Engineered mRNA turns your body into a drug-making and drug secreting biofactory to treat psoriasiform dermatitis and melanoma

Good news! This could be a very promising approach!

"Delivering genetic material tagged with a cellular “ZIP code” prompted cells to secrete proteins or drugs into the bloodstream that successfully treated psoriasis and cancer in mouse models ...
colleagues isolated a piece of mRNA that produces secretory SP derived from a protein called Factor VII that is involved in blood clotting. Next, they attached this SP-encoding mRNA fragment to four different mRNA sequences that produced various proteins: a fluorescent protein called mCherry that could provide a visual readout on whether it was secreted from cells; a human protein involved in blood production called erythropoietin; a therapeutic protein called etanercept used to treat inflammatory diseases; and another therapeutic protein called anti-PD-L1 used to treat cancer. They then packaged these modified mRNAs into lipid nanoparticles and delivered them to cells growing in laboratory dishes. Their results showed that the cells secreted SP-tagged proteins made from these mRNAs into the surrounding liquid, whereas the proteins without the secretory SP remained inside cells that received mRNAs. ..."

From the significance and abstract:

"Significance

Currently, the majority of nucleic acid–derived therapeutics are restricted to intracellular expression, thereby limiting their therapeutic potential solely to transfected cells. However, there are numerous inflammatory and autoimmune diseases that require systemic circulation of proteins, enzymes, and antibodies for therapeutic benefit. In this study, we identified a broadly applicable mechanism for inducing endogenous production and subsequent secretion of therapeutics into the bloodstream by engineering a host of different signal peptide sequences into mRNA constructs. Through this engineering approach, the body can be utilized as a bioreactor to produce and systemically secrete virtually any encodable protein that would otherwise be confined to the intracellular space of the transfected cell, thus opening up new therapeutic opportunities.

Abstract

Genetic medicines have the potential to treat various diseases; however, certain ailments including inflammatory diseases and cancer would benefit from control over extracellular localization of therapeutic proteins. A critical gap therefore remains the need to develop and incorporate methodologies that allow for posttranslational control over expression dynamics, localization, and stability of nucleic acid–generated protein therapeutics. To address this, we explored how the body’s endogenous machinery controls protein localization through signal peptides (SPs), including how these motifs could be incorporated modularly into therapeutics. SPs serve as a virtual zip code for mRNA transcripts that direct the cell where to send completed proteins within the cell and the body. Utilizing this signaling biology, we incorporated secretory SP sequences upstream of mRNA transcripts coding for reporter, natural, and therapeutic proteins to induce secretion of the proteins into systemic circulation. SP sequences generated secretion of various engineered proteins into the bloodstream following intravenous, intramuscular, and subcutaneous SP mRNA delivery by lipid, polymer, and ionizable phospholipid delivery carriers. SP-engineered etanercept/TNF-α inhibitor proteins demonstrated therapeutic efficacy in an imiquimod-induced psoriasis model by reducing hyperkeratosis and inflammation. An SP-engineered anti-PD-L1 construct mediated mRNA encoded proteins with longer serum half-lives that reduced tumor burden and extended survival in MC38 and B16F10 cancer models. The modular nature of SP platform should enable intracellular and extracellular localization control of various functional proteins for diverse therapeutic applications."

Engineered mRNA turns your body into a drug-making biofactory Engineered mRNA has turned cells into tiny biofactories, producing medications to successfully treat an inflammatory skin condition and two types of cancer, according to a new study. The tech paves the way for therapies in which patients’ bodies make their own drugs.

Bioengineering the body to make its own medicine (original news release) Signal peptide added to messenger RNA induces cells to secrete therapeutic proteins into the bloodstream, UTSW study shows

In situ production and secretion of proteins endow therapeutic benefit against psoriasiform dermatitis and melanoma (open access)

Fig. 1 Optimal signal peptides (SPs) drive protein secretion effectively following plasmid DNA (pDNA) delivery.