HIP transplants for diabetes

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.

Creating the next cell therapies for diabetes

As new encapsulation devices go on trial for type 1 diabetes, Vertex’s Doug Melton polishes strategies for insulin-producing cells that guard themselves against immune attack.

Two cell therapy candidates for treating type 1 diabetes took visible steps forward last week. Vertex Pharmaceuticals received Food & Drug Administration approval for a clinical trial of its VX-264 therapy, while Sernova announced that two patients in an ongoing trial received transplanted pancreatic islet cells in an upgraded version of its Cell Pouch capsule.

Vertex’s ongoing VX-880 clinical study, which combines stem-cell-derived islet cells with immune-suppressing drugs, in 2021 “cured” one patient of type 1 diabetes for at least several months. This drew great attention as the first clinical proof that stem-cell-derived islet cells could do useful work.

The VX-264 therapy now given an FDA green light employs the same cells but packages them in a surgically implanted “channel array” device. A VX-264 trial is already underway in Canada. The company expects to recruit about 17 volunteers globally.

As far as I know, Vertex has not released details on this device but it is based on an approach that began in the startup Cystosolv, which was acquired by Semma Therapeutics, which then was bought by Vertex. (Above, images of the approach in one perhaps-still-relevant patent.)

Sernova’s therapy is implanted in three steps: The Cell Pouch is surgically inserted, followed by two rounds of islet cell implants. The company expects to release interim results for this second cohort of patients by year-end. Its treatment uses cadaveric donor cells; Sernova plans to move future candidates to stem-cell-derived cells.

Also last week, Doug Melton outlined his research towards the next generations of stem-cell-drived cells during an American Diabetes Association webinar.

Melton, who led the development of stem-cell-derived insulin-producing beta cells for more than 20 years at Harvard and is on leave at Vertex, focuses on two main challenges. First, gaining complete mastery over cell composition. Second, eliminating the need for systemic immune suppression.

His group is bringing large-scale genetic screening to the job. “We can knock out one gene at a time in the embryonic stem cell stage, and then look for genes which improve composition or provide immune protection,” Melton said. “We’ve identified pathways that I had never thought about as being important for beta cell formation.”

He believes that optimal cell therapies will include the right mix of various types of hormone-producing pancreatic islet cells, not just the insulin-producing beta cells. Similar amounts of alpha cells, which produce glucagon that counter-acts insulin, also seem good. Additionally, there may be a helpful much smaller role for the delta cells that generate somatostatin, which inhibits the release of insulin, glucagon and other hormones. Other cell types should be weeded out.

While much work remains ahead, “we’re on the path to having complete mastery over the final composition of the stem-cell-derived product,” Melton said. “Now, how do we deal with this annoying immune system?”

Here his goal is genetically modified islet cells that provide some immune evasion, if not complete immune tolerance. Melton acknowledged that immunologists roll their eyes when he mentions immune tolerance, the Holy Grail for such therapies, but insisted that it may be achievable.

Many labs have pursued many ways to modify cells that might aid in dodging immune attacks. The standard method to evaluate these strategies for type 1 is by injecting candidate islet cells into an immuno-compromised mouse that models the disease. (“There’s no way in which it reproduces what happens in a human type one diabetic,” Melton acknowledged. “Nevertheless, it’s a start.”)

“There’s nothing novel about this approach,” he commented. “The novelty comes from figuring out what is the right combination.” In one early but encouraging achievement, published in a January Cell Reports Medicine paper, one combo (below) engineered by his Harvard group greatly improved mouse survival over nine weeks.

In a separate Vertex effort based on its acquisition of Viacyte last year, the giant biotech is already enrolling patients for a clinical trial of VCTX-211, a “hypoimmune” cell therapy Viacyte created with CRISPR Therapeutics.

May all of these efforts point toward a real cure.

“My dream would be that when a young child is diagnosed with type one diabetes, the endocrinologist says, I’m sorry for you and your family, but I have good news for you,” Melton said. “I have here in my freezer some cells which will control your blood sugars, and your body won’t reject them for a long time. I’m going to inject them into your belly. And good luck, get back to kindergarten!”

“That sounds like a dream, and it is sort of a dream,” Melton added. “But I don’t see any reason we shouldn’t aim for that.”

P.S. Decades of experimentation with encapsulated cell therapies have not been encouraging. But Sigilon Therapeutics, another contender, hopes to ask the FDA next year to approve a type 1 trial with its “Shielded Living Therapeutics” 1.5mm alginate spheres. Sigilon argues (below) that its capsules will guard islet cells better than any modification of the cells themselves.

Cell help for diabetes

Clinical trials designed to cure type 1 diabetes with insulin-producing cells derived from stem cells are slowly ramping up.

