Zika virus-specific therapy protects the fetal mouse brain

Date:
November 10, 2021
Source:
Cell Press
Summary:
A gene-silencing therapy protected against Zika virus transmission
from pregnant mice to the mouse fetuses, finds a new study. The
treatment, which harnesses nanoparticles called small extracellular
vesicles (sEVs) for drug delivery, crossed the placenta and
blood-brain barrier to greatly reduce fetal neurological damage,
including virus-induced brain shrinkage.



FULL STORY ==========================================================================
A gene-silencing therapy protected against Zika virus transmission
from pregnant mice to the mouse fetuses, finds a study published
November 10th in the journal Molecular Therapy. The treatment, which
harnesses nanoparticles called small extracellular vesicles (sEVs) for
drug delivery, crossed the placenta and blood-brain barrier to greatly
reduce fetal neurological damage, including virus-induced brain shrinkage.


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"Our experiments indicated that targeted delivery via modified sEVs is a promising alternative to the traditional methods of delivery, especially
for the treatment of brain viral infection," says senior study author
Zhiwei Wu of Nanjing University. "Increasing the yield and efficiency
of producing sEVs and developing sEVs that target other tissues will
broaden their application and will expand the effectiveness of this
gene delivery technique." The Zika virus epidemic swept across the Asia-Pacific region in 2015-2017 and remains a global health threat to
this day. The virus causes neurological and congenital conditions such
as microcephaly, in which the baby's head is smaller than expected. It
can cross the placenta and the blood-brain barrier -- a network of blood vessels and tissue that is made up of closely spaced cells.

The blood-brain barrier controls the exchange of substances between
the central nervous system (CNS) and the blood, helping to keep
harmful substances from reaching the brain. Few drugs specifically
target brain tissue, and most are highly toxic and do not efficiently
cross the blood-brain barrier. Treatment for viral infections of the
brain is generally ineffective due to blood-brain barrier blocking of
drugs. "Currently, there is no Zika virus-specific therapy or vaccine available," Wu says. "Safe and effective antiviral drugs that can
effectively cross the blood-brain barrier and placental barrier are
urgently needed, especially to prevent microcephaly." In particular,
gene silencing therapies using oligonucleotides have demonstrated unique advantages in clinical settings, but the delivery of nucleic acids into
cells remains a major challenge. One potential solution is offered by sEVs
-- natural, biodegradable nanoparticles that are released from cells and
are important mediators of cell-to-cell communication. Emerging evidence suggests that they could be a powerful tool to deliver drugs for the
treatment of cancer, cardiovascular conditions, and infectious diseases.

Recently, Wu and his collaborators leveraged sEVs to deliver an antiviral molecule across the placental barrier to inhibit Zika virus infection
in the mouse fetus.

In the new study, Wu and his team demonstrated for the first time that
sEVs could deliver antiviral drugs to achieve targeted suppression
of Zika virus infection in the fetal CNS and to control neurological
damage. To home in on neurons, the researchers engineered sEVs that
expressed rabies virus glycoprotein (RVG) on their surface. They then
loaded them with Zika virus- specific small interfering RNA (siRNA)
and injected them into pregnant mice.

The RVG-modified sEVs crossed the placental barrier and blood-brain
barrier, protecting against Zika virus transmission to the fetus. They concentrated in the fetal brain, where they suppressed infection and
reduced inflammation and neurological damage, including microcephaly
and defects in a brain region called the cerebellum. The findings echo
another recent study showing that RVG- modified sEVs could cross the blood-brain barrier in mice to treat manifestations of Parkinson's
disease. "Our therapeutic approach expanded the application of sEVs to
treat viral infection of brains by intravenous injection," Wu says.

Despite the promising results, many questions remain. For example,
the researchers delivered the virus and the first dose of the therapy simultaneously, so it is not clear whether treatment after a time lag
would also be effective. "A delayed injection after viral infection may
provide more confidence in the ability to translate this research to
human trials," Wu says.

"Nevertheless, our study provides a proof of concept for such a
possibility." Moving forward, the researchers plan to investigate
the molecular mechanisms by which the sEVs penetrate the placenta
and blood-brain barrier. They will also pin down the precise rate
of sEV penetration and determine the factors that control delivery
efficiency. "Since small extracellular vesicles are of biological origin,
they can be a safe drug delivery vehicle," Wu says.

"However, the current study remains preliminary and many more issues need
to be resolved. For human use, there is a long way to go." This work
was supported by National Natural Science Foundation of China, the Major Research and Development Project, Nanjing University-Ningxia University Collaborative Project.

========================================================================== Story Source: Materials provided by Cell_Press. Note: Content may be
edited for style and length.


========================================================================== Journal Reference:
1. Rui Zhang, Yuxuan Fu, Min Cheng, Wenyuan Ma, Nan Zheng, Yongxiang
Wang,
Zhiwei Wu. sEVsRVG selectively delivers antiviral siRNA to
fetus brain, inhibits ZIKV infection and mitigates ZIKV-induced
microcephaly in mouse model. Molecular Therapy, 2021; DOI:
10.1016/j.ymthe.2021.10.009 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/11/211110131634.htm

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