Novel approaches for correcting gene expression insufficiency

23
Novel approaches for correcting gene expression insufficiency


Novel approaches for correcting gene expression insufficiency
taRNAs built from an array of IRESs increase reporter gene translation. Credit: Nature Communications (2023). DOI: 10.1038/s41467-023-42252-z

A new molecular technology capable of binding to mRNA and regulating gene expression may offer a new avenue for treating diseases caused by haploinsufficiency, or the absence of one functional gene copy, according to a study published in Nature Communications.

Messenger RNA, or mRNA, contains instructions for DNA to produce proteins. Many diseases, including cancer and several genetic disorders, result from insufficient gene—and therefore protein—expression, but few strategies exist to correct that kind of dysregulation at a molecular level.

The new technology, dubbed “translation-activating RNAs” (taRNAs), consists of small molecules programmed to attach to specific mRNA molecules to directly control their translation into proteins, said Alfred L. George Jr., MD, the chair and Alfred Newton Richards Professor of Pharmacology and a co-author of the study.

“This technology opens the door for a new way to enhance the expression of a gene at the protein level. There are lots of ways to knock down a gene. There are very few ways to upregulate the gene and produce more protein from the copy of the gene that’s not disabled by a mutation,” said George, who also directs the Center for Pharmacogenomics.

The study was a collaborative effort between George and Bryan Dickinson, Ph.D., professor of Chemistry at the University of Chicago, who was senior author of the paper.

In the study, investigators combined snippets of sequences within RNA molecules to create taRNAs that can target PTEN, an mRNA known to act as a potent tumor-suppressor, and ABCA7, an mRNA often found to be deficient in patients with Alzheimer’s disease. After administering the taRNAs to cultured human cells, investigators found that the levels of both mRNAs had increased.

Investigators then programmed mRNAs to bind to PTEN and CDKN1A, another gene linked to tumor suppression, in a human sample of aggressive triple-negative breast cancer. Following an injection of taRNAs, tumor growth slowed by half, according to the study.

George and his collaborators then utilized the taRNAs to stimulate the production of SYNGAP1 in human neurons. SYNGAP1 is a major regulator of synaptic activity, and children born with only one functional copy of this gene suffer from epilepsy and severely impaired neurodevelopment.

Human neurons generated from patient-derived induced pluripotent stem cells in the George laboratory that received the taRNAs showed restoration of the SYNGAP1 protein to normal levels, according to the study.

The findings of the study offer a promising new strategy for treating a variety of diseases stemming from gene and protein expression insufficiency, George said.

“The fact that this approach worked in human neurons is very exciting,” George said. “There are several technologies that work in the laboratory in artificial systems, but don’t work as well in human cells. Human neurons are particularly challenging.”

The study is a great example of institutional collaboration powering new discoveries, George said.

“Faculty at Northwestern have invested a lot of effort to develop cell lines from children with rare neurogenetic and neurodevelopmental disorders, like SYNGAP1-related intellectual disability. This cell resource is a goldmine for testing novel therapeutic strategies, like the one featured in this paper,” George said.

“This study is good example of collaboration between Chicagoland institutions as well as between a chemical biologist and my laboratory, which investigates human disorders with stem cell models of the disease.”

More information:
Yang Cao et al, RNA-based translation activators for targeted gene upregulation, Nature Communications (2023). DOI: 10.1038/s41467-023-42252-z

Citation:
Novel approaches for correcting gene expression insufficiency (2023, November 17)
retrieved 18 November 2023
from https://phys.org/news/2023-11-approaches-gene-insufficiency.html

This document is subject to copyright. Apart from any fair dealing for the purpose of private study or research, no
part may be reproduced without the written permission. The content is provided for information purposes only.




Disasters Expo USA, is proud to be supported by Inergency for their next upcoming edition on March 6th & 7th 2024!

The leading event mitigating the world’s most costly disasters is returning to the Miami Beach

Convention Center and we want you to join us at the industry’s central platform for emergency management professionals.
Disasters Expo USA is proud to provide a central platform for the industry to connect and
engage with the industry’s leading professionals to better prepare, protect, prevent, respond
and recover from the disasters of today.
Hosting a dedicated platform for the convergence of disaster risk reduction, the keynote line up for Disasters Expo USA 2024 will provide an insight into successful case studies and
programs to accurately prepare for disasters. Featuring sessions from the likes of The Federal Emergency Management Agency,
NASA, The National Aeronautics and Space Administration, NOAA, The National Oceanic and Atmospheric Administration, TSA and several more this event is certainly providing you with the knowledge
required to prepare, respond and recover to disasters.
With over 50 hours worth of unmissable content, exciting new features such as their Disaster
Resilience Roundtable, Emergency Response Live, an Immersive Hurricane Simulation and
much more over just two days, you are guaranteed to gain an all-encompassing insight into
the industry to tackle the challenges of disasters.
By uniting global disaster risk management experts, well experienced emergency
responders and the leading innovators from the world, the event is the hub of the solutions
that provide attendees with tools that they can use to protect the communities and mitigate
the damage from disasters.
Tickets for the event are $119, but we have been given the promo code: HUGI100 that will
enable you to attend the event for FREE!

So don’t miss out and register today: https://shorturl.at/aikrW

And in case you missed it, here is our ultimate road trip playlist is the perfect mix of podcasts, and hidden gems that will keep you energized for the entire journey

-

This website uses cookies to improve your experience. We'll assume you're ok with this, but you can opt-out if you wish. Accept Read More