Under the Microscope with Midhat Abdulreda, PH.D.
Teams of scientists throughout the Diabetes Research Institute are advancing their research through a first-of-its-kind technique that allows them to view, in real time, how transplanted insulin-producing cells function when they are inside a living organism. The ‘Living Window‘ program, as it’s called, is a stunning example of how the DRI is combining knowledge, innovation and technology to move us closer to a biological cure for diabetes.
The technique was developed by researchers at the DRI. In pre-clinical studies, insulin-producing islets are transplanted into the eye, then using a sophisticated microscope, researchers can observe the cells through the naturally-transparent cornea in real time — as if through a living window. They are able to watch as islets engraft onto the iris, grow blood vessels and respond to stimulation. They can also observe how the immune system launches its attack on the islet cells and watch the body’s response to new therapeutic strategies that attempt to protect islets from this deadly immune system attack.
The Living Window program is led by Per-Olof Berggren, Ph.D., a professor in experimental endocrinology at Karolinska Institutet in Stockholm, Sweden, and adjunct professor of surgery at the University of Miami Miller School of Medicine. At the DRI, he is joined by Midhat Abdulreda, post-doctoral Scholar in our Cell Biology and Signal Transduction program, who talked with us about the Living Window.
Why the eye?
The eye is the only perfectly transparent tissue in the body. Through the cornea, it’s possible to “see” into the body. And now, through generous funding from the Diabetes Research Institute Foundation, we have an extraordinary opportunity to take advantage of this view. In experimental models, we transplant pancreatic islets into the anterior chamber of the eye; a very simple and minimally-invasive procedure. From there, we can monitor both the integrity and survival of the islets, as well as how the immune system responds during attack after transplantation.
What are the most important observations you’ve made through the living window?
We recently discovered that T-lymphocytes, which are responsible for islet destruction after transplantation, display a unique behavior during ongoing immune attack against transplanted insulin-producing islets. They move around at a rate far greater than previously thought, which may contribute to rapid graft rejection. Now that we know how those cells behave, we’re working to modify that behavior to prevent or delay transplant rejection. Discoveries like this come to light only because we are able to monitor the movement of the same set of islet cells, in real time, over a long period of time, non-invasively.
While we set out to use the living window to monitor transplanted tissue, the technology is also allowing us to explore the eye as a possible clinical site for islet transplantation. In initial living window studies, blood sugars normalized after islets were transplanted into the eye. One reason may be that the anterior chamber – or front – of the eye is one of a few sites in the body that has something called ‘immune privilege.’ In other words, it appears to be somewhat shielded from the immune system. Researchers have known about this phenomenon for decades but we want to be the first to use it to scientific advantage. The theory is that if foreign tissue, such as insulin-producing islets, is transplanted into the eye, the site’s immune privilege – under certain conditions – may help shield the islets from immune system attack.
It’s hard to imagine a therapy that involves placing something into the eye.
Many people have that same initial reaction. I’m constantly asked if the work we’re doing threatens the eye or interferes with vision. The answer is, we don’t believe it does. In our models, we’ve transplanted islets in a way that does not physically obstruct the pupil and according to the eye experts, there’s no indication that we are affecting vision.
So, once you see that this is feasible, the picture changes. It’s very exciting. We recently transplanted insulin-producing cells into the eye of a diabetic, non-human primate (baboon). Through the living window, we could see that the transplanted islets engrafted very well. In fact, we could identify the exact point in time when the islets fully established their blood supply, which could never have been done in the living animal without this sophisticated technology. Within three months, and with limited immunosuppression, wild fluctuations in the animal’s blood glucose levels were minimized and daily insulin requirements were dramatically reduced. Plus, we were able to achieve these results using just one-fifth of the amount of islets that are typically required for transplantation in other sites, thanks to better survival of the transplanted islets and the relative ease and minimally-invasive impact of transplanting into the eye. The results were so promising we’re expanding that study in collaboration with researchers from the College of Medicine at the Seoul National University in South Korea.
