A Deeper Look at Beta Cell Research with Frank Martin
Frank Martin is a Director of Research at JDRF, focusing on beta cell therapy. Recently he spoke with Beyond Type 1 about JDRF’s mission to cure T1D, some of the current obstacles of beta cell transplants, exciting trials currently underway and more. This interview on Type 1 Diabetes Research was created in partnership with JDRF through the JDRF – Beyond Type 1 Alliance.
Can you tell me about your background and how you got involved at JDRF?
I have a PhD in pharmacology. I’ve worked both in academia and in industry, doing drug development in industry, first around cancer, then around infectious disease, and then around autoimmune diseases. Then after my postdoctoral work, I was working as a scientist at Novartis, and I was looking for the next step in my career. Before that, I didn’t have a very close personal connection to Type 1 other than people I’ve met along the way. It’s almost six years now that I’ve been at JDRF.
Talk to me broadly about JDRF’s strategy to cure diabetes
JDRF has a focus around a cure – we want to find a way to cure Type 1 diabetes. We know now that that requires both work on the beta cell side of things and the immune side of things. The immune side of things is basically correcting autoimmunity, correcting whatever it is that’s causing your immune cells to turn on yourself and start killing your beta cells… Because we know that people living with Type 1 diabetes still have beta cells – insulin-producing beta cells. They still have them. However, they either get killed by your immune cells or they don’t function properly.
What’s the deal with islet cell transplants?
JDRF has taken two approaches to this. The first one that a lot of people have heard about in the news is taking beta cells from someone else and putting them into a person with Type 1. Right now, we can transplant islets – parts of the pancreas – into people and basically give them back the ability to produce insulin and at least reduce their complications of Type 1 and reduce their insulin dependence. Some people have come off insulin.
This is typically restricted to people who are experiencing some of the complications of Type 1 like hypoglycemia unawareness, or people who have already experienced a severe complication of Type 1, for example, their kidneys are failing and losing function. The latter are candidates for an organ transplant, and when they go in for their kidney transplant to fix that complication, they can then also receive islets.
However, in both those situations you’re receiving cells from someone else, and your immune system doesn’t like that. Your immune cells want to attack the foreign cells that are being put into your body. So those people who get these transplants are on chronic immunosuppression to help their body keep from rejecting either the pancreas islet transplant or the kidney.
Are there other obstacles with transplants?
One – there’s not enough of these donor islets to go around. There’s not enough of these to provide to every single person living with Type 1 diabetes today. That’s because we rely on cadavers, or people who have died, and their doctors are able to obtain the organ in the particular fashion so that it’s appropriate for a pancreas islet transplant. There’s not enough of those to go around.
And immunosuppression that you need to use is not without its own side effects. People who are on immunosuppressants for organ transplants are at higher risk of certain cancers and infectious diseases.
So while it can be truly curative for these people, it’s still not a burden-free life. JDRF is trying to find ways to address the dearth of pancreatic islets for transplant and the immunosuppressive nature of the transplant. That brings us to our beta cell replacement program.
What can you tell us about that program?
Our beta cell replacement program has been looking for ways to capitalize on islets from other sources, like pigs or even stem cells, and see if we can produce those in large enough quantities and of sufficient quality to put into people instead of those cadaveric islets. These still would require immunosuppression. You can’t just put them into a person because of certain restrictions around stem cell work or animal work and putting that into people.
Companies like Semma and ViaCyte and just a ton of academic investigators, a lot of them stimulated by the JDRF Encapsulation Consortium, have started to devise methods to protect these artificially produced islets from your immune system. Those clinical trials are being done right now where they’re testing different cassettes (different containment units) for their ability to keep the islets alive and for their ability to keep them vascularized, to protect them from immune cells, et cetera. All those things are going to need to be solved before we actually can put one of these into someone and have that cure their Type 1.
Who is working on beta cell regeneration? And what does that look like?
Just as we have teams working specifically on beta cell replacement, we also have teams working specifically on beta cell regeneration. They’re basically two approaches to the same goal.
Officially, we call it beta cell regeneration and survival. So, that’s looking for ways to specifically protect your own beta cells, and looking for drugs that can keep them alive longer to protect them from immune attack or the stressors they might feel during Type 1 diabetes that might cause them to lose function or viability.
We’ve been funding research for years to try and find a good therapy that could stop beta cells from getting killed or losing function during Type 1 diabetes. In the last couple years, we’ve had I think two great results from small clinical trials showing that this is possible.
Can you tell me about any promising potential beta cell regeneration treatments?
As background, JDRF had funded research to find that there are actual cellular components that can control cell stress, and during the course of Type 1 diabetes your beta cells get stressed. Sometimes they die, sometimes they lose function. So, we were funding investigators to look for drugs that were already available for other diseases that could specifically block or improve beta cell stress.
One of these drugs was a cancer drug called Gleevec that was developed initially to treat leukemia, and after a bunch of funding and a bunch of research, we found out that could also help Type 1. And so the clinical trial finished and the results came out and showed that if you give someone in the honeymoon phase Gleevec, it can really slow their loss of insulin production. Because everyone living with Type 1, the honeymoon phase doesn’t last forever, and you start to lose your ability to produce insulin more and more. And so it turns out Gleevec can stop that process or at least slow it down.
A year later, a drug that works a little differently than Gleevec but also is trying to alleviate beta cell stress showed similar results. That drug is called verapamil. It’s a blood pressure/migraine drug that’s been around for ages and ages. The investigator had found out that verapamil could alleviate beta cell stress in conditions that the beta cell experiences during Type 1 diabetes. Those results came out last year and also showed the same. It can hold you in the honeymoon period for a long time, almost halting the disease progression after diagnosis.
So now with both of those drugs what we want to see is, if you go into a stage of the disease when a person may still have a lot of functioning beta cells, they’re not necessarily feeling symptomatic, they have Type 1 diabetes but it’s sort of happening silently, if we can start treating those people we might actually prevent them from ever becoming insulin-dependent.
Are there any trials that are either recruiting or happening now that you’re particularly excited about?
So, there are a couple of trials right now that I’m pretty excited about. One is baricitinib, which is happening in Australia. Baricitinib is an immune drug that’s been shown to be very helpful for people with other autoimmune diseases like rheumatoid arthritis. JDRF has funded research that showed that this drug and other drugs like it not only block the bad activities of your immune cells—they block autoimmunity—but they also function as a beta cell survival drug. They also have direct actions on the beta cell that allow it to stay alive when there are bad immune cells around or there are other stressors.
So, I’m personally really excited about this one because with the one drug, you’re hitting the beta cell problem and the immune cell problem. So I’m really hoping that this one’ll work very well in people living with Type 1. And again, the trial’s just getting ready to start in Australia. They haven’t recruited their first person yet.
We are just starting a trial here in the United States with verapamil and closed loop systems. You can test two different things at once and see if those two different things help each other. This is going to be in kids — there will be a group that’s getting both verapamil and a hybrid closed loop system, so we’ll be able to see if the improved glucose control from the closed loop system is additionally improved by verapamil.
So I thought that’s a pretty neat study. And it’s a trial that’s being run in 6 sites across the United States. And again, it’s for young people.
To learn more about all the great T1D research being funded by JDRF, visit their research and impact page here.