Our best hope for curing type 1 diabetes is transplants of insulin-producing pancreatic beta cells created from induced pluripotent stem cells (iPSCs). So how’s that quest going? Some recent highlights:

The lead player is Vertex, whose VX-880 clinical trial has produced encouraging preliminary results. The Boston biotech giant is enrolling a few more patients for this study and seeking FDA approval for another trial that would protect the transplanted cells not with the usual immunosuppression drugs but within a protective device whose design has never been published.

Vertex bought Viacyte, the first major player in cell therapy for diabetes and Vertex’s most likely competitor, in September. Viacyte had partnered with CRISPR Therapeutics on the first-ever trial with beta cells that had been genetically modified to minimize the need for immunosuppression. I haven’t seen any public update on the status of that trial, which had planned to recruit 40 volunteers.

In November, the FDA gave Sernova of London, Ontario a thumbs-up to recruit up to seven more patients for the type 1 trial of its Cell Pouch system. “The Cell Pouch is made of cylindrical chambers of polymers with removable plugs that are implanted against the abdominal muscle and become wrapped with blood vessels,” says the company. Surgeons then remove the plug and transplant islet cells (beta cells and their hormone-producing pancreatic neighbors). These cells will come from human cadavers, the default source until now. The latest trial recruits will be given an updated version of the Pouch. Sernova expects to release early clinical results for that cohort this year.

iPSC-derived pancreatic islet cells manufactured by Evotec in Hamburg, Germany, will replace the donor cells in Sernova’s next clinical trials. The two companies plan to seek regulatory approvals for this round in 2024.

Sernova also is working with the lab of Alice Tomei at the University of Miami on a way to shield transplanted islet cells against immune system attack with a “conformal coating” of hydrogels that encapsulates the cells. This procedure has an encouraging history of results with animal models.

With iPSC-derived cells now commercially available from Evotec and other suppliers, solving this immunosuppression puzzle seems to be the one remaining (huge) barrier to successful cell therapies for type 1 diabetes. It’s particularly tough in this illness because the immune system is already fully geared up to wipe out the patient’s own beta cells.

Startup firm iTolerance is taking another approach to protectively wrapping the transplanted cells, with a technique that performed well in a study of macaque monkeys over six months. The strategy is based on a protein called Fas that is expressed on the surface of T cells; those cells die if a Fas ligand (FasL) protein binds to the Fas protein.

The researchers whipped up a dual-protein combination of FasL and streptavidin, a protein that dampens T cell activation and proliferation. These protein combos were attached to microgel beads, then mixed with islet calls “and then transplanted to a bioengineered pouch formed by the omentum—a fold of fatty tissue that hangs from the stomach and covers the intestines.” (Yes, it’s hard to visualize the omentum; islet transplants traditionally have gone into the liver.)

This work was a joint project among investigators at Georgia Tech, the University of Missouri, Massachusetts General Hospital and other institutions. Camillo Ricordi of the University of Miami, a prominent pioneer in diabetes and cell therapy studies, is chief scientist for the Miami-based iTolerance.

Delivering FasL locally like this should work out better than genetically modifying islet cells to over-express the protein, which doesn’t always work out in immunosuppression experiments, the researchers suggested.

But other approaches to gene therapy for immunosuppression keep marching ahead. One group is targeting the A20 protein, which is “like a thermostat for the immune system; it can turn it down to a simmer, or ramp it up to be more aggressive,” according to Shane Grey at Sydney’s Garvan Institute of Medical Research.

Grey and colleagues have followed this track for many years, with promising early results for diabetes in mice, and in human and pig cells. “The genetically engineered cells seem to re-educate the immune system to accept the transplant as self,” Grey commented in a news release. “The transplant can tweak the whole immune system.” The Royal Adelaide Hospital in Adelaide, South Australia will kick off a trial with A20-enhanced islet cells in mid-2024.

Perhaps more dramatically, this month stem cell maestro Doug Melton and co-workers published research on a Swiss army knife approach to genetically modifying human islet cells to become “immune-tolerizing”. The scientists modified the cells to target human leukocyte antigens (keystones in activating T cells) and the PD-L1 immune checkpoint protein and to secrete three cytokines that help to recruit regulatory T cells to protect the transplanted islets. This seemed to work quite well in humanized versions of the standard mouse model for type 1 diabetes.

“Overall, our approach may eliminate the need for encapsulation or immunosuppression, a longstanding goal of the islet transplantation field,” the researchers wrote. Maybe it’s no coincidence that Melton announced plans to take a leave from Harvard to join Vertex last April, just about the time this paper was submitted.

About 8 million people worldwide live with type 1 diabetes, with half a million more diagnosed each year. So says the Type 1 Diabetes Index, which predicts this population will soar to more than 13 million people by 2040. (And maybe 10 times more people with type 2 diabetes will need insulin by then.) Let’s hope that actual cures will be widely available and affordable many years before that.