What else is on the horizon?
One of the biggest challenges to islet transplantation is the current need for transplant recipients to take powerful anti-rejection drugs for the rest of their lives. We believe the eye may one day be used to deliver local and minimal immunosuppression, through either eye drops or implantable slow-release anti-rejection drugs. This will help prevent or minimize devastating systemic side effects associated with the chronic use of such drugs. More importantly, we think the eye could also play a role in the development of transplant immune tolerance. If we could teach the immune system to accept – or tolerate – transplanted cells (immune tolerance), chronic immunosuppression wouldn’t be necessary. That’s where this concept of immune privilege re-enters the picture. Could the same mechanisms that maintain immune privilege of the anterior chamber of the eye shield transplanted islets from immune system attack and induce tolerance? If so, it might be possible to transplant a small amount of islets into the eye, establish tolerance to those cells, then transplant more islets – from the same donor – elsewhere in the body.
How will this research lead us to a cure for diabetes?
The living widow technology which has proven to be an extremely valuable and versatile tool for teams throughout the DRI and from other departments; immunologists, nephrologists and developmental biologists are using this technology to advance their research. It offers such an extraordinary opportunity to view biological processes in real time, it’s no wonder we’re constantly being approached by laboratories and scientists around the world interested in using it for everything from cancer studies to drug screening. For me, however, I’m committed to using these tools to advance our collective efforts to cure diabetes. I recently lost my father to complications of diabetes, so I’m personally invested, as are many of my fellow researchers at the DRI.
(DRIFocus Spring 2011)
While the DRI is based in Miami, FL, it is the hub of the DRI Federation, a worldwide network of 35 research centers.
“We have become a global enterprise that is unprecedented in academic medicine,” said DRI’s Scientific Director Camillo Ricordi, M.D.
In addition to the Federation, the DRI is part of The Cure Alliance, a group of scientists working to cure different diseases. They share strategies and results, believing that what they learn about one disease could help cure another.
Such collaboration is a core value of the DRI. It’s never been more important than now – as we push to accelerate the development of the DRI BioHub.
Since the BioHub was announced in March, it has received a tremendous amount of attention.
People with diabetes and their families are excited about the potential, and have been asking many important questions.
To get answers, we went “Under the Microscope” with DRI Director Camillo Ricordi, M.D.
When will the BioHub be available to patients?
We are aggressively moving the BioHub toward clinical trials. We anticipate that the first clinical trials to test components of the BioHub will take place in 2014, and we’ve already started down the regulatory path with the FDA. We will test transplanting islets alone within scaffolds made of clinical grade silicone. This material has been used clinically in many applications and therefore should more easily receive FDA approval. The study will also evaluate the placement of this BioHub platform within the omentum (abdominal lining) and its ability to regulate blood sugar levels.
We also are submitting protocols to the FDA in collaboration with Dr. Suzanne Ildstad at the University of Louisville, and with Northwestern University, to perform the first trials that will specifically target islet transplantation that completely remove anti-rejection drugs.
So it’s very exciting.
How can people enroll in the clinical trials?
The best way to remain informed as to when clinical trials will begin is by becoming a DRInsider. For sure, we will announce it and it will be known when enrollment will begin. We expect to be enrolling patients possibly before the end of this year and for sure next year.
What progress have we seen leading up to these clinical trials?
We have tested several components of the BioHub in sub-human primates, including co-transplanting islets with “helper” cells (mesenchymal stem cells) within the scaffold platform, and testing this within an omental pouch (an abdominal lining).
We have also tested our conformal coating cell encapsulation strategy in which we “shrink wrap” the islet cells with a protective barrier. After several modifications, the coatings were able to protect transplanted islets from rejection while maintaining normal blood sugar levels in the experimental models. In these studies, diabetes was reversed in less than one week and the islets continued to function long term without the use of any anti-rejection drugs.
