How a two-faced molecule can silence problematic genes

Date:
February 28, 2022
Source:
Tokyo Medical and Dental University
Summary:
Researchers have developed a technology, heteroduplex
oligonucleotide (HDO), that silences certain genes whose high
expression levels fuel disease. Adding a specific molecular tag
allowed them to target the HDO to immune cells called lymphocytes
safely and efficiently. Doing so with an HDO specific to a gene
called Itga4 improved symptoms in a mouse model of multiple
sclerosis, suggesting this technology may be developed to use in
human immune disorders.



FULL STORY ==========================================================================
T and B lymphocytes, which are part of a group of immune cells commonly
called white blood cells, work together to eliminate foreign invaders
in the body such as viruses. However, certain diseases can arise
when T and B cells are activated at inappropriate times, including
autoimmune disorders and various cancers. In a recent article published
in Nature Communications, a team led by researchers at Tokyo Medical
and Dental University (TMDU) describe a technology called a heteroduplex oligonucleotide (HDO) that they developed to deliver to lymphocytes and regulate their functions.


==========================================================================
Gene expression is at the root of controlling cellular activity. Disease
can result when certain genes are either improperly turned off or
are uncontrollably expressed. Therefore, scientists have aimed to
develop therapeutic methods to restore gene expression levels to their
healthy state, ideally only in the abnormal cells. One such modality is delivering specifically engineered DNA or RNA molecules that can locate
the misexpressed gene messages and direct the cell to lower them back
to normal levels. However, the most difficult part of this is ensuring
the therapeutic molecules can efficiently reach their proper destination without being degraded by the cell.

"Our team designed a DNA/RNA hybrid molecule called an HDO," says lead
author of the study Masaki Ohyagi. "The specific sequence of the HDO can
be altered to target a particular gene of interest, while its backbone
makes it stable within cells." A key part of the team's HDO design is
the addition of a molecule called a- tocopherol, which is crucial to its
proper delivery. Because a-tocopherol is essential for proper lymphocytic immune responses, adding this allows the HDO to be delivered within
peripheral blood and directed to lymphocytes. The team designed HDOs for several mouse genes and then intravenously injected them into lab mice.

"We found that our HDO technology was able to specifically silence
these genes in mouse lymphocytes more robustly and stably, and also
with less toxicity, than other previous versions of this method," states Takanori Yokota, senior author of the article. "Our studies also showed
that the HDOs enter these cells through a process called endocytosis."
After finding that their technology was effective at gene silencing, the
TMDU team investigated if it could be useful as a disease treatment. They designed an HDO targeting a gene called Itga4, which is central to
the pathogenesis of experimental autoimmune encephalomyelitis (EAE),
a mouse model for multiple sclerosis (MS).

"Intravenously injecting these mice with an Itga4-targeting HDO delayed
the onset and improved EAE symptoms and reduced both inflammatory cell infiltration and spinal cord demyelination," explains Ohyagi.

This work demonstrates the powerful gene silencing effects of the HDO technology, as well as its superior delivery capabilities relative
to other similar methods. Most significantly, the Itga4-specific HDO
was able to improve outcomes in an MS mouse model, suggesting it may
be useful as a novel therapeutic that could be developed for human immune-mediated diseases.

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


========================================================================== Journal Reference:
1. Masaki Ohyagi, Tetsuya Nagata, Kensuke Ihara, Kie Yoshida-Tanaka,
Rieko
Nishi, Haruka Miyata, Aya Abe, Yo Mabuchi, Chihiro Akazawa,
Takanori Yokota. DNA/RNA heteroduplex oligonucleotide technology
for regulating lymphocytes in vivo. Nature Communications, 2021;
12 (1) DOI: 10.1038/ s41467-021-26902-8 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/02/220228114422.htm

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