Diabetes Research Institute Foundation Annual Report 2015

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annual report 2015 >

ADVANCING RESEARCH TO PATIENTS

ONE GOAL: A CURE

Message from the Director

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Research Review

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The Diabetes Education and Nutrition Service at the DRI

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Faculty and Staff

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Executive Officers’ Report

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Financial Summary

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To Our Donors

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The Heritage Society

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Boards of Directors

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DRI Foundation Staff

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MESSAGE FROM THE DIRECTOR

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This annual report offers a unique insight into the most recent advances in cure-focused research for T1 diabetes, a complex disease which affects millions of children and families around the world. It’s for these families that the faculty and staff at the Diabetes Research Institute continue to work so diligently towards a real and practical cure for the disease in the shortest time possible.

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It’s my pleasure to share with you the many research accomplishments that took place at the Diabetes Research Institute in the past year, including progress made on the BioHub platform and some other exciting highlights below: • 10 year milestone reached for transplant patients off insulin Some of our patients celebrated more than a decade off insulin therapy after receiving an islet cell transplant.

Read about Chris, Karla, and Jill and their stories of how life-changing a successful transplant can be when you no longer need multiple insulin injections a day.

• BioHub clinical trial launches to test new transplant site, the omentum The first BioHub transplant took place in 2015 using a novel biodegradable scaffold, and testing the feasibility of a new location for insulin producing cells (islets) to be transplanted into the body. More patients will be scheduled for transplant in the coming months, but here you can read Wendy’s compelling story about her new life without insulin injections – and the groundbreaking results obtained in the trial’s first patient.

• Inroads into sustaining long-term islet function Many laboratories at the DRI are working on the complex autoimmune challenges presented by this disease – ones that must be overcome for a permanent biological cure to reach patients. This, in fact, is our largest area of intense research activity. Areas where progress is being made include adoptive Treg therapies, targeting islet cells in vivo to deliver immune modulating agents, and engineering new encapsulation materials to conformally coat and protect transplanted islets from immune system attack, among others.

• New clinical trials under development New trials are in final planning stages, and their aim is the halting of autoimmune attacks characteristic of T1D and the preservation of islet cell function. The goal is to conduct these important trials in multiple centers at the same time, thus speeding the collection of data and development of meaningful therapeutic strategies.

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• Ensuring a plentiful supply of cells for transplant Read about the advances that DRI investigators have made in the area of cellular reprogramming and regeneration. Using a single, FDA-approved agent, much progress has been made in this year alone towards this important goal.

DRI scientists, in conjunction with our many partners and supporters around the world, are proud to present our research pipeline and report on the critically important work that is taking place for the benefit of those with T1D and their families. Advancing research to patients until the disease is cured – this is our mission and this is our promise.

With warm regards,

Camillo Ricordi, M.D. Stacy Joy Goodman Professor of Surgery Distinguished Professor of Medicine Professor of Biomedical Engineering, Microbiology & Immunology Director, Diabetes Research Institute and Cellular Transplantation University of Miami

A DECADE OF FREEDOM FROM INSULIN THERAPY Jill Eastman, 54, diagnosed at 18 months “I’m living the life that I always saw everyone else living.

Everyone else that wasn’t testing their blood sugars, that wasn’t wearing an insulin pump attached to them every day. And it’s miraculous. I mean it…it…it’s hard to put into words…You guys learned things from every patient before me. I’m standing on their shoulders…They're [Patients to come] going to be standing on my shoulders.”

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They are different ages, reside in different zip codes, and have lived for a varying number of years with type 1 diabetes, but every patient who has had an islet transplant shares the same frightful experience: despite the considerable advances in diabetes care, the availability of state-of-the-art technologies, and the best attempts to manage their blood glucose levels, they were unable to achieve optimal metabolic control without suffering repeated, life-threatening episodes of hypoglycemia unawareness.

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Karla Edge, 55, diagnosed at age 6

Chris Shuh, 64, diagnosed at age 30

“It feels like a whole new way of life. It feels fantastic! It gives me chills just thinking about it – how my life was before compared to now, it’s like freedom…there’s no longer that worry for me or my family…I hope that by the research they’re doing at the DRI, that it enables other people to live the life I’m living now.”

“The fact that it has worked so long is an incredible delight.

To not worry about testing every time you walk out the door or having to test 10 times a day…I watched my only daughter get married, my husband and I are both retired and enjoying life…

Today is my 64th birthday! And I’m happy to be alive!...The cure is coming. It will happen in your lifetime…do not dismay.

The cure is coming!”