We also are conducting clinical trials at collaborating DRI Federation centers, showing that it is possible to substantially decrease immunosuppression after infusion of mesenchymal stem cells.
Clinical trials at collaborating Cure Alliance centers are indicating that it is possible to discontinue anti-rejection drugs after tolerance-inducing protocols.
We now have new immunomodulatory molecules that were not available a few years ago. These already have been shown to be effective in reversing type 1 diabetes in experimental model systems.
We now have oxygen-generating technology and drug delivery systems to optimize the local micro-environment of the BioHub, which were not available a few years ago.
All of these advances make us increasingly optimistic about our ability to successfully transfer these components to the BioHub platform — and that biologic replacement of insulin producing cells without systemic immunosuppression is within our reach.
The BioHub is a combination of several interrelated strategies. How do you envision these emerging?
I see us restoring self-tolerance and eliminating autoimmunity by inducing chimerism (ongoing collaboration with Cure Alliance’s Dr. Suzanne Ildstad from University of Louisville and collaborators).
The same technology already has been successful in eliminating immunosuppression — anti-rejection drugs — in organ transplantation. That’s been working for more than three years and counting. We believe we can use this when transplanting insulin-producing cells within the BioHub
The additional technologies incorporated in the BioHub could represent alternative or complementary ways to avoid treating the recipients with anti-rejection drugs. That remains the central objective of the entire project.
The BioHub will eventually be applicable to any source of insulin-producing cells. Using islets is just the first, not the final, step.
What source of islets do you believe holds the most promise for widespread use?
The DRI is pursuing a number of cell sources. These include porcine (pig) islets since pig insulin is almost identical to human insulin with the exception of one amino acid; regenerating islet cells from a patient’s precursor cells; reprogramming (transdifferentiating) other cell types in the body to become insulin-producing cells; and different sources of stem cells.
Who will be eligible to receive a BioHub? People of all ages who have type 1 diabetes? What about those with type 2?
For now, the BioHub is focused on type 1 diabetes. However, it could benefit many people with type 2 by providing healthy insulin-producing cells to override or replace their lost and/or defective cells.
Participants for initial trials will probably be required to meet the same criteria as those eligible for current Clinical Islet Transplantation (CIT) trials.
Some of the criteria include: ages 18-65, more than five years with diabetes and the inability to sense low blood sugar (hypoglycemic unawareness).
Our ultimate goal is to avoid the need for any immunosuppressive drugs, which will open the door to treat children and adults alike.
What do you see as the main challenge in getting the BioHub through clinical trials?
The main challenge is the relative complexity of the platform technology – the fact that there are several parts to the BioHub. Regulatory agencies are used to evaluating the testing of one variable at a time, so this could introduce delays.
That’s why we choose to move in parallel. So, while we are testing the scaffold in a pilot trial here, we may be testing a new immunomodulatory strategy with centers in Europe. In Canada, we may test another approach for an alternative site of implantation, and so on.
All of these components working in parallel will allow us to move the project forward as fast and efficiently as possible. Still, I believe the barriers are not just scientific but also possibly regulatory.
When an announcement like the BioHub is made, there is concern about “hype,” or raising false hopes. How sensitive are you to this?
We are always cautious not to raise false hopes about potential cures. But we continue to work with the intensity, the concentration and the relentless effort as if the next trial could be the last one. Progress and momentum have never been so promising. Yes, I have been optimistic before, but I will continue to move with the same degree of enthusiasm as I had five or 10 years ago. To me, someone who thinks that a cure could be farther than 5-7 years from now should work on something else — maybe a mouse model where there is plenty of funding available, and where no one will ask or verify whether something is clinically relevant and/or to make a concrete effort toward timely translation to the clinical setting.
I maintain my optimism and determination not to stop and to keep the focus on the cure.
(DRIFocus Fall 2013)