A team of researchers has established a ribonucleic acid (RNA)-based method that causes the body’s cells to produce therapeutic proteins and secrete them into the bloodstream. The approach could potentially extend the lifespan of drugs in the body, reducing the burden for patients who require frequent drug administrations.
The researchers, based at UT Southwestern Medical Center, took advantage of a natural biomolecule called a signal peptide that determines where cells send proteins (acting as a shipping label) to release proteins into the blood that would normally remain in the cell. In a report published in Proceedings of the National Academy of SciencesThe new approach enabled secretion and increased circulation time of a therapeutic protein compared to standard injections in a mouse model of psoriasis, demonstrating beneficial effects in these mice and, separately, in animal models of cancer.
The modular nature of the technique suggests that it could be adapted to address a wide range of diseases.
“This could potentially be a powerful technological platform. By linking a signal peptide to any particular protein (insulin for patients with diabetes, for example), you could very easily adapt this technique to different diseases,” said Jermont Chen, Ph.D., program director in the Division of Discovery Science and Technology at the National Institute of Biomedical Imaging and Bioengineering (NIBIB).
messenger RNAor mRNA, is a biomolecule that provides instructions for cellular machinery to produce proteins. Scientists have managed to introduce mRNA into the body so that cells produce specific proteins, as occurs with mRNA vaccines. But with this approach, the proteins often become trapped inside the cell. For autoimmune disorders, some cancers, and many other diseases, therapeutic proteins work best when they circulate throughout the body through the bloodstream.
Seeking to bring therapeutic proteins out of their cellular confines, Daniel Siegwart, Ph.D., professor of biomedical engineering and biochemistry, was inspired by natural proteins normally found in the bloodstream.
Blood proteins produced by the liver have small structures at their ends called signal peptides, which determine the fate of a protein. Some of these peptides instruct cells to transport proteins to the cell membrane or nucleus, while others cause proteins to be delivered to a cellular organelle called the endoplasmic reticulum (ER), where they are prepared for release into the circulation.
“We wanted to know if we could copy and paste specific signal peptides from secreted proteins to other proteins that normally remain in the cell, to get them into the bloodstream. If that was feasible, then we could create a factory in the body to produce and secrete drugs,” said Siegwart, corresponding author of the study.
The study authors designed mRNA sequences that would attach a signal peptide from a blood clotting protein to the ends of other proteins. They packaged sequences into special nanoparticles that the team previously designed to deliver mRNA to the liver.
In a series of experiments, the authors tested their approach, called Signal Peptide Engineered Nucleic Acid Design, or SEND, in mice with a psoriasis-like skin condition.
Psoriasis can be treated with an injection of a synthetic protein called etanercept. To evaluate their SEND platform, the researchers generated an mRNA construct that directed cells to produce a version of etanercept that includes a signal peptide to navigate the secretion process through the ER. Once the therapeutic protein reaches the ER, the signal peptide is cleaved, allowing the cell to release an identical version of the drug etanercept into the bloodstream.
For comparison, the researchers injected etanercept intravenously into one group of mice and DELIVERED mRNA-filled nanoparticles into another group. They then recorded how long the protein remained in each group’s blood.
They found that when injected directly, the protein circulated for less than 24 hours, while proteins produced through SEND lasted almost a week. During the experiment, the animals’ own cells produced about 12 times more etanercept than the amount injected into the mice in the other group.
The skin of mice treated with SEND also recovered significantly compared to the skin of animals that received nanoparticles carrying the signal peptide but not the therapeutic protein.
In another series of experiments, the authors tested the effects of SEND in mouse models of two different types of cancer, adenocarcinoma and melanoma. This time, they linked the same signal peptide to the anti-cancer drugPDL1.
Compared to treatment with nanoparticles that lacked the mRNA to produce the drug, full SEND treatment reduced tumor growth and extended the animals’ survival for both types of cancer.
Now, the authors have their sights set on additional applications, such as enzyme replacement therapy and larger animal models to bring the SEND platform closer to the clinic.
“We imagine that, if translated to humans, this platform could allow someone to receive anti-inflammatory medications once a month instead of a few times a week, for example,” Siegwart said. “And since the COVID-19 vaccine established a new healthcare delivery model for mRNA-based drugs, all of this could be done in the pharmacy or at home.”
This research was supported by grants from NIBIB (R01EB025192) and the National Cancer Institute (P30CA142543).
This prominent scientist describes a basic research finding. Basic research increases our understanding of human behavior and biology, which is critical to promoting new and better ways to prevent, diagnose, and treat diseases. Science is an unpredictable and incremental process: each research advance builds on past discoveries, often in unexpected ways. Most clinical advances would not be possible without knowledge of fundamental basic research.
Study reference: Qiang Cheng et al. The in situ production and secretion of proteins confer a therapeutic benefit against psoriasiform dermatitis and melanoma. Proceedings of the National Academy of Sciences. DOI: 10.1073/pnas.2313009120
