Bioengineering the Body to Make its Own Medicine

BioTech INSIDER

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. The findings could lead to new therapies in which patients’ bodies produce their own drugs, avoiding the drawbacks of many intravenously administered medicines.

The researchers ooked to signal peptides (SPs to direct proteins produced from genetic material to where they are needed. Although most known SPs direct proteins to organelles within cells, some — called secretory SPs — cause proteins to be secreted from cells into systemic circulation.

They 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.

This observation inspired the researchers to examine whether the body could serve as a biofactory to produce and secrete therapeutic proteins. Indeed, when the researchers treated mice with psoriasis with the modified mRNA coding for etanercept, the psoriasis plaques in their skin were significantly decreased, as were molecular markers for inflammation. Similarly, when the researchers treated mice bearing two types of cancer with modified mRNAs coding for anti-PD-L1, tumor growth was significantly decreased, and the mice survived twice as long as those that were not treated.

According to the researchers, using the body’s own machinery to make and deliver therapeutic proteins may help to overcome side effects and increase the efficacy of protein drugs that currently must be delivered by infusion. It could also decrease the hassle of having to receive frequent and sometimes lengthy infusions. Using this technology to produce these drugs within the body could eventually improve health and quality of life for patients with inflammatory diseases, cancers, clotting disorders, diabetes, and a range of genetic disorders.

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