Sana Biotechnology’s ‘hypoimmune pluripotent’ genetic engineering creates insulin-producing cells that dodge immune attacks in monkeys and mice.
Any true cure for type 1 diabetes must successfully replace the insulin-producing pancreatic beta cells that have been destroyed by the body’s own immune system, and then defend those replacement cells from that trigger-happy immune system without immunosuppressive drugs.
Clinical studies, most dramatically the Vertex Pharmaceuticals VX-880 trial, have shown that we now can generate reasonably good replacement cells via pluripotent stem cell science. And this week Vertex received Food & Drug Administration approval for a trial to test its cells in a new encapsulation device without immunosuppression.
To date, however, no such encapsulation scheme has ever worked well in humans.
Given remarkable progress in immunology and gene editing, many labs are working to modify the beta cells themselves to pass muster with the immune system.
Vertex again leads in the clinic, by picking up a collaboration with CRISPR Therapeutics that it acquired with last-year’s purchase of Viacyte. The trial with Viacyte “VCTX210” cells began dosing patients early in 2022 but apparently no results have been reported to date, which might point to limitations. Vertex’s own inhouse quest for “hypoimmune” cell therapies continues under stem cell guru Doug Melton.
This week Sana Biotechnology published encouraging preclinical results in Nature Biology for its “hypoimmune pluripotent” (HIP) cells in rhesus macaques, which often act as the final animal model for drug candidates before first-in-human trials.
Most strikingly, Sana scientists took macaque pancreatic islets (which contain beta cells and various hormone-producing buddies) and created HIP-edited versions of the islet cells. When these cells were transplanted into another macaque, they survived for 40 weeks without immunosuppression. In contrast, transplanted unedited cells quickly died.
The collaborators also generated human HIP pancreatic islet cells that not only survived in humanized diabetic mice for 40 weeks but dramatically dropped blood sugar levels.
So, how do cells get HIP?
Sana researchers, who aim to make cells hypoimmune with as few genetic manipulations as possible, modify three genes for HIP.
Like every other attempt to cloak transplanted cells from the immune system, the Sana strategy starts by turning down the expression of human leukocyte antigen (HLA) proteins that are the cornerstones of attacks from T cells and other players in the adaptive immune system. To do so, the HIP genetic engineering targets the cBM2 and CIITA genes.
Cells also need to be protected from the innate immune system, including natural killer cells and macrophages. Here, HIP builds on years of research by Sonja Schrepfer, a professor of surgery at University of California/San Francisco and a scientific founder at Sana.
As a transplant surgeon, Schrepfer saw the desperate need for better ways to prevent the body’s rejection of transplanted organs. She began pondering why during pregnancy, the fetus is not rejected by the mother’s immune system although half its proteins are from the father. That search led her to the CD47 protein, sometimes called “the don’t eat me, don’t attack me molecule,” she told me in an interview for a 2019 Knowable story. After many many experiments, HIP’s third genetic modification is to overexpress the CD47 gene.
All candidate cell therapies based on pluripotent cells that go into trials probably also will bundle in a genetic suicide switch that can be induced by a drug to destroy the cells if they turn untrustworthy. (In this case, making them terminally HIP, sorry.)
Founded in 2019 and based in Seattle, Sana belongs to the rare lofty set of startup biotechs that gathers enormous amounts of capital long before kicking off any clinical trials. In 2021, the company raised $588 million in its initial public offering. Sana develops two main types of engineered cell treatments—allogeneic (off-the-shelf) cell therapies, like those we’re discussing here, and treatments designed to heal damaged existing cells in place, an even tougher goal.
Sana’s lead HIP program is an off-the-shelf chimeric antigen receptor (CAR) T-cell therapy for certain blood cancers, now in clinical trial. The company expects initial results this year. If successful, the CAR-T trial will be strong encouragement for the HIP approach.
Also in 2023, Sana may get early results from an unusual clinical study for patients with type 1 diabetes. This is an investigator-sponsored trial at an undisclosed European center with HIP-edited cadaveric islet cells. That’s about all we know about this trial, which doesn’t yet appear on European or U.S. clinical trial websites. As far as I know, this is the first clinical study to make such extensive genetic manipulations to cadaveric islets, which are highly difficult to acquire and typically not tremendously robust.
As we’ve been seeing, the mainstream in cell therapies for diabetes instead is cells generated with pluripotent techniques. Sana is developing “SC451” HIP-edited pancreatic islet cells and hopes to file a clinical trial application with the FDA next year.
Top image, mouse pancreatic islet cells, courtesy the James Lo lab at Weill Cornell Medicine. Second image, rhesus macaques by Mark Murchison for Tulane University.