I first wrote about CRISPR here in 2017. We are used to medical hyperbole and hype failing to materialize, but at the time I characterized CRISPR as having legitimate promise as a game-changing medical intervention. It’s still early days in this technology, but advances are moving fast. A recent study looking at CRISPR in the treatment of cancer gives a good indication of how useful this technology can be.

For a quick overview, CRISPR stands for Clustered Regularly Interspaced Short Palindromic Repeats. They are a technology borrowed from certain bacteria that use the technique as part of their immune response to viruses. Researchers realized that we could use CRISPR for genetic engineering – to cut or insert DNA in a targeted location in the genome. The Cas9 enzyme is what cuts the DNA, while the CRISPR portion contains a targeting sequence that binds to the desired location on the DNA and also includes the sequence that you want inserted. This is referred to as the CRISPR-Cas9 system. I will note that there are other enzymes that can be used also, but for now Cas9 is the most common.

The applications of this technology are many, the most obvious being in genetics research and genetic engineering. The CRISPR-Cas9 system is fast, easy, and cheap, which allows many research labs to use it, promising to accelerate the pace of genetics research.

What still remains unknown is how this technology will translate to direct medical applications. Perhaps the most obvious such application is in fixing genetic errors, but there are a couple of limiting factors. One is the issue of off-target changes. How often does CRISPR target the wrong part of the DNA? This is a concern, but researchers are quickly figuring out how to minimize off-target effects, and how to trade speed for accuracy.

Another limiting factor is getting CRISPR-Cas9 into live cells, but only the cells you want. This was the problem that the current study sought to overcome, and that is really the new technology they are introducing. If we could get CRISPR into only cancer cells, for example, we could use it to kill those cancer cells while leaving healthy cells alone. Existing targeting systems used to deliver chemotherapy to cancer cells cannot handle the large size of the CRISPR-Cas9, and have limited penetrance – they don’t get into enough of the target cancer cells.

Their solution was to use lipid nanoparticles. They write:

Lipid nanoparticles (LNPs) are clinically approved nonviral nucleic acid delivery systems capable of delivering potentially such large payloads. Cationic ionizable lipids are the key component of LNPs that enables efficient nucleic acid encapsulation, cellular delivery, and endosomal release.

They had to modify the LNPs to deliver a larger molecule and to be able to deliver the payload into many different tissue types. The CRISPR itself is targeted at tumor survival genes. Disrupting these genes should cause the cancer cell to at least stop replicating and also hopefully die and undergo apoptosis. To study their new LNP delivery system with CRISPR-Cas9 targeting tumor survival genes, they studies glioblastoma and ovarian cancer in mice. What they found was extremely encouraging.

Glioblastoma is the most aggressive form of brain cancer, with a mean survival of about 15 months. This cancer has proven very resistant to treatments with chemotherapy and radiation and are not resectable because of the way they invade throughout the brain. The researchers deliberately targeted glioblastoma for this reason. They performed a single injection of the LNPs with the CRISPR-Cas9 payload into the brains of mice with glioblastoma. The found:

…up to ~70% gene editing in vivo, which caused tumor cell apoptosis, inhibited tumor growth by 50%, and improved survival by 30%.

If that translates to humans, it is an impressive result. It is not a cure, which is true of all new anti-cancer treatments, but this would contribute significantly to the steadily-increasing survival of cancer patients.

They also studied ovarian cancer and found:

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%.

That is even more impressive. Of course I have to emphasize that this was a study in mice, not people. It is also a first study of this technology and has to be replicated and expanded. But it is difficult to overhype how significant these results are. They show the potential of the combination of LNPs to deliver CRISPR-Cas9 to targeted cells. They plan next to test this approach in blood borne cancer. Hopefully they will be able to continue to tweak the technology to get further uptake in the target cells.

The study also found that the LNP system was safe and did not provoke a host immune response. Further, because the treatment itself is not chemotherapy, overall the side effects were minimal, and there is no expectation that the tumor will be able to develop resistance. Evolving resistance to each round of chemotherapy is one of the greatest limiting factors in targeted chemotherapy – but there is no resistance to having your DNA sliced up.

The researchers also emphasize that this system of LNPs delivering CRISPR-Cas9 is not specific to cancer type or to cancer itself. Once the basic technology is perfected, it can be applied to other cells types. It could be used, for example, to target infectious organisms. I can imagine that bacterial sepsis (blood infection) would be a likely application.

In short, this is an incredibly promising new approach to treating cancer, including the worst types of solid tumors that currently have a poor prognosis. To balance the hype, however, we need to keep in mind that there is a lot of clinical research between this potential treatment and use on actual patients in the clinic. It will be years before these treatments get approval, and that is if everything goes well.

But I do think the strong probability is that this or something like this will eventually be used to treat cancer. It represents a new treatment paradigm that will be complementary to existing treatments, and has the potential to significantly improve cancer survival in many types of cancer.


Posted by Steven Novella

Founder and currently Executive Editor of Science-Based Medicine Steven Novella, MD is an academic clinical neurologist at the Yale University School of Medicine. He is also the host and producer of the popular weekly science podcast, The Skeptics’ Guide to the Universe, and the author of the NeuroLogicaBlog, a daily blog that covers news and issues in neuroscience, but also general science, scientific skepticism, philosophy of science, critical thinking, and the intersection of science with the media and society. Dr. Novella also has produced two courses with The Great Courses, and published a book on critical thinking - also called The Skeptics Guide to the Universe.