doing this."
At
his lab at the University of Pennsylvania, Mitchell is now working on new
nanotechnologies that target bone marrow and immune cells for treating other
diseases, especially blood cancers such as multiple myeloma.