Scientists at Tel Aviv University (TAU) report that the CRISPR/Cas9 system is effective in treating metastatic cancers, which they say marks a significant step on the way to finding a cure for cancer. The researchers developed a lipid nanoparticle-based delivery system that specifically targets cancer cells and destroys them by genetic manipulation. The CRISPR-LNPs system carries a messenger RNA which encodes for the CRISPR enzyme Cas9 that acts as molecular scissors that cut the cells’ DNA.

The work was conducted in the laboratory of Dan Peer, PhD, VP for R&D and Head of the Laboratory of Precision Nanomedicine at the Shmunis School of Biomedicine and Cancer Research at TAU. The research was conducted by Daniel Rosenblum, PhD, together with PhD student Anna Gutkin and colleagues in Peer’s laboratory and other collaborators.

The study “CRISPR-Cas9 genome editing using targeted lipid nanoparticles for cancer therapy” appears in Science Advances.

“Harnessing CRISPR-Cas9 technology for cancer therapeutics has been hampered by low editing efficiency in tumors and potential toxicity of existing delivery systems. Here, we describe a safe and efficient lipid nanoparticle (LNP) for the delivery of Cas9 mRNA and sgRNAs that use a novel amino-ionizable lipid,” write the investigators.

“A single intracerebral injection of CRISPR-LNPs against PLK1 (sgPLK1-cLNPs) into aggressive orthotopic glioblastoma enabled up to ~70% gene editing in vivo, which caused tumor cell apoptosis, inhibited tumor growth by 50%, and improved survival by 30%. To reach disseminated tumors, cLNPs were also engineered for antibody-targeted delivery. Intraperitoneal injections of EGFR-targeted sgPLK1-cLNPs caused their selective uptake into disseminated ovarian tumors, enabled up to ~80% gene editing in vivo, inhibited tumor growth, and increased survival by 80%.

“The ability to disrupt gene expression in vivo in tumors opens new avenues for cancer treatment and research and potential applications for targeted gene editing of noncancerous tissues.”

“This is the first study in the world to prove that the CRISPR genome editing system can be used to treat cancer effectively in a living animal,” said Peer. “It must be emphasized that this is not chemotherapy. There are no side effects, and a cancer cell treated in this way will never become active again. The molecular scissors of Cas9 cut the cancer cell’s DNA, thereby neutralizing it and permanently preventing replication.”

To examine the feasibility of using the technology to treat cancer, Peer and his team chose two of the deadliest cancers: glioblastoma and metastatic ovarian cancer. Glioblastoma is the most aggressive type of brain cancer, with a life expectancy of 15 months after diagnosis and a five-year survival rate of only 3%. The researchers demonstrated that a single treatment with CRISPR-LNPs doubled the average life expectancy of mice with glioblastoma tumors, improving their overall survival rate by about 30%.

Ovarian cancer is a major cause of death among women and the most lethal cancer of the female reproductive system. Most patients are diagnosed at an advanced stage of the disease when metastases have already spread throughout the body. Despite progress in recent years, only a third of the patients survive this disease. Treatment with CRISPR-LNPs in a metastatic ovarian cancer mice model increased their overall survival rate by 80%.

“The CRISPR genome editing technology, capable of identifying and altering any genetic segment, has revolutionized our ability to disrupt, repair or even replace genes in a personalized manner,” continued Peer. “Despite its extensive use in research, clinical implementation is still in its infancy because an effective delivery system is needed to safely and accurately deliver the CRISPR to its target cells. The delivery system we developed targets the DNA responsible for the cancer cells’ survival. This is an innovative treatment for aggressive cancers that have no effective treatments today.”

The researchers note that by demonstrating its potential in treating two aggressive cancers, the technology opens numerous new possibilities for treating other types of cancer as well as rare genetic diseases and chronic viral diseases such as AIDS.

“We now intend to go on to experiments with blood cancers that are very interesting genetically, as well as genetic diseases such as Duchenne muscular dystrophy,” explained Peer. “It will probably take some time before the new treatment can be used in humans, but we are optimistic. The whole scene of molecular drugs that utilize messenger RNA is thriving…in fact, most COVID-19 vaccines currently under development are based on this principle.”

“When we first spoke of treatments with mRNA twelve years ago, people thought it was science fiction. I believe that in the near future, we will see many personalized treatments based on genetic messengers—for both cancer and genetic diseases. Through Ramot, the Technology Transfer Company of TAU, we are already negotiating with international corporations and foundations, aiming to bring the benefits of genetic editing to human patients.”

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