A gene therapy designed to fight pulmonary fibrosis (PF) by extending the lifespan of lung cells has been found safe and does not cause or increase the risk of cancer in the lungs, despite some concerns to the contrary, a mouse study shows.
Earlier this year, a research team at the Spanish National Cancer Research Centre (CNIO), led by molecular biologist Maria A. Blasco, PhD, developed a gene therapy for PF that treats the disease as age-related. The therapy is based on the reactivation of the telomerase gene.
Activation of the telomerase gene has the potential to promote cancer, which is why CNIO researchers set out to prove this is not the case with their gene therapy.
The study, “AAV9-mediated telomerase activation does not accelerate tumorigenesis in the context of oncogenic K-Ras-induced lung cancer,” was published in the journal PLOS Genetics.
Telomeres are protein structures located at the end of the tip of chromosomes, and are known as the cell’s clock since they keep track of cell division and lifespan. Specifically, telomeres work as caps that protect the chromosomes from damage, similar to the aglets at the end of shoelaces.
As time goes by, though, telomeres are shortened and lose their protective ability. The outcome is that chromosomes are no longer protected and begin to accumulate damages in each cell division. Eventually, the cells stop dividing, halting regeneration and triggering aging.
PF is one of the diseases linked to this telomeric shortening, with patients having shorter telomeres.
The gene therapy developed by the CNIO researchers activates the enzyme telomerase that works to repair and increase the length of telomeres. In a previous study, they showed that the therapy was able to improve lung function and reduce inflammation and fibrosis in a PF mouse model.
To introduce the telomerase gene into lung cells, the gene therapy uses the AAV9 viral vector, a virus modified to be harmless to humans. However, activating telomerase is also one of the mechanisms cancer cells use to be able to grow continuously.
The AAV viral vector used is not able to penetrate the cell’s DNA — doing so would allow it to be permanently maintained throughout the cell division process — which means that the telomerase activation is limited to a few rounds of dividing cells.
With each cell division, bits of the vector are loss, and after a few rounds it disappears, minimizing the risk for cancer development.
However, to really assess the gene therapy’s cancer-associated risk, CNIO researchers have now tested it in a mouse model of human lung cancer, which was generated to completely lack the TP53 gene, one of the most important tumor suppressors in the genome, and to have a cancer-promoting gene (known as oncogenes) called K-RAS activated.
“In our research, we were already seeing that this gene therapy does not increase the risk of cancer, but we wanted to conduct what is known as a ‘killer experiment,’ an experiment that creates the worst conditions for your hypothesis to hold true; if it survives even under those circumstances, the hypothesis is truly solid,” Blasco said in a press release.
“That is why we chose these mice; they are animals that spontaneously develop a type of lung cancer that is very similar to the human form, which normally never appears in normal mice. We can’t think of any other experiment that would provide a better demonstration of the safety of this therapy,” she said.
Mice received one injection of the gene therapy. Results showed that the telomerase-activating gene therapy had no effect (either increased or decreased) on the onset or progression of lung cancer in this mouse model.
“These findings suggests that gene therapy with telomerase appears to be safe, even in a pro-tumor context,” Blasco said.
Overall, the “findings expand on the safety of AAV-mediated telomerase activation as a novel therapeutic strategy for the treatment of diseases associated to short telomeres,” the team concluded in the study.