Costing out a cure

As Vertex buys Viacyte, is that good news for people with type 1 diabetes?

For 20 years I’ve been rooting for Viacyte, the pioneering startup in growing insulin-producing cells for transplant into people with type 1 diabetes.

Founded in 1999 as Novocell, the San Diego company began its research with human embryonic stems cells rather than the not-yet-discovered induced pluripotent stem cells (the cells re-engineered from adult cells that quickly became the most likely source of stem cell therapies).

Viacyte launched its first clinical trial in 2014 and has doggedly moved ahead in many attempts to optimize its cells and the enscapsulation devices designed to hold the cells. Last month, one patient in a trial finally showed clear clinical benefit, although on immunosuppression drugs.

This month, though, Viacyte announced it will merge with Vertex Pharmaceuticals, its major rival, in a $320 million cash deal.

Based in Boston’s Seaport (above), Vertex is a very different biotech, selling $7 billion of cystic fibrosis drugs each year. In 2021, Vertex’s net income was 31% of revenues and the company was sitting on $7.5 billion in cash.

Vertex broke into the diabetes field with the $950 million acquisition in 2019 of Semma Therapeutics. Semma was a well-funded startup built on research by Doug Melton, Harvard superstar of stem cell research. Melton, who joined Vertex this spring, told me back then that the problem of churning out functional insulin-producing cells in volume had been solved. Melton also was impressed with a “very clever and effective” encapsulation device that Semma was quietly polishing.

Viacyte holds many patents but its encapsulation devices have never lived up to our hopes, and Vertex already owns the world’s most advanced technologies to churn out insulin-producing cells. So it seems that Viacyte’s highest technology card probably is progress in genetically modifying insulin-producing cells to dodge attacks from the immune system, done in partnership with CRISPR Therapeutics.

In February, the two companies announced that a volunteer in a clinical trial had received such genetically redesigned cells. This was a “historic, first-in-human transplant of gene-edited, stem cell-derived pancreatic cells for the treatment of diabetes designed to eliminate the need for immune suppression,” commented James Shapiro of the University of Alberta, an investigator in the trial and world expert on such matters.

Melton has been working on such immune-dodging-cell techniques for years, and Vertex was an early investor in CRISPR Therapeutics. But knowledge gained from the Viacyte/CRISPR trial can only help.

However, my guess is that Vertex mostly bought the smaller firm to take out its leading competitor, and that this move eventually will bring higher pricing for patients.

Case in point, Vertex’s lead cystic fibrosis combo costs almost $300,000 a year.

In 2020 the Institute for Clinical and Economic Review (ICER), a well-respected Boston non-profit that analyzes cost-effectiveness for prescription drugs, took a look at Vertex’s suite of cystic fibrosis products. Among ICER’s findings:

“Despite being transformative therapies, the prices set by the manufacturer – costing many millions of dollars over the lifetime of an average patient – are out of proportion to their substantial benefits. When a manufacturer has a monopoly on treatments and is aware that insurers will be unable to refuse coverage, the lack of usual counterbalancing forces can lead to excessive prices. Patients who receive the treatments will benefit, but unaligned prices will cause significant negative health consequences for many unseen individuals.”

That’s Vertex’s current economic model. That’s my worry.

True, diabetes unlike cystic fibrosis is not a rare disease. Something like 1.9 million people in the U.S. have type 1 diabetes, which makes it more than 50 times as common as cystic fibrosis. And most insulin actually goes to people with type 2 diabetes that can’t be managed well by other medications, who would also be candidates for cell treatment.

So, given this widespread need, would diabetes be different? The sad story of insulin, which people with type 1 need to stay alive, says not.

Insulin has been available around the world for decades and costs maybe $3/vial to manufacture. But about one in four people dependent on insulin in the U.S. go through periods when they can’t afford the surprising high pricetags for the drug, whose lack immediately puts those folks at truly serious risk. A small number of them die.

Lilly, Novo Nordisk and Sanofi see that situation as a minor public relations problem. And despite an ever-expanding public chorus of cries for cheaper insulin, insulin provisions magically disappeared last week from the pending Senate bill on medications.

Moreover, in a problem extending far beyond the realm of diabetes, nobody knows what limits will be set on costs for cell therapies, those shiny super-powered new kids on the block.

Partly the charges for these treatments will be based on actual effectiveness and value, as per ICER analyses. Beyond that, we might expect biotechs to follow the classic pricing strategy here: charge as much as you can while keeping a straight face. In preliminary public discussions of pricing, cell treatments often are lumped together with the gene therapies that generally seem to cost more than a million bucks.

My guess is that Vertex will create successful cell therapies for type 1 diabetes in my lifetime. My hope is that everyone who desperately needs these therapies can afford them. I’m a little less hopeful now.

