TargetGene develops more precise gene editing

Dan Weinthal and Dr. Yoel Shiboleth Photo: Haim Varsano

The Israeli company's solution takes the new CRISPR gene-cutting technology one better.

The first trial of human gene editing using the CRISPR (clustered regularly interspaced short palindromic repeats) method began last September. Both before and after that, several legal and illegal trials of this technology were conducted in China. Everyone in the genetics field knew that this would happen. CRISPR, a relatively new method of gene editing that is relatively easy to use and which has high rates of success, is the biggest hope in gene engineering for people.

At the same time, recent renewed studies show that sometimes, and perhaps always, this method also cuts genes from unintended places, and is liable to cause various diseases, including cancer, if the gene that is cut by mistake is related to cell reproduction control.

Even before they heard about CRISPR, TargetGene Biotechnologies founders COO Dan Weinthal and CEO Dr. Yoel Shiboleth worked in genetic engineering of plants. For the purpose of their work, they invented a kind of "improved CRISPR," which they say cuts more precisely. At the beginning, the company engaged in agriculture, but in recent years, with the increase in public opposition to genetic engineering of food and the renaissance in human genetic engineering following the emergence of CRISPR, they decided to focus on medical applications of their technology.

Shiboleth, a former researcher at the Agricultural Research Organization Volcani Center, also has experience in human genetics research aimed at developing drugs at companies such as Quark Biotechnology (QBI), ViroGene, and Rosetta Genomics. He met Weinthal when they were both doing post-doctorates at the University of Michigan. Weinthal has a PhD in plant editing at Tel Aviv University and did post-doctorate work at Ben Gurion University of the Negev and the University of Michigan.

"I believe that we can replace CRISPR in every trial in which it is currently used," says Shiboleth. "There are products in the market that already do genetic editing using methods that preceded CRISPR, and we don't aim to replace them. But genetic editing currently in a trial before the human stage? There's nothing to lose by checking whether our product happens to be more precise and safer."

Taking away cancer's immune system brakes

In order to understand how TargetGene's product works, Weinthal first explains what the breakthrough in CRISPR was. "The method that preceded CRISPR, which is still in use, is called Zinc Fingers (or TALENs in a slightly earlier version). The basic idea of both Zinc Fingers and CRISPR is to break DNA is a specific place using cutting enzymes. The break makes it possible to edit DNA and replace or change a defective gene.

"In Zinc Finger's method, a protein is used to detect the point where the cut has to be made, and to guide the cutting enzymes. A new protein had to be designed for every point to identify only that point. Proteins behave like a key and a lock - they will cut only where their form exactly matches the form at the desired cutting point. The failures of Zinc Fingers happened because the proteins constructed for the cutting did not always exactly match the point we wanted to cut.

"CRISPR works differently. It is a combination of a cutting protein and RNA that identifies the point. This protein isn't something that a person designed. It developed among bacteria, which use it to defend against viruses that attack them by cutting the DNA from the virus. There are many types of viruses and CRISPR is always the same protein, but the bacteria always put different RNA next to the CRISPR, which is able to cut exactly the virus that the bacteria have identified as dangerous."

Nature has provided us with genetic scissors that cut DNA at a specific point that depends on the RNA code attached to them. It is much easier to design RNA that identify a specific DNA sequence than to build a protein with exactly the right shape for this point.

The problem that is now emerging is that the DNA contains recurring sequences that appear in both the "bad" genes that we want to cut and the "good" genes that must not be cut, and it is necessary to distinguish between them.

What is different about TargetGene's method? Imagine that we want to cut, not DNA, but a report in "Globes." While CRISPR is able to cut everywhere that the word "capital" appears, TargetGene's protein cuts only where the phrase "venture capital" appears, and does the cutting at the hyphen between the two words. If we cut only when the two words appear, rather than just one, we will cut in fewer places, and only the places we want to cut.

TargetGene designed a unique protein. It does not come from nature, but like CRISPR, it contains a cutting protein that can be put next to RNA. In order to work, this protein has to identify two different sequences, and to cut only when it has identified both of them. It makes the cut at one point - exactly in the middle, between them.

"Globes": If we divide the genetic treatment world into "gene that does not work" treatments, "gene that works but not the way you want" treatments, and "gene that should not work too much" treatments, it is logical for you to be in the third category. After all, it is easier to break than to break and repair.

Shiboleth: "There are diseases in which if you succeed in preventing a gene's activity before you put a new one in, the disease should be cured. Examples include retinitis pigmentosa (RP), a large group of inherited vision disorders that can cause blindness, and achondroplasia, which causes dwarfism.

"We decided to begin with another application - gene treatment outside the body for cancer. Today, the most exciting drugs in the cancer field are checkpoint inhibitors (for example, Merck's famous Keytruda. These drugs block a receptor on immune system cells used by the cancer to put the brakes on the immune system in order to prevent the immune system from attacking the cancer.

"In principle, however, it is possible to take cells from the immune system, remove them from the patient's body, edit them so that they won't have these brakes, and put them back into the body. If the brakes are treated with drugs, more and more brake inhibitors must be taken throughout the patient's life. If the brakes are completely removed from the immune cells used by the cancer to stop the cells, it can be a one-time curative treatment." Cancer is a complicated disease, and cancer cells tend to deceive the body in more than one way, but this approach can certainly be part of the solution.

"They are already trying to do this in the market now with CRISPR, and that's great for us. As far as we're concerned, they'll open the way, and we can do it better," Shiboleth says.

"The goal - To bring the product to market"

The first investment in TargetGene was $2.1 million by Makhteshim Agan, before that company abandoned the biological aspect of pesticides in order to concentrate on the chemical aspect. The next was seeds company Monsanto, later acquired by Bayer, which invested an undisclosed amount in TargetGene and developed the products for agriculture. When TargetGene decided to focus on the medical sector, the technology was spun off to Monsanto.

TargetGene recently signed a new agreement with a global drug manufacturer. "The manufacturer doesn't necessarily intend to use this technology to manufacture drugs in its factory; it will be a distributor of our technology for companies that are its customers and want to use it for research and producing drugs. In addition to the money we got from them, we'll also get royalties from this activity," Shiboleth says. This agreement does not prevent the company from developing independent products or contracting agreements with other companies. TargetGene is currently looking for additional financing.

"My overriding goal is not to get rich, although I wouldn't mind it," Shiboleth says. "I want to bring the product to market. If our system isn't as good as CRISPR, then all right - let CRISPR win. If we're better, may CRISPR rest in peace."

Published by Globes, Israel business news - - on December 26, 2018

© Copyright of Globes Publisher Itonut (1983) Ltd. 2018

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Dan Weinthal and Dr. Yoel Shiboleth Photo: Haim Varsano
Dan Weinthal and Dr. Yoel Shiboleth Photo: Haim Varsano
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