Tiny mineral particles are better vehicles for promising gene therapy


Date:
July 2, 2020
Source:
University of Wisconsin-Madison
Summary:
Researchers have developed a safer and more efficient way to
deliver a promising new method for treating cancer and liver
disorders and for vaccination.



FULL STORY ========================================================================== University of Wisconsin-Madison researchers have developed a safer and
more efficient way to deliver a promising new method for treating cancer
and liver disorders and for vaccination.


==========================================================================
The technology relies on inserting into cells pieces of carefully
designed messenger RNA (mRNA), a strip of genetic material that human
cells typically transcribe from a person's DNA in order to make useful
proteins and go about their business. Problems delivering mRNA safely
and intact without running afoul of the immune system have held back
mRNA-based therapy, but UW-Madison researchers are making tiny balls of minerals that appear to do the trick in mice.

"These microparticles have pores on their surface that are on the
nanometer scale that allow them to pick up and carry molecules like
proteins or messenger RNA," says William Murphy, a UW-Madison professor
of biomedical engineering and orthopedics. "They mimic something commonly
seen in archaeology, when we find intact protein or DNA on a bone sample
or an eggshell from thousands of years ago. The mineral components helped
to stabilize those molecules for all that time." Murphy and UW-Madison collaborators used the mineral-coated microparticles (MCMs) -- which
are 5 to 10 micrometers in diameter, about the size of a human cell --
in a series of experiments to deliver mRNA to cells surrounding wounds
in diabetic mice. Wounds healed faster in MCM-treated mice, and cells
in related experiments showed much more efficient pickup of the mRNA
molecules than other delivery methods.

The researchers described their findings today in the journal Science
Advances.

In a healthy cell, DNA is transcribed into mRNA, and mRNA serves as the instructions the cell's machinery uses to make proteins. A strip of mRNA created in a lab can be substituted into the process to tell a cell to
make something new. If that something is a certain kind of antigen, a
molecule that alerts the immune system to the presence of a potentially
harmful virus, the mRNA has done the job of a vaccine.



==========================================================================
The UW-Madison researchers coded mRNA with instructions directing cell ribosomes to pump out a growth factor, a protein that prompts healing
processes that are otherwise slow to unfold or nonexistent in the diabetic
mice (and many severely diabetic people).

mRNA is short-lived in the body, though, so to deliver enough to cells typically means administering large and frequent doses in which the
mRNA strands are carried by containers made of molecules called cationic polymers.

"Oftentimes the cationic component is toxic. The more mRNA you deliver,
the more therapeutic effect you get, but the more likely it is that
you're going to see toxic effect, too. So, it's a trade-off," Murphy
says. What we found is when we deliver from the MCMs, we don't see that toxicity. And because MCM delivery protects the mRNA from degrading, you
can get more mRNA where you want it while mitigating the toxic effects."
The new study also paired mRNA with an immune-system-inhibiting protein,
to make sure the target cells didn't pick the mRNA out as a foreign
object and destroy or eject it.

Successful mRNA delivery usually keeps a cell working on new instructions
for about 24 hours, and the molecules they produce disperse throughout
the body.

That's enough for vaccines and the antigens they produce. To keep lengthy processes like growing replacement tissue to heal skin or organs, the
proteins or growth factors produced by the cells need to hang around
for much longer.



========================================================================== "What we've seen with the MCMs is, once the cells take up the mRNA and
start making protein, that protein will bind right back within the
MCM particle," Murphy says. "Then it gets released over the course
of weeks. We're basically taking something that would normally last
maybe hours or even a day, and we're making it last for a long time."
And because the MCMs are large enough that they don't enter the
bloodstream and float away, they stay right where they are needed to
keep releasing helpful therapy. In the mice, that therapeutic activity
kept going for more than 20 days.

"They are made of minerals similar to tooth enamel and bone, but designed
to be reabsorbed by the body when they're not useful anymore," says
Murphy, whose work is supported by the Environmental Protection Agency,
the National Institutes of Health and the National Science Foundation
and a donation from UW-Madison alums Michael and Mary Sue Shannon.

"We can control their lifespan by adjusting the way they're made,
so they dissolve harmlessly when we want." The technology behind
the microparticles was patented with the help of the Wisconsin Alumni
Research Foundation and is licensed to Dianomi Therapeutics, a company
Murphy co-founded.

The researchers are now working on growing bone and cartilage and
repairing spinal cord injuries with mRNA delivered by MCMs.

This research was supported by grants from the Environmental Protection
Agency (S3.TAR grant 83573701), the National Institutes of Health
(R01AR059916, R21EB019558, NIH 5 T32 GM008349) and the National Science Foundation (DMR 1105591, DGE-1256259).


========================================================================== Story Source: Materials provided
by University_of_Wisconsin-Madison. Original written by Chris
Barncard. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Andrew S. Khalil, Xiaohua Yu, Jennifer M. Umhoefer, Connie S.

Chamberlain, Linzie A. Wildenauer, Gaoussou M. Diarra, Timothy
A. Hacker, William L. Murphy. Single-dose mRNA therapy
via biomaterial-mediated sequestration of overexpressed
proteins. Science Advances, 2020; 6 (27): eaba2422 DOI:
10.1126/sciadv.aba2422 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/07/200702144052.htm

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