RNA-based technologies, such as the COVID-19 vaccine, are quickly advancing and hold promise to treat diseases ranging from inherited metabolic conditions and autoimmune disorders to cancer and cardiovascular disease.

Mass General Brigham's Gene and Cell Therapy Institute is launching the RNA Therapeutics Core to take advantage of these new technologies. This new facility will be a resource for the entire Mass General Brigham research ecosystem and beyond. The Core aims to accelerate the investigation of new targets and the translation of medicines into clinical practice by using cutting-edge RNA and lipid nanoparticle (LNP) delivery systems.

"The approved mRNA vaccines are really just the start of the next wave of RNA therapeutics that are slowly making their way toward the clinic," says Robert Alexander Wesselhoeft, PhD, who is leading the Core. "The RNA Therapeutics Core will provide high-quality, customizable, and reasonably priced long RNA to meet the needs of investigators throughout Mass General Brigham."

Fueling discovery with RNA-based materials
The RNA Therapeutics Core will support research and development across Mass General Brigham. From the very earliest stages of research, it will help fuel discovery by providing the materials researchers need to realize their vision for the biological system or therapeutic platform they want to study.

The Core will also help guide preclinical investigations, including studies in animal models. "We will produce materials at the scale and purity that's required for these studies," Dr. Wesselhoeft says.

Finally, the Core will facilitate the translation of lab discoveries into the clinic by producing good manufacturing practice-grade RNAs and LNPs at the scale needed to enable further research. This includes use in early-phase clinical trials.

A focus on circular RNA technology
One key part of the RNA Therapeutics Core's focus is the creation of circular RNAs (circRNAs).

"Circular RNAs exist naturally in everyone's body, and a few of them have been characterized to have important biological roles," Dr. Wesselhoeft says. "But the type of circular RNA we'll be making will be synthetic and optimized for specific use cases. We expect these circular RNAs to be useful for gene delivery and noncoding functions in both academic research and therapeutics, similar to plasmids, viruses, or mRNA."

Dr. Wesselhoeft explains that circRNA has the potential to improve upon mRNA in several ways. For one thing, these molecules are highly stable. They also allow for high levels of expression and the ability to encode multiple proteins in the same drug substance.

In addition, the molecules have lower levels of immunotoxicity, showing minimal cytokine responses after administration in vitro and in vivo. They also are less expensive to manufacture, due in part to a simplified process and a requirement for fewer reagents.

"We can get a lot of protein out of these molecules, sometimes much more than mRNA, depending on the target cell type," Dr. Wesselhoeft says. "This opens the door to new therapeutic approaches."

Dr. Wesselhoeft and his colleagues see many potential applications for circRNA, including improving CAR T therapies. In in vivo studies, circRNAs delivered systemically via LNPs appear to be highly potent for the expression of CARs in immune cells.

Helping to drive new therapeutic applications
With the exception of vaccines, Dr. Wesselhoeft notes, RNA technologies have not yet made it into therapeutic applications. Quality, price, potency, and manufacturing turnaround time are all factors that have historically limited the development of new RNA-based medicines at the earliest stages of research.

By making it easier to access high-quality material, Dr. Wesselhoeft hopes that researchers will explore using RNA in their research and development projects.

"There are four reasons to come to the Core: cost, quality, customization, and unique offerings," he says. "And if something is promising in preclinical models, we aim to support the next step into clinical trials as well."

The facility is scheduled to be operational in the second half of 2024.

Source:https://www.massgeneralbrigham.org/en/about/newsroom/articles/rna-therapeutics-core-to-drive-cutting-edge-research