This past year, several of the DRI's islet transplant recipients reached a significant milestone – 10 years of freedom from insulin injections – demonstrating that this cell replacement therapy can restore natural insulin production in those with type 1 diabetes.

This particularly feared complication of type 1 diabetes, in which patients cannot sense that their blood sugar level is dropping to dangerously low levels, can lead to seizures, loss of consciousness and even death. Roughly 30 to 40 percent of those with type 1 diabetes experience impaired awareness of hypoglycemia and the risk increases with diabetes duration.

For the patients who apply for and meet the selection criteria for clinical trials, islet transplantation has been a game changer.

Gone is the fear of severe lows. In fact, within days of receiving the donor cells, patients recover glucose awareness allowing them to sense fluctuations in their blood sugar levels – quite often for the first time in years.

Gone is a diminished quality of life. Many of these individuals are living without the need for insulin therapy. Some, like the DRI patients pictured here, have not needed any insulin injections for more than 10 years. Others who have followed remain insulin-independent since undergoing the therapy as well.

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For all of the advances in diabetes technologies, islet transplantation is the only procedure, outside of a full pancreas transplant, that has demonstrated the ability to restore natural insulin production in patients living with type 1 diabetes. But, as DRI researchers undeniably recognize, several challenges remain before this cell replacement therapy can be offered to the millions living with this disease.

In addition to identifying an optimal location in the body to house the transplanted cells – researchers have known for years that the liver, the current transplant site, is not ideal – there are two additional overarching issues: developing a reliable and plentiful supply of insulin-producing cells or regenerating the person’s own islets; and solving the significant immune system challenges that initially caused the body’s attack on its own cells.

Overcoming these hurdles and discovering a biological cure for diabetes is the sole mission at the Diabetes Research Institute.

The strategic path to accomplishing this goal is being pursued with an intense focus on Advancing Research to Patients.

The DRI BioHub – A Unique Solution for Restoring Natural Insulin Production

Reaching the Biological Cure >

Building upon decades of progress in islet transplantation, researchers are developing the DRI BioHub, a bioengineered mini-organ that mimics the native pancreas, containing real insulin-producing cells and other vital components that keep the cells healthy, protected from immune system attack, and able to function long term.

Re-educating the Immune System Restoring immune system balance to protect insulin-producing cells and prevent the recurrence of the autoimmune process, which mistakenly destroys a person's own cells.

Co-delivery of “Helper� Cells Certain cells in the body that have beneficial properties can be added to help promote long-term islet survival.

Localized Drug Delivery Local delivery of low-dose drugs directly into the site can reduce inflammation and protect islets from an immune attack, with the goal of eliminating systemic anti-rejection drugs.

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The BioHub attempts to replicate the cells’ ideal environment, where islets thrive prior to their destruction by the immune system. Inside the pancreas, the insulin-producing cells have sufficient oxygen, adequate space and all the nutrients needed to perform the demanding job of normalizing glucose levels in precise response to the rise and fall of blood sugars.

Unlike mechanical devices that are used to manage the disease and the many other technological approaches currently in development, the BioHub is a biological solution for restoring natural insulin production in those with type 1 diabetes.

overcome in order to reach a biological cure. These key research areas, which are addressed through the BioHub strategy, include: the Site – identifying an optimal location in the body to house the insulin-producing cells; Sustainability – shielding insulin-producing cells from attack using protective barriers and, ultimately, rebalancing the immune system to prevent the recurrence of autoimmunity; and Supply – creating a reliable and plentiful supply of insulinproducing cells or regenerating a patient’s own cells.

Over the last year, DRI scientists have continued to make progress in the various initiatives that make up the BioHub, with some projects advancing to or nearing the clinical trial phase of testing.

Through their decades of experience in clinical islet transplantation, DRI scientists have gained critical insight about the main challenges that need to be

Increasing Cell Supply

Encapsulation

Identifying, developing and/or regenerating a limitless supply of cells to sense glucose levels and produce insulin.

Protective barriers that conform to the individual size and shape of each islet and allow the free flow of nutrients, glucose and insulin while screening out harmful immune system cells.

Structural Housing Three dimensional structure provides spacing and a physical site, similar to the native pancreas, that can be monitored and modified, and retrieved, if necessary.

Oxygen Delivery Oxygen-generating materials provide the critical oxygen needed until new blood vessels grow.

Clinical Trials Advancing promising research and moving cutting-edge therapies to patients.

