Small balls of minerals are a better vehicle to promise mRNA-based therapies

Reviewed by Emily Henderson, B.Sc.July 2, 2020

Researchers at the University of Wisconsin-Madison have developed safer and more efficient methods that offer promising new methods for the treatment and vaccination of cancer and liver disorders. It contains the COVID-19 vaccine from Moderna Therapeutics and is in clinical trials in humans.

This technique relies on the insertion of carefully designed fragments of messenger RNA (mRNA) into cells. It’s a strip of genetic material that human cells normally transcribe from human DNA to make useful proteins and drive your business. While the problem of delivering mRNA safely and unharmed without adversely affecting the immune system has hampered mRNA-based therapies, UW-Madison researchers say a small ball of minerals that appears to do the trick in mice. Is making.

The surface of these particles has nanometer-scale pores that can pick up and carry molecules such as proteins and messenger RNA. When found intact proteins and DNA in thousands of years old bone samples and eggshells, they mimic what is often found in archeology. The mineral components helped to stabilize those molecules much more. “

William Murphy, Professor of Biomedical Engineering and Orthopedics, UW-Madison

Murphy and UW-Madison collaborators used mineral-coated microparticles (MCMs) in a series of experiments to deliver mRNA to cells around wounds in diabetic mice (MCMs) were 5-10 micron in diameter. In meters, about the size of a human cell. Wounds healed faster in MCM-treated mice, and cells in relevant experiments showed much more efficient pick-up of mRNA molecules than other delivery methods.

Researchers explained today’s findings in the journal Scientific progress..

In healthy cells, DNA is transcribed into mRNA, which acts as a command that the machinery of the cell uses to make proteins. Lab-created mRNA strips can be replaced by a process that tells cells to make something new. If something is a molecule that alerts the immune system to the presence of a particular type of antigen, a potentially harmful virus, the mRNA serves as a vaccine.

UW-Madison researchers have coded mRNAs with instructions that direct cellular ribosomes to export growth factors. Growth factors promote a healing process that is otherwise slow-developed or absent in diabetic mice (and many people with severe diabetes).

Although mRNAs are short-lived in the body, adequate delivery to cells usually means that the mRNA strands are frequently given in large doses carried by containers made of molecules called cationic polymers.

“In many cases, the cationic component is toxic. The more mRNA, the more therapeutic effect you will get, but the more likely you are to have a toxic effect. That’s a trade-off,” Murphy said. Says. .. What we found is that when delivered from MCM, it is not toxic. In addition, MCM delivery prevents mRNA degradation, allowing you to get more mRNA where you need it while reducing toxic effects. “

The new study also combined mRNAs with immune system inhibitory proteins to prevent target cells from taking the mRNA as a foreign substance, destroying or excreting it.

Normally, upon successful delivery of mRNA, cells continue to work for about 24 hours according to new instructions, and the molecules they produce are dispersed throughout the body. That is enough for vaccines and the antigens they produce. To maintain long-term processes such as the growth of tissue substitutes and the healing of skin and organs, the proteins or growth factors produced by the cells need to stay much longer.

“What I saw in MCM is that as cells take up mRNA and begin to make proteins, the proteins bind immediately within the MCM particles,” Murphy says. “Then it will be released in the next few weeks. Basically, I usually take something that lasts for hours or a day, and it lasts for a long time.”

Also, the MCM is large enough that it doesn’t enter the bloodstream and doesn’t float, so it stays where it’s needed to continue to release useful treatments. In mice, its therapeutic activity lasted for more than 20 days.

“They are made of tooth enamel and minerals that resemble bones, but are designed to be reabsorbed by the body when it becomes useless,” says the Environmental Protection Agency, National Institutes of Health, Donations from National Science Foundation and UW-Madison graduates Michael and Mary Sue Shannon.

“Adjusting the manufacturing process controls the lifespan so it can be harmlessly dissolved when needed.”

The technology behind the particles is patented with the support of the Wisconsin Alumni Association and licensed to Murphy’s co-founded company Dianomy Therapeutics.

Researchers are currently working on bone and cartilage growth and repair of spinal cord injury by mRNA delivered by MCM.