Researchers use CRISPR to penetrate solid tumors

Some cancers are difficult to treat because solid tumors surround themselves with a wall of molecular defenses that is difficult to penetrate with medicine. Now CRISPR can change that.

Researchers at UT Southwestern have found a way to use CRISPR technology to reengineer lipid nanoparticals so they can more easily penetrate the hard shells of tumors, to deliver a gene editing system that alters the DNA inside, blocking the tumor’s growth and activating the immune system.

The study, “Enhancing CRISPR/Cas gene editing through modulating cellular mechanical properties for cancer therapy,” was published in “Nature Nanotechnology.” It found the new nanoparticles stopped the growth of ovarian and liver tumors in mice.

Study leader Daniel Siegwart, associate professor of Biochemistry at UT Southwestern, said the results demonstrate the potential of CRISPR technology in the war on cancer. Researchers have used CRISPR-Cas9 technology to selectively edit the DNA inside living cells. The challenge has been to deliver CRISPR-Cas9 to solid tumors, where it can do the same.

In the new study, researchers used nanoparticles that they had optimized to travel to the liver, then added a small piece of RNA called short interfering RNA (siRNA) to shut off focal adhesion kinase (FAK), a gene that is critical to the physical defenses of a number of tumors.

Attacking FAK weakens a tumor’s barricades and makes it easier for the nanoparticles to enter. This permitted the delivery of CRISPR-Cas9 to edit the PD-L1 gene in the tumor.  PD-L1 is used by many cancers to produce PD-L1 protein, which impairs the immune system’s ability to attack tumors.

Once unimpaired, the immune system can kill cancer cells.

UT Southwestern researchers tested their improved nanoparticles in mouse models of ovarian and liver cancer. The siRNA shut down FAK, making the tumors’ defenses easier to penetrate. Then the nanoparticles reached the cells and altered the PD-L1 gene. Ultimately, researchers found that tumors in the treated mice shrank to about one-eighth the size of untreated mice. An increase in immune cells in these mice also helped them live twice as long as the untreated mice.

The study demonstrates that the effectiveness of new therapies depends on how well they can be delivered to the target tissue. Researchers’ use of LPN technology as a delivery system opens exciting possibilities for medicine.