Type 1 diabetes goes on trial

2022 will offer many clinical clues on cell therapies for insulin-dependent disease.

This year might be make or break for several ambitious cell therapies designed to treat type 1 diabetes, a thoroughly puzzling and dangerous disease. Some clinical projects to watch:

Viacyte and CRISPR Therapeutics are launching a Canadian trial that will be the first in humans with insulin-producing beta cells that are genetically re-engineered to dodge the immune system with little or no immunosuppression drugs.*

Viacyte has been plugging away valiantly on therapies with beta cells derived from stem cells for more than 20 years. Results have been mixed. Most recently, two papers published in December showed partial success with partially differentiated pluripotent cells embedded in Viacyte’s latest capsule (above left), which is open to blood vessels and requires immunosuppression.

“It is the first reported evidence that differentiated stem cells implanted in patients can generate meal-regulated insulin secretion, offering real hope for the incredible potential of this treatment,” said James Shapiro of the University of Alberta, lead author on a Cell Reports Medicine paper. But only six of the 17 subjects in the study showed signs of significant insulin production and no clinical benefit was demonstrated, although that goal apparently was achieved for one subject enrolled later in the trial.

CRISPR Therapeutics will bring its genetic editing wizardry to create allogeneic (off-the-shelf rather than individually tailored) beta cells for the Canadian trial. The company first deployed this strategy in CAR-T cells, treating patients with B-cell blood cancers with allogeneic T cells. First results for the CAR-T trial appeared in October in a news release rather than a peer-reviewed paper. My non-expert guess is that the allogeneic engineering tricks worked fairly well, with the obvious caveats that blood cancers are very different from diabetes, these are very early days, and the type 1 autoimmune attack takes no prisoners.

This first generation of off-the-shelf-we-hope CAR-T cells combines tweaks to T-cell-specific proteins with removal of one class of major histocompatibility complex (MHC) proteins, which help T cells distinguish your own cells from outside threats. CRISPR Therapeutics may make additional immune-dodging engineering changes to its beta cells, among them immune checkpoint proteins (which reassure T cells that the cell is a good citizen) and/or suicide genes that can wipe out the cells if they go wrong and an otherwise non-toxic drug is administered.

Vertex Pharmaceuticals continues its early trial of stem-cell-derived beta cells with immunosuppressive drugs, which did restore one patient with type 1 to relative normality, which was mislabeled as a cure by the NY Times.

This year the large biotech hopes to launch a followup study that would package these cells in a capsule to bypass or minimize the need for immunosuppression drugs. The capsule builds on implantable device research acquired along with cell technology based on discoveries in Doug Melton’s Harvard lab when it bought Semma Therapeutics in 2019. “Semma has developed a very clever and effective encapsulation device,” Melton told me then. Details on the device or its performance aren’t public although there may be hints in Vertex patents (see one image from a patent application below).

Last week Sernova announced early results of a trial with its “Cell Pouch” (above right). Two participants achieved insulin independence, one of them for more than 21 months. “We believe Sernova is the first company to report that its first two transplanted T1D cell therapy study patients achieved sustained insulin independence,” said chief executive Philip Toleikis. The trial used immunosuppressive drugs and islet cells (clusters of cells in the pancreas that include beta cells and other hormone-producing cells) from cadavers (rather than the stem-cell-derived cells that are becoming available in vastly greater quantities).

“The Cell Pouch,” Sernova says, “is designed as a scaffold made of non-degradable polymers, formed into small cylindrical chambers which, when implanted in the abdominal wall, becomes incorporated with tissue and microvessels to the circumference of removable plugs within as early as two weeks as demonstrated in preclinical studies. After the tissue incorporation, the plugs are removed, leaving fully formed tissue chambers with central void spaces for the transplantation of therapeutic cells.”

2021 was not a good year for another corporate contender in encapsulated cell therapies, Sigilon Therapeutics. The FDA stopped the clinical trial for its lead candidate for hemophilia and then Sigilon found that in one trial participant its cell-holding microcapsules were becoming covered with fibers. Last fall, the company put hemophilia on hold and laid off more than a third of its employees. Sigilon is still partnering with Lilly on type 1 diabetes but there’s still no FDA approval for a clinical study.

Over in academia, scientists at the University of Miami are continuing a trial in which pancreatic islet cells are transplanted into the eyes of people with type 1 who are legally blind in at least one eye. The transplant will go in between the cornea and the iris, a location that seemed promising in animal tests. Recipients will get immunosuppression drugs, but “we believe the eye can confer some benefits that favor long term islet survival and, if we can demonstrate this concretely and over time, we may be able to reduce the anti-rejection drugs,” the researchers say. There’s been some question as to whether this location offers enough space for a sufficiently large transplant for diabetes; one experiment in a monkey suggested that it may.

