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Amid Nobel Prize Suspense, Making Sense Of Latest Gene-Editing News

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on making cells more amenable to recombination, things that “are too early to share.”

Many others are working on it, too. One group just made a big splash. Late last week, scientists at Seattle Children’s Research Institute and other Seattle-based entities published work that might make recombination a lot easier in an important subset of cells. SCRI pediatrician and immunologist Andrew Scharenberg and colleagues discovered that a workhorse of gene therapy—the adeno-associated virus (AAV), transformed into a gene delivery vehicle—is very good for shuttling genes into T cells and perhaps hematopoietic stem cells (HSCs). It was once generally considered too difficult, because those cells divide quickly, which would “wash out” the genetic material delivered by the invasive virus. They also defend themselves well against viral invaders.

The Seattle team was looking for a way to add new functions to T cells, a hot topic right now thanks to the early success of experimental T cell therapies, called CAR-T, for blood-borne cancers. T cell manipulation could also open up possibilities of using modified T cells in other cancers, autoimmune diseases, and—a primary focus of the Seattle Children’s team—making organ transplants easier and safer.

But nothing was working. “We had run out of ideas,” says Scharenberg. So they turned to AAV, which was long known to be an agent for splicing and mixing genes—but not in the cells Scharenberg’s group wanted to modify. They tested a panel of different forms of AAV, including new ones developed in recent years. They also made improvements to the gene they wanted to splice in—a piece of code called a promoter that helps the cell stitch the new gene into its DNA.

“We’ve demonstrated that it works in T cells,” says Scharenberg, adding that there’s still more work to show the same results in HSCs.

“It’s very exciting work,” says Jacob Corn, scientific director of the Innovative Genomics Initiative in Berkeley, CA (which was cofounded by Jennifer Doudna). IGI scientists are working on a gene editing treatment for sickle cell disease, as I reported this summer. They’re extracting HSCs from mice with an approximate version of the disease; using CRISPR/Cas9 to replace the faulty hemoglobin gene with a healthy one; and putting the edited cells back in the bone marrow. Data from the mouse study should be ready in five weeks and perhaps point toward a human clinical trial. Corn wants to see how Scharenberg’s team builds upon the HSC work, “but the approach looks very promising.”

Renier Brentjens, the director of cellular therapeutics at Memorial Sloan Kettering Cancer Center in New York, called the paper “beautiful” but had reservations. He has been modifying T cells with other forms of viral manipulation to make CAR-T therapies—Juno Therapeutics (NASDAQ: JUNO) has license to them—and “right now our cells work,” says Brentjens, using a gene transfer process as efficient as what Scharenberg and colleagues reported. His main worry is that the AAV method will take too long, leaving the cells in culture until they lose their potency or die, like a patient whose drawn-out surgery proves too traumatic.

Scharenberg acknowledges the time problem, but says “lots of labs” will work on making the process more efficient. In part, that’s because all are free to tinker with it. His team’s insights were based on a lot of other work hiding in plain sight, especially that of Arun Srivastava at the University of Florida. “The IP for AAV has been around so long, there’s not a lot of ground to grab,” said Scharenberg. “This is an advance that everyone will be able to adopt.”

—Steps Toward Human Testing: As IGI waits to see if its sickle cell work can become an experimental treatment, other groups are moving gene editing treatments toward the clinic. Editas is working on sickle cell disease, too, but its officials have spoken with greater detail about a program to treat a rare form of blindness, leber congenital amaurosis—taking care to say it’s not necessarily their lead program. Intellia Therapeutics, also in Cambridge, is working with Novartis on CAR-T cell therapies and genetic blood disorders.

Editas, Intellia, and a third company, CRISPR Therapeutics, have raised hundreds of millions of dollars in private funding as they race to the clinic with therapies created with CRISPR/Cas9.

For clinical work, however, CRISPR/Cas9 is well behind zinc finger nucleases, which are owned by Sangamo. As noted, Sangamo has already reached the clinic with an HIV treatment. At the National Academy meeting Monday, Sangamo’s Urnov outlined what would be another milestone: the first gene editing treatment where the editing happens without first removing the cells from the patient.

Sangamo has received a green light from a National Institutes of Health advisory committee to start a trial in hemophilia B patients. Despite losing its development partner Shire last month, the company still plans to ask for the FDA’s permission by the end of the year, Urnov said, which means a trial could start in 2016. (For more on the competition to treat hemophilia with gene therapy and gene editing, read Ben Fidler’s March feature.)

Sangamo also has sickle cell and beta-thalassemia programs partnered with Biogen (NASDAQ: BIIB) but with no publicly declared goals to start human testing.

One Step Closer To A Patent Showdown? There are no patent ambiguities with zinc fingers: Sangamo owns them, full stop. But the situation is far more unsettled with CRISPR/Cas9. In recent weeks, the big patent fight over ownership of CRISPR/Cas9, which I first wrote about here, saw a development.

The Patent and Trademark Office issued a memo on September 15 that seems to confirm what I’ve heard from sources close to the case. The camp associated with Jennifer Doudna and U.C. Berkeley appears to have built enough of a case to get the PTO to re-examine the patents granted to Zhang and the Broad in April 2014. Those were the first ever in the CRISPR field. Five months later, the Berkeley camp asked the PTO for interference—PTO-speak for a reconsideration of the patent in the face of a challenger—and has been building its case with thousands of documents, including positive testimony from Utah’s Dana Carroll.

The PTO doesn’t have to grant the Berkeley request, and to be clear, nothing’s been announced. But three weeks ago, the PTO released a review of the Berkeley group’s main patent application—which was originally deemed to have lost to the Broad side.

The review allowed many of the application’s claims and rejected others. I asked a biopharma patent attorney unaffiliated with the case if those rejections were an ominous sign for the Berkeley group. On the contrary, most of the rejections were for trivial or administrative reasons and are easily fixed, said Muna Abu-Shaar of Biospark Intellectual Property Law in Cambridge, who has been following the case.

There’s no guarantee that the PTO will open interference, but from the looks of the PTO memo, Abu-Shaar said, the Berkeley group should be able to make some tweaks and get its patent application in shape to go head-to-head with the Broad group’s applications.

Once that happens, each side will try to prove with lab notebooks, photographs, e-mail and other evidence that it was the first to invent this new gene-editing technology. (Since the Berkeley and Broad patent applications were filed, the U.S. patent system has switched to a “first to file” reward, likely making this the last great “first to invent” fight in U.S. patent history.)

The outcome of the bake-off, however, can be appealed up through the U.S. court system. “I’ve seen some of these things go through 10 years of interference and appeals,” said Abu-Shaar.

A settlement at some point is more likely. Meanwhile, the parties are making their cases in other ways: publishing scientific journals, sitting for profiles in the mainstream press, gathering awards, and helping drive the ethical debate, as Doudna has done.

Doudna and Zhang actually sat together on a panel at the NAS meeting Monday to discuss the underlying technology. It was unremarkable. The universe did not melt down. In fact, their joint appearance amid a whirlwind of presentations, debates, and criticism—one commenter at the end of the meeting warned that the field threatened to fall into a “dictatorship of commercial technical enterprise”—was a welcome reminder. They are now but small players among forces they’ve helped unleash but cannot control.

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