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Swift Gene-Editing Method May Revolutionize Treatments for Cancer and Infectious Diseases

For the first time, scientists have found a way to efficiently and precisely remove genes from white blood cells of the immune system and to insert beneficial replacements, all in far less time than it normally takes to edit genes.

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Gina Kolata
, New York Times

For the first time, scientists have found a way to efficiently and precisely remove genes from white blood cells of the immune system and to insert beneficial replacements, all in far less time than it normally takes to edit genes.

If the technique can be replicated in other labs, experts said, it may open up profound new possibilities for treating an array of diseases, including cancer, infections like HIV and autoimmune conditions like lupus and rheumatoid arthritis.

The new work, published Wednesday in the journal Nature, “is a major advance,” said Dr. John Wherry, director of the Institute of Immunology at the University of Pennsylvania, who was not involved in the study.

But because the technique is so new, no patients have yet been treated with white blood cells engineered with it.

“The proof will be when this technology is used to develop a new therapeutic product,” cautioned Dr. Marcela Maus, director of cellular immunotherapy at Massachusetts General Hospital.

That test may not be far away. The researchers have already used the method in the laboratory to alter the abnormal immune cells of children with a rare genetic condition. They plan to return the altered cells to the children in an effort to cure them.

Currently, scientists attempting to edit the genome often must rely on modified viruses to slice open DNA in a cell and to deliver new genes into the cell. The method is time-consuming and difficult, limiting its use.

Despite the drawbacks, the virus method has had some success. Patients with a few rare blood cancers can be treated with engineered white blood cells — the immune system’s T-cells — that go directly to the tumors and kill them.

This type of treatment with engineered white cells, called immunotherapy, has been limited because of the difficulty of making viruses to carry the genetic material and the time needed to create them.

But researchers now say they have a found a way to use electrical fields, not viruses, to deliver both gene-editing tools and new genetic material into the cell. By speeding the process, in theory a treatment could be available to patients with almost any type of cancer.

“What takes months or even a year may now take a couple weeks using this new technology,” said Fred Ramsdell, vice president of research at the Parker Institute for Cancer Immunotherapy in San Francisco. “If you are a cancer patient, weeks versus months could make a huge difference.”

“I think it’s going to be a huge breakthrough,” he added.

The Parker Institute already is working with the authors of the new paper, led by Dr. Alexander Marson, scientific director of biomedicine at the Innovative Genomics Institute — a partnership between University of California, San Francisco and the University of California, Berkeley — to make engineered cells to treat a variety of cancers.

In the new study, Marson and his colleagues engineered T-cells to recognize human melanoma cells. In mice carrying the human cancer cells, the modified T-cells went right to the cancer, attacking it.

The researchers also corrected — in the lab — the T-cells of three children with a rare mutation that caused autoimmune diseases. The plan now is to return these corrected cells to the children, where they should function normally and suppress the defective immune cells, curing the children.

The technique may also hold great promise for treating HIV, Wherry said.

The HIV virus infects T-cells. If they can be engineered so that the virus cannot enter the T-cells, a person infected with HIV should not progress to AIDS. Those T-cells already infected would die, and the engineered cells would replace them.

Previous research has shown it might be possible to treat HIV in this way. “But now there is a really efficient strategy to do this,” Wherry said.

The idea of engineering T-cells without using a virus is not new, but the immune cells are fragile and hard to keep alive in the lab, and it has always been difficult to get genes into them.

Scientists usually introduced replacement genes into T-cells with a type of virus that was disarmed so that it would not cause disease and that can insert new genes into cells. But when these viruses insert the genes into a cell’s DNA, they do so haphazardly, sometimes destroying other genes.

“We needed something targeted, something fast and something efficient,” Marson said. “What if we could just paste in a piece of DNA and avoid the viruses altogether?”

The idea would be to slip a type of molecular scissors, known as Crispr, into cells that would slice open DNA wherever scientists wanted a new gene to go. That would avoid the problem of using a virus that inserts genes pretty much at random.

And along with the scissors, they would add a piece of DNA containing the new gene to be added to the cells.

One way to do that would be to use an electrical field to make the cells permeable. It required a herculean effort by a graduate student, Theo Roth, to finally figure out the right molecular mixture of genes, gene-editing tools and electrical fields to modify T-cells without a virus.

“He tested thousands of conditions,” Marson said.

Already the scientists are talking to the Food and Drug Administration about using the new method to precisely attack solid tumors, as well as blood cancers.

“Our intent is to try to apply this as quickly as possible,” Ramsdell said. So when they knew they had a system that worked, did they break out the champagne? Have a party?

Well, no, Roth said in an interview. He just took the data to Marson.

“We certainly had an exuberant walk to Alex’s office,” he recalled.

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