Successful class of therapeutics attack and shut down unique and harmful genes

Viruses infect the body by inserting their genetic code (RNA and DNA) into cells and multiplying. A potential class of therapeutics that uses synthetic nucleic acids to attack and shut down unique, harmful genes while still preventing viral spread is gathering momentum.

Successful class of therapeutics attack and shut down unique and harmful genes
Aaliyah Shodeinde, a fourth-year graduate researcher in the McKetta Department of Chemical Engineering working in professor and drug delivery pioneer Nicholas Peppas’ lab. Image Credit: The University of Texas at Austin.

However, only a few siRNA or other RNA interference-based therapeutics have received approval. One of the most difficult challenges is bringing the siRNA into the body and directing it to the target.

The Cockrell School of Engineering’s chemical engineering researchers hopes to address this issue while also enhancing the targeting efficacy of siRNA. The researchers developed various types of nanoparticles and tested them for their ability to deliver and defend siRNA from the body’s immune system in a recent paper published in the Journal of Controlled Release.

The human body is such a diverse place with so many systems to protect us from foreign materials. So, whenever you try to introduce a synthetically derived material, it almost immediately activates the immune system’s defenses, so you need some kind of protection for the siRNA.”

Aaliyah Shodeinde, Fourth-Year Graduate Researcher, McKetta Department of Chemical Engineering

Shodeinde is also working in professor and drug delivery pioneer Nicholas Peppas’ lab. Several types of nanoparticles developed in Peppas’ lab were successful at siRNA delivery. The researchers assessed how well the particles can take in stimuli from their surroundings, such as shifting pH levels, and respond without breaking down.

The researchers wanted to strike the right balance between siRNA safety and efficacy in silencing harmful genes while still reducing particle toxicity.

Researchers need to keep in mind that a perfect system may not be feasible at this time because of the need to find a balance with so many moving parts. What we’ve been able to achieve successfully is modulating so many different parameters to find that sweet spot.”

Aaliyah Shodeinde, Fourth-Year Graduate Researcher, McKetta Department of Chemical Engineering

Researchers are excited about siRNA because it can be fine-tuned to inhibit a wide range of genes in the body. They then directly target the mRNA (messenger RNA), which tells cells what to do.

mRNA has recently entered the popular lexicon since many COVID-19 vaccines use mRNA to instruct cells to develop antibodies to combat the coronavirus spike proteins.

Shodeinde observes that symptoms of certain disorders are caused by an excess or deficiency in proteins. siRNA can be programmed to look for genes that are responsible for this irregular protein production and, to some extent, shut them down. Traditional therapies, according to Shodeinde, are incapable of achieving this “upstream” solution.

siRNAs come in before the protein expression level, so we’re hoping that using them to alter the gene expression levels can give us better results.”

Aaliyah Shodeinde, Fourth-Year Graduate Researcher, McKetta Department of Chemical Engineering

This work builds on previous papers from Peppas’ lab that concentrated on designing nanoparticles and hydrogels for drug delivery. Peppas, Shodeinde, and Deidra Ward, a Ph.D. student in chemical engineering, published a new paper about this in Advanced Healthcare Materials just last week.

The authors explore their vision for the potential of RNA-based therapeutics in the treatment of some forms of cancers in the paper.

The results of this new research from our laboratories are promising and add on to our previous research on siRNA delivery that commenced about 10 years ago and has led to about 15 refereed publications and two issued U.S. patents,” said Nicholas Peppas, principal investigator of the siRNA paper.

The researchers’ next goal is to enhance cell targeting. It is important, according to Shodeinde, to ensure that the siRNAs only communicate with target cells and do not shut down anything else.

Source:
Journal reference:

Spencer, D. S., et al. (2021) Cytocompatibility, membrane disruption, and siRNA delivery using environmentally responsive cationic nanogels. Journal of Controlled Release. doi.org/10.1016/j.jconrel.2021.03.004.

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