Researchers at the University of Waterloo have developed a new way to prevent and treat chlamydia, the most common sexually transmitted bacterial infection in the world. The new treatment differs from the traditional antibiotic treatment as it is a type of gene therapy that is delivered via nanotechnology and is showing a 65% success rate in preventing chlamydia infection on a single dose.
“As antibiotic resistance continues to develop, people may experience chlamydia infections that cannot be treated through conventional means, which is causing increasing public health challenges,” said Emmanuel Ho, a professor at Waterloo‘s School of Pharmacy. “If left untreated or if treatment takes an extended period of time it can lead to infertility and other reproductive issues so finding new ways to treat this common infection is important.
“As the Food and Drug Administration in the US has recently approved the first siRNA-based drug for market, we’re hopeful this kind of research will be able to be widely available in the future.”
The new treatment created in Ho’s lab targets chlamydia infection by preventing the majority of bacteria from entering cells in the genital tract and destroying any bacteria that is able to penetrate a cell wall. The team was able to achieve this by using a small interfering ribonucleic acid (siRNA) to target a specific gene called PDGFR-beta in the female reproductive tract, which creates a protein that binds to chlamydia bacteria.
“By targeting PDGFR-beta we’re able to stop the creation of the protein that chlamydia will use to enter genital tract skin cells,” said Ho. “As a result, an incoming infection has fewer targets to latch onto and infection is less likely to occur.”
If chlamydia bacteria can bind to cells and enter them the nanomedicine treatment is designed to activate autophagy, a cellular process where infected skin cells are able to form a bubble around that bacteria and destroy it.
On its own, siRNA cannot enter skin cells to reduce PDGFR-beta expression and prevent chlamydia binding. The new gene therapy uses a unique nanoparticle that enables siRNA to enter the cells, reduce chlamydia’s ability to bind and destroy invasive bacteria and prevent the disease from spreading.
C. trachomatis is the most common sexually transmitted bacterial infection in the world. Although the infection can be easily controlled by the use of antibiotics, several reports of clinical isolates that are resistant to antibiotics have prompted us to search for alternative strategies to manage this disease. In this paper, we developed a nanoparticle formulation (PDGFR-β siRNA-PEI-PLGA-PEG NP) that can simultaneously induce autophagy in human cells and knock down PDGFR-β gene expression, an important surface binding protein for C. trachomatis, as a strategy to reduce vaginal infection of C. trachomatis. PDGFR-β siRNA-PEI-PLGA-PEG NP significantly induced autophagy in human vaginal epithelial cells (VK2/E6E7) 48 hr post treatment by improving autophagic degradation activity without causing inflammation, apoptosis or any decrease in cell viability. Beclin-1, VPS34 (markers for initiation stage of autophagy), UVRAG, TECPR-1 (markers for degradation stage of autophagy) were found to be significantly upregulated after treatment with PDGFR-β siRNA-PEI-PLGA-PEG NP. Furthermore, PDGFR-β siRNA-PEI-PLGA-PEG NP decreased PDGFR-β mRNA expression by 50% and protein expression by 43% in VK2/E6E7 cells 48 hr post treatment. Treatment of cells with PDGFR-β siRNA-PEI-PLGA-PEG NP significantly decreased the intracellular C. trachomatis and extracellular release of C. trachomatis by approximately 65% and 67%, respectively, in vitro through augmenting autophagic degradation pathways and reducing bacterial binding simultaneously.
Sidi Yang, Yannick Traore, Celine Jimenez, Emmanuel A Ho