[Corrected, 10/24/16, 2:44 p.m. See below.] In 2009, Jennifer Adair was helping treat a brain cancer patient in an experimental study. The trial required genetic modification of the patient’s blood stem cells in a specialized sterile room at Seattle’s Fred Hutchinson Cancer Research Center, where Adair is a gene therapy researcher. Over the course of four days, Adair and her colleagues followed strict anti-contamination procedures, stripping off gowns when they stepped out for a meal or a bathroom break, then washing up and “gowning in” again to re-enter the room.
There has to be a better way, she thought. What if the same procedure could take place faster and in any clinic, not just a multimillion-dollar facility with a dozen or more highly trained workers? Her idea was bolstered by experiences working with HIV, which is also a target of experimental gene therapy that, if ever approved, would have a hard time reaching millions of people who need it.
Adair (pictured) set out to build what she calls “gene therapy in a box”—a benchtop system that could automate many of the tasks now performed in only a handful of clean rooms around the world. She and her colleagues have tested the machine—it looks a bit like R2-D2’s head—on mice and a few monkeys, showing that the system stayed sterile and modified enough cells to help the animals restart healthy blood production. The work was published today in the journal Nature Communications.
It’s a first step, but one of several required to convince medical regulators that the tabletop system can be used to test gene therapy in humans, which Adair thinks could happen next year in collaboration with an under-the-radar biotech company in New York City.
“This would represent a significant leap forward for gene therapy if brought to bear,” says Brian Sorrentino, a doctor at St. Jude Children’s Research Hospital in Memphis, TN, who treats patients with stem cell gene therapies produced in St. Jude’s 60,000-square-foot clean room. “It’s almost like being a surgeon in an operating room, except here we’re operating on cells. Sometimes it’s quite difficult to do. This system offers the potential to automate the entire process,” says Sorrentino, who is familiar with Adair’s work but was not involved.
[This paragraph has been changed to clarify the difference between the original and modified versions of the Prodigy device.] Adair has collaborated with the German medical equipment maker Miltenyi Biotec, whose blood-separation devices and reagents are used widely in labs, to modify a $150,000 box called Prodigy. The original device takes in a patient’s blood or bone marrow, separates out the stem cells, and pumps the cells into an IV bag that can be brought back to the patient. Adair’s modified version can also make genetic modifications to the stem cells.
The blood disorders sickle cell disease and beta-thalassemia are among myriad diseases that might be corrected by knocking out or correcting genes in a person’s hematopoietic stem cells (HSCs), which live in the bone marrow and produce all the specialized cells that make blood. There is also the possibility of modifying HSCs to help cancer patients withstand toxic chemotherapies—the reason Adair was working on the brain cancer trial back in 2009.
If all goes well, the first group of people to receive tabletop gene therapy in a clinical trial would be patients with Fanconi anemia, a rare genetic bone marrow failure that causes a host of serious physical abnormalities and a higher risk of cancer. The only known cure is a bone marrow transplant from a matching donor, such as a sibling.
Rocket Pharmaceuticals in New York has been funding Adair to come up with a special “kit”—including the disposable components and the chemicals needed to genetically modify the cells. Reached at a conference in Italy, Rocket executives told Xconomy they hope to start a trial for Fanconi patients in 2017 if regulators approve the kit. The FDA has already approved the Prodigy machine, according to Adair.
The Rocket team declined to say how much funding they have provided to the lab. They also declined to comment about their only regulatory filing to date, which showed in January 2016 that the company had raised more than $16 million in a potential $38 million offering.
Adair and her coauthors report the cost of the kit used in the experiments as $26,000, but she and Rocket executives say it’s too early to determine real-world costs per patient—they would “be specific to the disease being treated,” Adair says.
Those costs—whatever they turn out to be—when added to the price of a Prodigy machine, would represent a razor-and-blade business model, with the box the one-time outlay. “150,000 dollars seems steep, but a GMP [manufacturing] facility costs millions of dollars to build and run,” says Matthew Porteus, a Stanford University doctor who works with gene-editing technology and treats children with blood disorders and cancers. “I am very enthusiastic about this first step towards bringing what are now complicated cell and gene-based therapies to a much broader population.”
What Adair and her coauthors describe in their paper is a system that deploys lentiviruses to insert into HSCs a healthy copy of a gene. Lentiviral gene therapy is also the technology that Bluebird Bio (NASDAQ: BLUE) is using in three clinical studies to genetically alter the HSCs of patients with sickle cell disease, beta-thalassemia, and adrenoleukodystrophy. Bluebird recently said it had changed some manufacturing processes without having to re-do clinical trials, as some observers had worried could happen.
Bluebird officials could not be reached for comment about the benchtop system. Sorrentino of St. Jude called the Prodigy box a potential “competing model for companies now commercializing gene therapy.”
Many academic and for-profit researchers are also using gene editing, especially the widespread CRISPR-Cas9 system, to alter genes in HSCs and develop treatments. Adair says the “gene therapy in a box” could be used with CRISPR-Cas9, too. But in some cases, the Prodigy box wouldn’t be ready as is. One popular way to get the “scissors” of CRISPR-Cas9 into cells to make their cuts is by zapping the cells with electricity—a process called electroporation. The Prodigy box would have to be modified to attach to an electroporator, but Adair says the system is built to accommodate additional hardware and software (or as she puts it, “a choose-your-own-adventure”).
There are other improvements to make. Adair’s Prodigy tests showed less success with stem cells collected directly from bone marrow, which is no surprise. They are more difficult to genetically modify and transplant than stem cells that have been collected from circulating blood. (Patients can be given drugs to chase, or “mobilize” stem cells out into the circulating blood, but for some diseases and some patients, mobilization isn’t an option.) Adair says changes to the machine’s software and to the chemicals used for the gene modification should help the system’s performance with bone marrow cells.
Another hurdle is intellectual property. Adair’s employer Fred Hutch, as the center is known, and Miltenyi are in dispute over the rights to the software program, Adair says. With a resolution, and with a successful first trial in Fanconi anemia, Adair says she thinks companies will adopt the Prodigy system. But ideally, she says, “I’d love to make this readily available to everyone. If this is in hands of graduate students all over the country, the possibilities are endless.”
Photo courtesy of the Fred Hutchinson Cancer Research Center.