In a new study from UT Southwestern Medical Center, researchers found that delivering genetic material with a cellular “ZIP code” prompted cells in mouse models to produce and release proteins or drugs into the bloodstream. This approach successfully treated psoriasis and cancer.
The findings in PNAS suggest future therapies where patients’ bodies make their medicines, potentially offering advantages over intravenous treatments. Daniel Siegwart, Ph.D., Professor of Biomedical Engineering and Biochemistry at UT Southwestern, highlighted the potential for patients to receive treatments less frequently, improving their quality of life.
Scientists have long explored genetic medicines, where genetic material is delivered to cells to produce proteins that replace missing or defective ones. These gene therapies are used or studied for many diseases. However, these therapies typically keep the produced proteins inside cells. Dr. Siegwart and his team aimed to change this by using signal peptides (SPs) as cellular “ZIP codes” to guide proteins where needed. They focused on secretory SPs, which direct proteins to be released from cells into the bloodstream.
They engineered mRNA fragments encoding a secretory SP from Factor VII, a protein in blood clotting. They attached them to mRNA for proteins like mCherry (for visualization), erythropoietin (blood production), etanercept (anti-inflammatory), and anti-PD-L1 (cancer treatment). Packaging these modified mRNAs into lipid nanoparticles, they successfully induced cells in lab dishes to secrete these proteins into the surrounding fluid, demonstrating a potential new approach for systemic therapy.
The researchers were inspired to explore whether the body could produce and release therapeutic proteins like a biofactory. They tested this by treating mice with psoriasis using modified mRNA for etanercept, which significantly reduced skin plaques and inflammation markers.
Similarly, treating mice with two types of cancer using modified mRNAs for anti-PD-L1 slowed tumor growth and doubled survival compared to untreated mice.
Dr. Siegwart highlighted that using the body’s processes to make and deliver therapeutic proteins could reduce side effects and improve the effectiveness of current protein drugs that require infusion. This technology also simplifies treatment schedules, reducing the need for frequent and lengthy infusions.
In the future, this technology can potentially enhance health and quality of life for patients with conditions like inflammatory diseases, cancers, clotting disorders, diabetes, and various genetic disorders.
Journal reference:
- Qiang Cheng, Lukas Farbiak, et al., In situ production and secretion of proteins endow therapeutic benefit against psoriasiform dermatitis and melanoma. PNAS. DOI: 10.1073/pnas.2313009120.