Type 1 diabetes has proved a tough nut to crack, but now the literature is awash with novel therapeutic approaches aimed directly at its underlying pathology. Professor Bart Roep, of the City of Hope (Duarte, California, USA) and the University of Leiden (the Netherlands), discusses the latest developments – and the seminal collaboration that made it all possible.
On a mission to cure type 1 diabetes: Professor Bart Roep (City of Hope, Duarte, California, USA, and the University of Leiden, the Netherlands).
Thomas Brown
In contrast to the majority of autoimmune diseases, type 1 diabetes as yet has no drug directly targeting its underlying cause; by giving patients insulin, physicians treat only the symptoms.
“The new era that we are embarking on is that we are actually now trying to target the cause,” says Roep.
I almost get goosebumps when I think of all the things that we have discovered in only 2 or 3 years – it’s unbelievable.
The turning point in the quest to understand – and therefore cure – type 1 diabetes came with the launch of the JDRF-backed Network for Pancreatic Organ donors with Diabetes (nPOD). The network is similar to an organ donor register, but involves patients who have type 1 diabetes or are islet autoantibody positive. The resulting donated tissue (pancreatic and related) is distributed among preapproved research groups across the world, enabling, for the first time, the systematic study of the underlying pathology of type 1 diabetes directly in humans, rather than in animal models.
“It’s incredible,” says Roep of the project. “I almost get goosebumps when I think of all the things that we have discovered in only 2 or 3 years – it’s unbelievable.”
“Some of it is a little bit discouraging,” he concedes, such as learning quite how variable type 1 diabetes is between patients, vastly reducing the chances of a one-size-fits-all approach to curing the disease. But at the same time, he says, it is comforting to learn why the disease has proved so resistant to intervention to date.
A vaccine for type 1 diabetes?
Roep’s own focus is on the immunological aspects of the disease. In collaboration with Mark Peakman, at King’s College London, he has uncovered specific peptides that trigger patients’ immune systems to attack their own beta cells. This provided the “final piece of the puzzle” for Roep’s group to develop their approach to stopping type 1 diabetes in its tracks: a vaccination.
He likens it to desensitization therapy for patients with allergies: “If you know the allergen, you can desensitize.”
The “allergen” in question is a modified proinsulin peptide produced by stressed beta cells. This binds very strongly to human leukocyte antigen (HLA)-DR4, which is associated with high risk for type 1 diabetes. So the team has put this allergen together with an adjuvant, with the aim of reeducating patients’ immune systems and quenching the autoimmune response.
The adjuvant is “nature’s conductor of the immune orchestra”, the dendritic cell. The team takes the patients’ own monocytes and incubates them with vitamin D3, causing them, as they differentiate into dendritic cells, to shift towards an anti-inflammatory profile. Thus, they create tolerogenic dendritic cells, which, when injected back into the patients along with the proinsulin peptide, hopefully amplifies its desensitizing effects.
Roep’s group is currently engaged in a first-in-man, open-label, placebo-controlled, dose-escalation study, assessing the feasibility and safety of the treatment in nine patients. In addition to the required safety endpoints, the team is also looking for a shift in the immune system to a more anti-inflammatory profile – gauged by measuring levels of interleukin-10.
We keep forgetting that this is a potentially deadly disease; if you give too little or too much insulin you die – it’s really terrible.
The trial participants have had type 1 diabetes for between 18 months and 4 years, so they are past the “honeymoon period”, on stable therapy, but hopefully with sufficient beta cells remaining to allow measurement of their function (via C-peptide levels), which is a secondary endpoint.
“We attempted to include patients who are basal C-peptide negative but positive after glucose tolerance test, and then my hope and dream is that some of these patients will actually also become basal C-peptide positive,” explains Roep.
The patients are all older than 18 years, but, assuming safety is demonstrated, phase II will almost certainly include children – even if there is no sign of efficacy in adults – because of the very different immune responses of children.
And Roep notes that even the issue of safety is a slightly debatable point. Safety is “not trivial,” he stresses, but “we keep forgetting that this is a potentially deadly disease; if you give too little or too much insulin you die – it’s really terrible.”
“So safety I take with a grain of salt, in the sense that the disease isn’t safe and so there is no free lunch – we have to accept a certain degree of risk when we start treating children.”
