New technology is poised to bring gene therapy to common chronic diseases
New research from Penn Medicine reveals a safe delivery system of DNA-loaded lipid nanoparticles directly to cells, which could transform treatment for common chronic diseases like heart disease, diabetes, and cancer.
2 min. read
A new process that transports DNA into cells using tiny fat-based carriers called lipid nanoparticles (LNPs) has been developed by researchers at the Perelman School of Medicine. The results show improvement in the process of turning on the DNA’s instructions in animal models to make proteins inside cells, which is crucial in fighting disease. By safely delivering therapeutic DNA to cells, the treatments for common chronic diseases like heart disease, diabetes, and cancer could be transformative. The research also points to an improvement in reducing treatment risks such as immune reactions as compared to older DNA transfer techniques. The team’s findings are published in Nature Biotechnology.
The new approach builds directly on the revolutionary development of safe messenger RNA (mRNA) therapies developed at Penn. “For 20 years, DNA delivery with LNPs has been a major goal in this field,” says Jake Brenner, an assistant professor of medicine and pharmacology. “We’re picking up where mRNA left off to tackle bigger challenges.”
In their Nobel Prize-winning work, Penn’s Katalin Kariko, and Drew Weissman, showed how to modify mRNA to make it safe for delivery in the body; those approaches were applied to the life-saving COVID-19 mRNA vaccines. Since then, mRNA-based treatments have entered clinical trials for a variety of vaccines and for delivering CRISPR proteins to edit genes in rare diseases. While mRNA therapies have advanced rapidly, they have limitations for chronic conditions because mRNA breaks down quickly in the body and cannot easily target specific cell types.
Past attempts to use LNPs to deliver DNA failed because they triggered severe immune reactions. Brenner’s team discovered why previous attempts to deliver DNA using LNPs were dangerous: these particles triggered the body's internal alarm system—a defensive pathway called STING that normally helps fight infections but causes harmful inflammation when activated inappropriately.
STING detects viruses, bacteria, or damaged DNA. To counter STING-induced inflammation, researchers studied the approach Karikó and Weissman had used 20 years earlier to make mRNA delivery safe: modifying nucleotides (the building blocks of mRNA and DNA). While that approach turned out not to work for STING’s interaction with DNA, it led Brenner’s team to the key: cells produce a natural anti-inflammatory molecule called nitro-oleic acid (NOA). By adding this protective molecule to the DNA-carrying particles, the researchers completely eliminated the fatal reactions that had previously made this approach impossible.
With this advancement, treated cells produced the intended therapeutic proteins for about six months from a single dose—much longer than the few hours seen with mRNA therapies.
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