And one more contender: James Shapiro of the University of Alberta, quoted above re the Viacyte trial, pioneered the Edmonton islet-transplantation protocol that proved cell therapies could work for type 1 diabetes. He is a major figure in the field, involved in a surprisingly broad spectrum of lab and clinical work. I was happy to interview him last year for a Nature story about ramping up cell therapies based on stem cells.

Shapiro and his colleagues are enlisting five participants for a small clinical trial somewhat along the lines of Sernova’s pouch, except without the pouch. That is, the transplant site is prepared in a separate procedure before the transplant. PubMed tells me that Shapiro was leading research in mice for both this concept and the Sernova approach a few years back.

The Shapiro lab’s device-less transplant method “was designed to harness an innate foreign body response in a favorable and controlled manner, to induce growth of new blood vessels to allow the survival of the insulin producing cells without the natural body response to foreign body. Briefly, this site transforms the inhospitable under-the-skin site into a viable location through the temporary implantation of a small tube called an angiocatheter.”

Will such a seemingly simple method work in humans? Let’s hope so. And let’s hope for the best with all the other attempts.

* The first patient in this Viactye/CRISPR Therapeutics trial now has been dosed.

Inflammatory statements

Maybe the culprit in type 1 diabetes isn’t T cells gone bad.

8ee03-beta-cell3_Itkin-Ansari

Follow diabetes research and you start obsessing about beta cells—maybe a gram of cells buried across the pancreas that produce the insulin we need to live. Or stop producing it, in the case of type 1 diabetes.

These cells are heroic microbeasts. “The beta cell is a wonder of nature,” Bart Roep of the City of Hope National Medical Center told me during an interview for a Knowable story. “It’s the hardest-working cell in our body. Every second, each beta cell can make two thousand molecules of insulin; that’s daunting. It also has to be able to release insulin when it’s needed and only when it’s needed.”

In type 1 diabetes, some mix of fairly well understood genetics and not very well understood environmental factors goes wrong. T cells go haywire and begin to wipe out beta cells. So type 1 is described as an autoimmune disease in tens of thousands of research papers.

But maybe things work the other way around: Beta cells stress out and misbehave, and the immune system is just doing its job.

“I actually think that type 1 diabetes is not an immune problem, it is a beta cell problem,” said Roep.

He and his colleagues laid out some evidence in a 2017 Nature Medicine article. “We showed that if beta cells get stressed, which they do very quickly, they produce new antigens like those that expose cancers and infections to the immune system,” he noted.

“I now contend that the immune system is not making a mistake,” Roep said. “It’s the beta cell, and the immune system is actually responding with the best intentions, namely to target stressed tissue… The immune system is not interested in happy tissue.”

Roep is not the only prominent scientist who questions the T-cells-gone-wrong framework for type 1. At the Joslin International Symposium last month in Boston, Olle Korsgren of Uppsala University made another case, skimming through decades of studies on human pancreatic tissue samples analyzed by many researchers.

Among his points, Korsgren cited data suggesting that the T cell attack is surprisingly weak, this attack goes after the whole pancreas rather than just beta cells, and there are frequent signs of beta cell stress such as bleeding. “Could bleeding cells attract the immune system?” he asked.

His hypothesis: Type 1 is not an autoimmune disease that targets beta cells. Rather, it’s an inflammatory disease affecting the entire pancreas. Moreover, the inflammation might be driven by gut microbes invading the pancreas next door.

And Korsgren’s theory just might dovetail very nicely with recent research on the role of the gut microbiome in type 1, now well documented in large epidemiological studies and explored in many labs.

12/20 review from Roep and colleagues. Image: Pamela Itkin-Ansari lab

Talking about regeneration

What experts are telling me about the march of pluripotent stem cell therapies.

Yes, it takes years to translate brilliant science into therapies, and the routes to translation aren’t predictable. Case in point, the California Institute for Regenerative Medicine, launched via state referendum 15 years ago among the excitement about pluripotent embryonic stem cells. The Institute has sponsored 56 clinical trials. By a quick count, only five of these trials are looking at pluripotent stem cells, the remainder testing adult stem cells for regeneration or cancer treatments.

The waters are muddied by hundreds of for-profit “stem cell clinics” that offer treatments with little or no clinical evidence. “There is no scientific basis for what these people are doing,” one prominent researcher told me. “It’s very important to draw a distinction between the malpractice and quackery of these unsubstantiated stem cell clinics and the incredibly high-tech serious science that is using all of the new targeted approaches to improve patient outcomes for really terrible diseases.”

