Tiny engineered therapeutic delivery system safely solves genetic
problems in mice
Nanomaterials show promise for treating hemophilia and cardiovascular
disorder

Date:
August 21, 2020
Source:
Ohio State University
Summary:
Inserting genetic material into the body to treat diseases
caused by gene mutations can work, scientists say - but getting
those materials to the right place safely is tricky. Scientists
now report that the lipid-based nanoparticles they engineered,
carrying two sets of protein-making instructions, showed in animal
studies that they have the potential to function as therapies for
two genetic disorders.



FULL STORY ========================================================================== Inserting genetic material into the body to treat diseases caused by
gene mutations can work, scientists say -- but getting those materials
to the right place safely is tricky.


========================================================================== Scientists report today (Aug. 21) in the journal Science Advances that
the lipid-based nanoparticles they engineered, carrying two sets of protein-making instructions, showed in animal studies that they have
the potential to function as therapies for two genetic disorders.

In one experiment, the payload-containing nanoparticles prompted the
production of the missing clotting protein in mice that are models
for hemophilia. In another test, the nanoparticles' cargo reduced
the activation level of a gene that, when overactive, interferes with
clearance of cholesterol from the bloodstream.

Each nanoparticle contained an applicable messenger RNA -- molecules
that translate genetic information into functional proteins.

"We demonstrated two applications for lipid-like nanomaterials that
effectively deliver their cargo, appropriately biodegrade and are well-tolerated," said Yizhou Dong, senior author of the study and
associate professor of pharmaceutics and pharmacology at The Ohio State University.

"With this work, we have lowered potential side effects and toxicity,
and have broadened the therapeutic window. This gives us confidence to
pursue studies in larger animal models and future clinical trials."
This work builds upon a collection of lipid-like spherical compounds
that Dong and colleagues had previously developed to deliver messenger
RNA. This line of particles was designed to target disorders involving
genes that are expressed in the liver.



==========================================================================
The team experimented with various structural changes to those particles, effectively adding "tails" of different types of molecules to them, before landing on the structure that made the materials the most stable. The
tiny compounds have a big job to do: embarking on a journey through the bloodstream, carrying molecules to the target location, releasing the
ideal concentration of messenger RNA cargo at precisely the right time
and safely degrading.

The tests in mice suggested these particles could do just that.

The researchers injected nanoparticles containing messenger RNA holding
the instructions to produce a protein called human factor VIII into
the bloodstream of normal mice and mouse models for hemophilia. A
deficiency of this protein, which enables blood to clot, causes the
bleeding disorder. Within 12 hours, the deficient mice produced enough
human factor VIII to reach 90 percent of normal activity. A check of
the organs of both protein-deficient mice and normal mice showed that
the treatment caused no organ damage.

"It can be helpful to think of this as a protein-replacement therapy,"
Dong said.

In the second experiment, nanomaterials were loaded with two types of instructions: messenger RNA carrying the genetic code for a DNA base
editor, and a guide RNA to make sure the edits occurred in a specific
gene in the liver called PCSK9. Dozens of mutations that increase this
gene's activity are known to cause high cholesterol by reducing clearance
of cholesterol from the bloodstream.



========================================================================== Analyses showed that the treatment resulted in the intended mutation
of about 60 percent of the target base pairs in the PCSK9 gene, and
determined that only a low dose was needed to produce high editing effect.

Dong credited academic and industry partners for helping advance
this work. Co- corresponding authors include Denise Sabatino of
Children's Hospital of Philadelphia and Delai Chen from Boston-based
Beam Therapeutics, who provided expertise in hemophilia and DNA base
editing, respectively.

Dong and first author Xinfu Zhang are inventors on patent applications
filed by Ohio State related to the lipid-like nanoparticles. This
technology has been licensed for further clinical development.

This work was supported by the National Institute of General Medical
Sciences, the National Heart, Lung and Blood Institute, and a startup
fund from Ohio State's College of Pharmacy.

Additional co-authors are Giang N. Nguyen of Children's Hospital of Philadelphia; Weiyu Zhao, Chengxiang Zhang, Chunxi Zeng, Jingyue Yan,
Shi Du, Xucheng Hou, Wenqing Li, Justin Jiang, Binbin Deng and David
McComb of Ohio State; and Robert Dorkin, Aalok Shah, Luis Barrera,
Francine Gregoire and Manmohan Singh of Beam Therapeutics.


========================================================================== Story Source: Materials provided by Ohio_State_University. Original
written by Emily Caldwell. Note: Content may be edited for style and
length.


========================================================================== Journal Reference:
1. Xinfu Zhang, Weiyu Zhao, Giang N. Nguyen, Chengxiang Zhang,
Chunxi Zeng,
Jingyue Yan, Shi Du, Xucheng Hou, Wenqing Li, Justin Jiang, Binbin
Deng, David W. Mccomb, Robert Dorkin, Aalok Shah, Luis Barrera,
Francine Gregoire, Manmohan Singh, Delai Chen, Denise E. Sabatino,
and Yizhou Dong. Functionalized lipid-like nanoparticles for in
vivo mRNA delivery and base editing. Science Advances, 2020 DOI:
10.1126/sciadv.abc2315 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/08/200821141315.htm

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