A crowded field
Exciting and novel as it is, Roep’s trial is just one of many launched on the back of the nPOD-facilitated renaissance of type 1 diabetes research. He lists an array of alternative approaches, including direct injection of antigenic peptides, blocking HLA, cytokine inhibition, and the in vitro expansion and reinfusion of patients’ own regulatory T cells, to name but a few.
You don’t want to suppress the immune system, you want to negotiate with it.
But Roep stresses: “Many of these are immune-suppressive in nature, which is something that bothers me a little bit,” considering that the majority of patients are children. “You don’t want to suppress the immune system, you want to negotiate with it,” he says.
“My approach is different in the sense that we have a tissue-specific vaccine. Our regulatory T cells will only become active if they see proinsulin as a target, and that limits their range of activity in the tissues where you want it to occur, which is the pancreas and the pancreatic lymph nodes.”
The downside of the personalized approach, however, is that, by its very nature, it will not work for everyone. The peptide used in Roep’s study can only be used in patients with HLA-DR4; this represents 70% of the type 1 diabetes population, but still necessitates a different vaccine for the other 30%.
So the more systemic approach taken by other research groups could benefit patients not (or not yet) eligible for more targeted approaches, Roep believes.
Missing puzzle pieces
Another caveat is the vexed question of what actually is causing patients’ beta cells to become stressed and trigger an autoimmune response.
“We don’t know: that’s the bottom line,” says Roep.
There are a few clues: islets of type 1 diabetes patients have active tissue transglutaminase, unlike those of healthy people; there is aberrant regulation of HLA, which could suggest a viral contribution; and even misplaced intestinal bacteria have been implicated. But the answer remains elusive for now.
The upshot of this though, is that however successful these attempts to manipulate the immune system prove to be, they are only addressing part of the problem.
Roep suggests that combination therapy may provide an answer, “if diabetes type 1 turns out to be a beta cell disease as much as an immune disease.”
Existing type 2 diabetes therapies, such as glucagon-like peptide (GLP)-1 analogs, “to put the islets at ease” combined with re-education of the immune system “could be the bullet approach to treat type 1 diabetes,” he says.
But the reality is likely to be even more complex. The “enormous diversity” between patients, revealed by the nPOD studies, “will probably point to the fact that we will not be able to get one immune intervention, one strategy, curing everyone,” Roep observes.
“It’s a very diverse disease, much like cancer, so we really need to do the fine diagnosis to understand whom to give which type of therapy.”
Confounding expectations: A wide window for intervention
A more optimistic finding from nPOD is that, in terms of a potential cure, it is certainly not all over for diabetes patients at the point of diagnosis.
“Textbook medicine always teaches us that it’s too late” to intervene at this point, says Roep. But rather than 90% of beta cells being destroyed at this time, as was once assumed, “it’s closer to 50%, I would say.” And the capacity for significant insulin production has been shown not only in patients who died near the point of diagnosis, but also in those who had lived with the disease for 50 years or more.
“That to me is the argument to even offer intervention, provided it is tolerable, to people who have had the disease for many years,” says Roep.
And he describes insulitis as the tip of the iceberg, with many more beta cells still present but not producing insulin. This “is curious, but they’re kind of hibernating, and we hope that we can – once we stop the chronic inflammation – actually re-engage those beta cells and have them produce insulin.”
This may sound far-fetched, he concedes, but experience with type 2 diabetes shows the profound effect of bariatric surgery on nonfunctioning beta cells: “On the operating table, beta cells immediately become functional again.” Also, 60% of type 1 diabetes patients who have undergone bone marrow transplantation experience diabetes remission lasting up to 9 years, Roep adds.
The unexpected joys of a consortium
Thanks to the nPOD project, preclinical type 1 diabetes research has been bubbling vigorously for several years, with the effects now spilling over into the clinical research arena. But for those scientists and clinicians who are part of it, the positive effects of the collaboration can extend even beyond the breakthroughs in understanding of type 1 diabetes.
...a very unselfish, collaborative fashion, which is really a joy to be part of.
The consortium includes many expert researchers, spread across the world, studying the same tissue from multiple angles – looking at its immunology, genetics, virology, and so on. It therefore represents “a completely new type of partnership,” says Roep, which is conducted in “a very unselfish, collaborative fashion, which is really a joy to be part of.”
He says: “The egos lose when it comes to this kind of study consortium, and that is another thing that is new and motivating in the area of type 1 diabetes.”