SuppliedThe liver often detects and degrades genetic drugs, preventing these drugs from reaching the target organ. A new genetic drug delivery system can avoid detection by the liver, delivering genetic drugs more effectively to the target location.
Dr. John Lewis, an oncology professor in the University of Alberta faculty of medicine and dentistry, is a principal investigator on the study detailing the new drug delivery platform. Dr. Lewis’ lab has identified genes involved in cancer progression and aims to develop genetic medicines to modify these genes.
“The issue is that the liver is fantastically evolved to detect things that aren’t supposed to be in the body and to suck them up and degrade them,” Dr. Lewis said.
The foreign materials detected by the liver are deoxyribonucleic acid (DNA) and ribonucleic acid (RNA). DNA and RNA are incorporated into genetic drugs in order to fix or replace faulty genes. According to Dr. Lewis, once injected into the blood, the DNA and RNA largely end up in the liver without reaching the target organ. This is due to the current genetic drug delivery platform which utilizes lipid nanoparticles (LNPs).
LNPs shield injected genetic material from liver detection
“LNPs are formulated with about 40 per cent cholesterol,” which is “pretty much controlled by the liver,” Dr. Lewis said. Although cholesterol poses a challenge, it allows the genetic material to enter target cells via endocytosis — when a cell swallows the drug.
Dr. Lewis’ team has developed Fusion Associated Small Transmembrane Proteolipid Vehicles (FAST-PLV), a genetic drug delivery platform to replace LNPs. FAST-PLV utilizes FAST proteins from a virus discovered by a Dalhousie University virologist, Roy Duncan. These FAST proteins are combined with fat molecules to create the FAST-PLV drug delivery platform.
“What we found is that if you put [the FAST protein] into lipid particles, it caused [the drug] to fuse directly with any cell and then dumped the DNA or RNA inside that cell,” Dr. Lewis said. Given that the genetic materials are dumped into the cell, and not engulfed, “they’re basically invisible to the liver.” This removed the need for high amounts of cholesterol found in LNPs.
Another benefit of the FAST-PLV platform not being engulfed is the ability to evade the immune system. The immune system, like the liver, also detects injected RNA or DNA as foreign material and proceeds to degrade it. However, the FAST-PLV platform prevents this.
According to Dr. Lewis, when the immune system identifies genetic material in these drugs, it “send[s] out emergency signals that there’s a foreign pathogen.” The FAST-PLV platform can avoid that because the platform fuses with the cells rather than becoming engulfed by the cells.
Applications of the FAST-PLV genetic drug delivery system
To assess the effectiveness of the FAST-PLV platform, the platform was used to alter muscle development in mice. A gene that causes Belgian blue cows to have enhanced muscularity was injected into mice with the FAST-PLV platform. Over six to eight months, Dr. Lewis observed a “50 per cent weight gain in these mice that was all muscle.” Their grip strength also roughly doubled.
Given the success with muscle development, Dr. Lewis believes FAST-PLV could potentially boost muscle growth in aged individuals with frailty.
Dr. Lewis’ company, Entos Pharmaceuticals, uses this new drug platform in its COVID-19 vaccine booster, Covigenix VAX-002. The team is also working on treating genetic disorders such as cancer and cystic fibrosis with the FAST-PLV platform. According to Dr. Lewis, the FAST-PLV platform could lead to potential cures or long-term treatments for various diseases.