Therapies based on induced pluripotent stem cells (iPSCs) are entering early studies. The first iPSC clinical trial for Parkinson’s disease launched last year in Japan, for example. jCyte kicked off a successful first trial to treat a degenerative eye condition in 2017 and should post early results of a follow-up study soon. Studies for cardiac condition are likely to launch in 2020, one based on research shown successful in macaques. Also next year, Sigilon Therapeutics expects to kick off a study for hemophilia A, and Semma Therapeutics is planning trials for insulin-producing pancreatic beta cells for type 1 diabetes. “I’m happy to tell you that Semma has solved the production problem for beta cells,” co-founder Douglas Melton told me.

Labs are gearing up for off-the-shelf cell therapies, by engineering “universal donor cells” that dodge immune reaction and/or retraining T cells and other bodyguards of the immune system. This is a very long road with many complexities and safety concerns. But progress is being made, with one example this year from Melton and colleagues.

Other researchers seek to apply what we’re learning about cell plasticity to form  desired cells directly within the body. Kristen Johnson of Scripps Research’s Calibr institute, for instance, leads a trial of a small molecule designed to make healthy new knee cells. At an earlier stage, diabetes researchers aim to develop insulin-producing cells by altering pancreatic alpha cells or a recently found population of pancreatic progenitor cells. Startups OxStem and Sana Biotechnology have wildly ambitious programs in this space.

We’ll see what actually translates but the scientists I talk with believe that stem cell research will change medicine dramatically and it won’t take 15 more  years.

Images courtesy Harvard Stem Cell Institute. On left, mouse induced muscle progenitor cells at various stages of differentiation, from Konrad Hochedlinger’s lab. Top right, human green kidney cells and red blood vessels, from work led by Jennifer Lewis and Ryuji Morizane. Bottom right, from the Melton lab, two clusters of human insulin-producing cells (pink), the cluster on the right demonstrating enrichment of these cells.

 

Capsule cures get beta

We’ve learned how to churn out zillions of insulin-producing cells and maybe even guard them from the immune system for a year or two.

The commercial “stem cell clinics” that have popped up across the U.S. like mosquitoes after rain, offering treatments with little clinic evidence, typically begin with the patient’s own cells. But the stem-cell-based therapies that will soon fundamentally change regenerative medicine will come off the shelf. Case in point, the insulin-producing treatments for type 1 diabetes that I’ve just covered in The Scientist, which are headed for the clinic in the next year or two. Scientists are mastering ways to make reasonably functional beta cells in high volume. ViaCyte is readying a new version of its capsule that doesn’t require immunosuppression and expects to resume clinical trials soon. Semma Therapeutics and Sigilon Therapeutics are reporting progress in pre-clinical studies. Fingers crossed here, but definite progress.

Images courtesy Sigilon Therapeutics.

Beta living through stem cells

Insulin-producing cells will be tested first in patients lacking a pancreas.

insulin

Diabetes is way complex. “But it’s a simple disease conceptually—your body doesn’t produce enough insulin,” notes Joslin Diabetes Center researcher Gordon Weir.

In type 1 diabetes, an autoimmune attack wipes out insulin-producing beta cells, which are found in clusters of pancreatic cells called islets. In type 2 diabetes, the beta cells are still there but not hauling all the freight. That disease can be treated with many other types of drugs, along with lifestyle changes. But over time, beta cells wear out. In fact, more people with type 2 take insulin than people with type 1.

And there’s no way to make insulin injections pleasant or easily controllable or as good as insulin production by beta cells.

Thus the huge interest in a long-term research project spearheaded by Harvard’s Doug Melton to create working beta cells by manipulating stem cells. An update on the ambitious project from Melton, Weir and other partners drew a crowd at Harvard on Monday.

Making insulin-producing cells good enough for clinical trials “turns out to be rather difficult; it took more than a decade,” Melton said. “We haven’t made it really perfect, but it’s at the goal line.”

Technology from Melton’s lab has been licensed exclusively to the startup Semma Therapeutics, which is joining with Joslin, Brigham & Women’s Hospital and Dana-Farber Cancer Institute to move toward clinical trials. Traveling under the ungainly title of the Boston Autologous Islet Replacement Therapy Program (BAIRT), the collaboration launched in June.

The first BAIRT studies, starting at least three years from now, will not be among people with type 1 diabetes. Instead, they will recruit people who have had their pancreases removed, usually because of uncontrollable pain after the organs are chronically inflamed by years of heavy drinking.

This approach bypasses the biggest problem in cell treatments for type 1 diabetes: the body renews its autoimmune attack and wipes out the newly introduced cells. “We decided to solve one problem at a time,” Melton explained.

Patients who have prostatectomies often now are given islet cells salvaged from their own pancreas, which helps to improve their diabetes control, but those cells may themselves be damaged or in short supply, said Brigham surgeon Sayeed Malek. Transplants of brand-new beta cells, made from the patients’ own blood, should help.

