Inspired by tiny particles that carry cholesterol through the body, chemical engineers have designed nanoparticles that can deliver snippets of genetic material that turn off disease-causing genes. This approach, known as RNA interference (RNAi), holds great promise for treating cancer and other diseases. However, delivering enough RNA to treat the diseased tissue, while avoiding side effects in the rest of the body, has proven difficult. The new particles, which encase short strands of RNA within a sphere of fatty molecules and proteins, silence target genes in the liver more efficiently than any previous delivery system.
Inspired
by tiny particles that carry cholesterol through the body, MIT chemical
engineers have designed nanoparticles that can deliver snippets of genetic
material that turn off disease-causing genes.
This
approach, known as RNA interference (RNAi), holds great promise for treating
cancer and other diseases. However, delivering enough RNA to treat the diseased
tissue, while avoiding side effects in the rest of the body, has proven
difficult.
The
new MIT particles, which encase short strands of RNA within a sphere of fatty
molecules and proteins, silence target genes in the liver more efficiently than
any previous delivery system, the researchers found in a study of mice.
"What
we're excited about is how it only takes a very small amount of RNA to cause
gene knockdown in the whole liver. The effect is specific to the liver -- we
get no effect in other tissues where you don't want it," says Daniel
Anderson, the Samuel A. Goldblith Associate Professor of Chemical Engineering
and a member of MIT's Koch Institute for Integrative Cancer Research.
Anderson
is senior author of a paper describing the particles in the Proceedings
of the National Academy of Sciences the week of Feb. 10. Robert
Langer, the David H. Koch Institute Professor at MIT, is also an author.
The
research team, which included scientists from Alnylam Pharmaceuticals, also
found that the nanoparticles could powerfully silence genes in nonhuman primates.
The technology has been licensed to a company for commercial development.
Natural inspiration
RNA
interference is a naturally occurring phenomenon that scientists have been
trying to exploit since its discovery in 1998. Snippets of RNA known as short
interfering RNA (siRNA) turn off specific genes inside living cells by
destroying the messenger RNA molecules that carry DNA's instructions to the
rest of the cell.
Scientists
hope this approach could offer new treatments for diseases caused by single mutations,
such as Huntington's disease, or cancer, by blocking mutated genes that promote
cancerous behavior. However, developing RNAi therapies has proven challenging
because it is difficult to deliver large quantities of siRNA to the right
location without causing side effects in other tissues or organs.
In
previous studies, Anderson and Langer showed they could block multiple genes
with small doses of siRNA by wrapping the RNA in fatlike molecules called
lipidoids. In their latest work, the researchers set out to improve upon these
particles, making them more efficient, more selective, and safer, says Yizhou
Dong, a postdoc at the Koch Institute and lead author of the paper.
"We
really wanted to develop materials for clinical use in the future," he
says. "That's our ultimate goal for the material to achieve."
The
design inspiration for the new particles came from the natural world --
specifically, small particles known as lipoproteins, which transport
cholesterol and other fatty molecules throughout the body.
Like
lipoprotein nanoparticles, the MIT team's new lipopeptide particles are spheres
whose outer membranes are composed of long chains with a fatty lipid tail that
faces into the particle. In the new particles, the head of the chain, which
faces outward, is an amino acid (the building blocks of proteins). Strands of
siRNA are carried inside the sphere, surrounded by more lipopeptide molecules.
Molecules of cholesterol embedded in the membrane and an outer coating of the
polymer PEG help to stabilize the structure.
The
researchers tuned the particles' chemical properties, which determine their
behavior, by varying the amino acids included in the particles. There are 21
amino acids found in multicellular organisms; the researchers created about 60
lipopeptide particles, each containing a different amino acid linked with one
of three chemical groups -- an acrylate, an aldehyde, or an epoxide. These
groups also contribute to the particles' behavior.
Targeted strike
The
researchers then tested the particles' ability to shut off the gene for a blood
clotting protein called Factor VII, which is produced in the liver by cells
called hepatocytes. Measuring Factor VII levels in the bloodstream reveals how
effective the siRNA silencing is.
In
that initial screen, the most efficient particle contained the amino acid
lysine linked to an epoxide, so the researchers created an additional 43
nanoparticles similar to that one, for further testing. The best of these
compounds, known as cKK-E12, achieved gene silencing five times more
efficiently than that achieved with any previous siRNA delivery vehicle.
In
a separate experiment, the researchers delivered siRNA to block a tumor
suppressor gene that is expressed in all body tissues. They found that siRNA
delivery was very specific to the liver, which should minimize the risk of
off-target side effects.
"That's
important because we don't want the material to silence all the targets in the
human body," Dong says. "If we want to treat patients with liver
disease, we only want to silence targets in the liver, not other cell
types."
In
tests in nonhuman primates, the researchers found that the particles could
effectively silence a gene called TTR (transthyretin), which has been
implicated in diseases including senile systemic amyloidosis, familial amyloid
polyneuropathy, and familial amyloid cardiomyopathy.
The
MIT team is now trying to learn more about how the particles behave and what
happens to them once they are injected, in hopes of further improving the
particles' performance. They are also working on nanoparticles that target
organs other than the liver, which is more challenging because the liver is a
natural destination for foreign material filtered out of the blood.
The
research was funded by Alnylam Pharmaceuticals and the National Institutes of
Health.
Story Source:
The
above story is based on materials provided by Massachusetts Institute of Technology. The
original article was written by Anne Trafton. Note: Materials may be
edited for content and length.
Journal Reference:
Y.
Dong, K. T. Love, J. R. Dorkin, S. Sirirungruang, Y. Zhang, D. Chen, R. L.
Bogorad, H. Yin, Y. Chen, A. J. Vegas, C. A. Alabi, G. Sahay, K. T. Olejnik, W.
Wang, A. Schroeder, A. K. R. Lytton-Jean, D. J. Siegwart, A. Akinc, C. Barnes,
S. A. Barros, M. Carioto, K. Fitzgerald, J. Hettinger, V. Kumar, T. I.
Novobrantseva, J. Qin, W. Querbes, V. Koteliansky, R. Langer, D. G. Anderson. Lipopeptide
nanoparticles for potent and selective siRNA delivery in rodents and nonhuman
primates. Proceedings of the National Academy of Sciences,
2014; DOI: 10.1073/pnas.1322937111
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