Technologies like CRISPR that alter a patient’s DNA to treat disease are transforming medicine, but a little-known roadblock could slow the revolution.
To insert new, potentially life-saving DNA inside the body’s cells, doctors typically rely on bespoke viruses manufactured in a few specialty labs that are frequently backlogged amid surging demand.
Researchers have been on the hunt for an alternative way to ferry DNA into cells. A new paper published Wednesday in the journal Nature presents an alternative method for T-cells, the infection-fighting cells at heart of the breakthrough cancer treatments known as CAR-Ts. If it pans out, this technique could make therapies faster and cheaper to develop -- and potentially more effective.
“It’s not the sexy part of the process, but it’s really important to get right,’’ said Fred Ramsdell , vice president of research at the Parker Institute for Cancer Immunotherapy in San Francisco. “While CRISPR is great and our ability to do gene editing is going to change humanity, you still have to get it into the cells.’’
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It might seem odd to use a virus to treat patients, but viruses are in fact masters at getting past the natural defenses of our cells. The bespoke viruses produced in specialty labs are known as viral vectors: typically disabled, they’re used to insert genetic code.
In the paper published in Nature, researchers at the University of California, San Francisco, put T-cells along with the desired new DNA and the gene-editing tool CRISPR-Cas9 together in a tiny well. The cell membrane is broken down with an electrical charge, allowing CRISPR to target the T-cell genome and insert new genetic code.
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In one experiment, the scientists genetically altered T-cells from three children with a mutation connected to a rare autoimmune disease. In vitro, they were able to repair the T-cell mutation that causes the disease. In another experiment, they were able to create new T-cell receptors that could home in on cancer cells and kill them.
“It’s kind of a plug-and-play system,” said Theo Roth, an M.D.-Ph.D. student in immunology at UCSF’s Marson Laboratory, who came up with the concept and is the lead author of the paper. “Doing this nonvirally is going to be quicker, faster, and more reliable but we also need to show it’s clinically relevant.”
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The method is early-stage, but the impact could be important for the novel CAR-T therapies, which have shown dramatic results for some patients with deadly blood cancer but had toxic side effects for others.
CAR-Ts -- only two have been approved so far from drugmakers Novartis AG and Gilead Sciences Inc. -- work by engineering a T-cell to attack a specific target. When using a virus to deliver new DNA, the cancer therapy adds a receptor telling the T-cell to kill the tumor, keeping the original receptor in place. If the two receptors interfere with each other, it could mean problematic side effects.
The UCSF method swaps out the old receptor for a new one, eliminating that risk.
“If confirmed and extended in future studies, it represents a big step forward: faster, more flexible, enabling larger DNA sequence editing, and accomplish all of this potentially more safely,” said Eric Topol , a geneticist at Scripps Research Institute in La Jolla, California, who wasn’t affiliated with the study.
Previous attempts to use CRISPR without a viral vector to alter a genome were only able to encode very short pieces of DNA, not enough to encode a protein.
“The amazing thing is we’ve been able to engineer T-cells to do things we couldn’t get them to do otherwise,” said E. John Wherry , director of the Penn Institute for Immunology in Philadelphia, a leader in CAR-T research.
Finding cheaper alternatives to viral vectors could have a major impact on production costs.
Oxford BioMedica Plc, a U.K. company, is the sole manufacturer of the viral vector that encodes Novartis’s Kymriah therapy -- the first ever CAR-T to be approved, with a list price of $475,000. Novartis said that under their July 2017 contract, Oxford BioMedica could receive as much as $100 million over the next three years for Kymriah and other CAR-T products, plus royalties on future sales.
“I would not be surprised if 10 or 20 percent of the drug cost was in the viral vector,” said Penn Institute’s Wherry. Novartis declined to comment on his estimate.
At viral-vector maker MilliporeSigma, business is booming, and its chief executive officer is unfazed about the possible competition from other methodologies.
“While this technique has much promise, there is still some way to go,” said Udit Batra, CEO of MilliporeSigma, a unit of German pharmaceutical company Merck KGaA. MilliporeSigma recently doubled capacity and has been working to make the customization process more efficient in order to meet high demand, he said.
Meanwhile at the Parker Institute, the preparation for a clinical trial to test an immunotherapy for an aggressive childhood brain cancer has run into a deadlock. The contractor who manufactures the therapy’s bespoke virus said it could take a year to make.
With a different methodology, children could get the experimental therapy sooner, said Ramsdell, the institute’s vice president of research.
“Some patients will never get the chance to try this treatment,’’ Ramsdell said.
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