These reengineered cells will be injected in the arm, where they will be easy to monitor  and to remove if necessary, said Semma CEO Robert Millman. Decades of experience transplanting cells from cadavers has shown that “you can put beta cells just about anywhere,” Weir added.

Against autoimmunity. If all goes well, the project will continue into trials for type 1 diabetes with non-personalized beta cells, where the autoimmune attack will be blunted via encapsulating the cells. Seema is spending about half its budget on encapsulation technologies, Millman said.

Encapsulation is the near-term solution to fend off the autoimmune attack. “The long-term solution is to use the power of biology to understand why the immune system has made this mistake,” Melton remarked.

He briefly mentioned two promising research thrusts. One effort is to learn from the rapid advances in knowledge about how cancer cells dodge the immune system.

Another, led by Chad Cowan of Massachusetts General Hospital, aims to create a “universal donor pluripotent stem cell.” Missing all the billboard signs that alert immune enforcers, these cells could play a role like that of O-positive cells in blood transfusions.

Asked about his own take on the causes of type 1, Melton mentioned one theory that the autoimmune attack may be triggered by gut cells that naturally produce insulin or similar substances under certain conditions.

Slow and steady. Bringing beta cell therapies to the clinic will be a marathon march with not only many scientific steps but many regulatory steps. Millman emphasized, however, that “the FDA is working with us very early on the regulatory path.”

Among potential safety risks, all stem cell therapies must be carefully vetted to avoid the growth of teratomas—tumors with a jumbled mix of cells, usually benign. These cellular junk piles would be relatively easy to remove, but much better to avoid altogether, Millman said.

Another concern is that the cells will secrete insulin even when it’s not needed, dropping the recipient’s blood sugar levels to dangerously low levels.

There also is much cause for worry that the cells won’t last long, a major problem in transplants of cadaver beta cells. However, built-from-scratch cells function “for more than a year in mice, which bodes well for people,” Weir commented. And Millman pointed out that the cells resemble juvenile cells, which may help them withstand the high stresses of transplantation better than worn-out adult beta cells do. “We hope these almost pristine cells going into the patients will last a lot longer,” he said.

None of this will come cheap. Asked about pricing for cell therapies, way down the road when and if they hit the market, Millman was understandably wary. Initial costs for these treatments will be very high, accompanied by very close regulatory scrutiny. Semma has raised about $50 million, but “we need philanthropy and we need institutions to support this,” he said.

Melton suggested, though, that successful cell-based therapies will make complete  economic sense, given the soaring numbers of people with diabetes and the huge costs of diabetes care. Each year the world spends about $30 billion on insulin alone. “Diabetes is not an orphan disease,” he said. “The cost will come down very quickly.”

Man petabytes dog

husky

One of the earliest stories I wrote about genomics past the gee-whiz aspects of the Human Genome Project covered the first whole-genome sequencing of a dog. Kerstin Lindblad-Toh of the Broad Institute patiently explained the project to me, and scientists who used dog models to study inherited blindness told me why they were more than excited about the prospects.

More than a decade later as I’m putting together a special report on big data for Nature, the genomic revolution has marched ahead, well, much as predicted.

The cost of genomic sequencing has dropped arguably faster than any other technology in human history. Research initiatives that most of us haven’t heard about are gathering genomic data on hundreds of thousands of people. This flood of data is multiplied with data from proteomics and other omics now scaling up to the genomic scale. We talk casually about petabytes (millions of gigabytes). Data scientists, many of them coming in from fields outside biology, are integrating these data and making some astonishingly good predictions about what drugs might work for a given condition, without needing any new wet-lab work. We’ve seen wonderful progress in stem cells and cellular models and genetic engineering tools. And this revolution is on television, also websites, social media and an entirely sufficient plenitude of TED talks.

Not so much in the clinic, though.

Of course omic research on many diseases is starting to pay off for actual patients—for example, The Cancer Genome Atlas has spun off clues for real advances in many cancers—and its grand march points straight ahead through enormous but movable objects.

But clinical steps are slow. Part of the reason is the sheer complexity of disease, for instance the ways cancers duck and weave to dodge treatments. And, of course, clinical trials can’t be rushed.

Last week I asked one neuroscientist why we still lack drugs that treat the causes of neurodegenerative diseases, as opposed to their symptoms. She responded, reasonably enough, that it takes years to build better lab models of the disease and push findings from those models into the long tunnel of pre-clinical work toward trials. She expected that some of the compounds coming from her work will help. She didn’t predict home runs.

But we haven’t lost the gee-whiz discoveries and our faith that they’ll end up in the clinic in our lifetimes. My favorite: Scientists can take a human skin cell, bombard it with select small molecules until it morphs into a reasonable facsimile of an insulin–producing cell (a notoriously fickle beast) and produce such cells in the millions. Maybe those cells will arrive in the next decade, bringing actual cures. And although I don’t follow discoveries in dog proteomics, I see that University of California/Berkeley researchers have restored vision to blind dogs via genetic therapy. Progress, yes. Dogged research!

 

Capping off

sphere_scarringAn MIT alginate microcapsule holding islet cells (in green) and being covered by immune cells (in blue and magenta). Image credit: Omid Veiseh, Joshua Doloff, Minglin Ma and Arturo Vegas.

There’s a worldwide deficit in insulin-producing beta cells, for people with either type 1 or type 2 diabetes, Harvard’s Doug Melton told a session at the ADA annual scientific conference on Friday.

“It’s a completely non-trivial thing that you can now make billions of human beta cells,” he said. “We spent more than a decade trying to march these cells through this procedure.”

Currently, it takes his lab about 40 days to produce the cells at a cost of about $6,000 per flask, but Melton is confident that these numbers can be chopped down.

The achievement required not only brilliant scientific detective legwork, especially on the last steps of differentiation, but lab drudgework on a dramatic scale.

Picking apart the steps that drive cells into beta shape, “we had to sort out three or four factors at a time,” he noted. The lab ran screens of small molecules to find what combinations were effective. Testing eight small molecules, in three concentrations, for different periods, in triplicate meant about 65,000 combinations to examine per screen.

The lab of MIT bioengineer Dan Anderson, collaborating with Melton to build microcapsules for the beta cells, took high-volume testing to a much higher level for various capsule designs.

Over the decades, many groups have tried to encapsulate beta cells in tiny spheres of alginate. Historically, “all these capsules end up covered in scar tissue,” Anderson told the ADA session.

But after endlessly tweaking the properties of these spheres, “we have a growing list of materials we could use,” he said.

One capsule material seems to work well in mice with strong immune systems—and in very early testing in macaques. Details on the material aren’t yet public, but the secret isn’t in the material’s permeability but in how the immune system reacts to it, Anderson said.

His group’s exhaustive testing also gave clues to how capsule size affects immune scarring. Last month, he and colleagues reported in Nature Materials that 1.5-mm-diameter capsules do better than 0.5-mm structures. Was that a surprise? “It was for us,” Anderson replied. “We thought smaller would be better.”

Beta than the real thing?

Melton_ beta_cellsHuman stem cells implanted successfully in a mouse. Image courtesy Doug Melton.

We know a true cure for type 1 diabetes will require both a new supply of insulin-producing beta cells and a new way to stop the autoimmune attack that wipes out the original cells. We’ve seen great progress in the past decade on the first challenge, as researchers have learned to morph embryonic stem cells and then normal skin cells into beta cells that now might be very much like the real thing. But despite all we’ve learned about the autoimmune attack and all the clever ideas that have emerged to stop it, so far there’s no clear way to do so.

Today the best bet for autoimmune defense is to embed engineered beta cells in intricately designed porous capsules. While most attempts use spherical capsules on a millimeter scale, last fall Viacyte launched a clinical trial for a device the size of a credit card. We’re all rooting for this trial’s success. But even if it works well, the encapsulated cells won’t function quite normally or last forever.

“I want a forever solution,” says Harvard’s Doug Melton, who has led much of the stem cell engineering work.

At a JDRF session in Boston back in March, Melton suggested two approaches to further modify those engineered cells to dodge the autoimmune bullets. “These are two of my favorite ideas, but I’ll remind you that most of my ideas turn out to be wrong,” he said wryly.

One idea follows the playbook of the hot new class of cancer immunotherapies known as “checkpoint blockaders” —or rather turns it on its head.

As cancer researchers began to discover two decades ago, T cells that charge in to wipe out tumor cells are stopped in their tracks if the tumor cells express certain proteins on their surfaces. Well, how about engineering beta cells to defend themselves by expressing these proteins on their surfaces? (Work in mice by other labs indeed has demonstrated protective effects.)

Melton prefers a second concept, which taps into one of the large questions of immunology: Why doesn’t a mother’s immune system attack the fetus she carries?

Cells called trophoblasts that initially wrap the embryo help to provide the immune shield, he notes. So why not express key trophoblast surface proteins in beta cells, so that the beta cells look like fetal cells to the immune system?

While autoimmune researchers have been kicking around both of these ideas for years, it’s still very early days for bringing beta cells with self-protective surfaces toward the clinic.

But some year, Melton told the JDRF crowd, “my dream is to tell you, not only can we make billions of beta cells but we can transplant them into any person and they won’t be rejected.”

I’m looking forward to hearing about more and better betas from him and from other leading researchers this Friday afternoon, at a session during the American Diabetes Association’s annual scientific conference in Boston.