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CLINICAL TRIALS PILOT BIOHUB TRIAL TESTING THE OMENTUM AS A TRANSPLANT SITE SHOWS EARLY POSITIVE RESULTS

In developing the BioHub, DRI researchers are working to identify an optimal site within the body to house the transplanted insulin-producing cells. Traditionally, islets have been infused into the patient’s liver, but many of the cells do not survive in that environment due to several factors. Additionally, the liver cannot accommodate a platform, like a BioHub, for housing the cells.

[ To overcome this challenge, the DRI has explored alternative sites within the body and has focused on the omentum, a highly vascularized tissue covering abdominal organs. The omentum is easily accessed by minimally invasive surgery, has a large surface area, and more importantly, has the same blood supply and drainage characteristics of the pancreas – where islets are originally found before they are destroyed in type 1 diabetes.

After receiving approval from the Food and Drug Administration (FDA) to proceed with a Phase I/II clinical trial to test the omentum as a transplant site for a BioHub, the DRI screened hundreds of patients with type 1 diabetes.

The DRI’s Clinical Cell Transplant Team, led by Dr. Rodolfo Alejandro, identified several candidates who met the stringent selection criteria for the clinical trial and were placed on the waiting list for a matching organ.

In late August of 2015, DRI researchers successfully performed the unique procedure on the first patient, who became insulin independent within days of receiving the donor cells – a record time for islet transplantation studies.

The islets were implanted within a “biodegradable scaffold,” one of the platforms for a BioHub, which is made by combining the patient’s own plasma with thrombin, a commonly used, clinical-grade enzyme. Together, these substances create a gel-like material that sticks to the

A press conference announcing the unprecedented transplant results was held three weeks after Wendy had the procedure. Pictured are (left to right) Dr. Pascal Goldschmidt, Dean, University of Miami Miller School of Medicine; Joshua Rednik, DRIF President and CEO; Dr. Dora Berman-Weinberg, Research Associate Professor of Surgery; DRI Director Dr. Camillo Ricordi; Wendy Peacock; Dr. Elina Linetsky, Director of Quality Assurance/Regulatory Affairs; Dr. Rodolfo Alejandro, Director of Clinical Islet Transplantation; and Dr. David Baidal, Assistant Professor of Medicine.

omentum and holds the islets in place. The omentum is then folded over around the biodegradable scaffold mixture. Over time, the body will absorb the gel, leaving the islets intact, while new blood vessels form to provide critical oxygen and other nutrients that support the cells’ survival.

This was the first tissue-engineered transplant using a “biodegradable scaffold” implanted on the surface of the omentum. The technique was specifically developed to minimize the inflammatory reaction that typically occurs when islets are implanted in the liver or in other sites where the cells have immediate contact with the blood.

Researchers have observed that the inflammation, coupled with other factors, leads to the loss of many of the transplanted islets.

The DRI’s pilot trial will include up to six patients and include the immunosuppressive regimen currently used for clinical islet transplantation studies. At the end of two years, DRI researchers will assess whether two primary endpoints have been met: the absence of severe hypoglycemia and an HbA1C (hemoglobin A1c) level of equal to or less than 6.5 in each of the study participants.

The results will also be confirmed in collaborative studies around the world, potentially ushering in a new era of islet transplantation and one in which more patients can benefit from the therapy.

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WENDY PEACOCK: FIRST PATIENT IN BIOHUB TRIAL REMAINS FREE FROM INSULIN THERAPY “Through all of the emotions that I’ve experienced throughout this process, the one emotion that has remained at the center is HOPE… Most of all, I truly hope my story can, in some small way, give hope to other T1s that even though this disease is a constant battle – it will not be their battle forever. I hope that all T1s see, feel, hold onto to this hope and truly believe a cure WILL happen!”

There are probably a million places that your average teenager would choose to spend their 17th birthday, but a hospital room in Seoul, Korea, is certainly not one of them.

But that’s where Wendy Peacock found herself that day after exhibiting a variety of symptoms that ranged from severe weight loss to unquenchable thirst. Her mother thought she might have “mono.” But, when Wendy was admitted to the medical center on the army base where her father was stationed, she had a blood sugar level of 630 and was diagnosed with type 1 diabetes.

Wendy was the only person in their community living with the disease, so she and her family had no support system around them nor anyone to turn to for advice. And while she didn’t know much about diabetes at the time, Wendy soon learned that she would need to carefully plan her meals, monitor her glucose levels and take insulin shots for the rest of her life. It was a “game changer,” she recalls. The following year, her father was re-assigned back in the U.S. and they moved to Texas, where Wendy and her family have lived ever since. She went on to attend college and law school and worked hard to manage her diabetes. Over the years, Wendy remained in close proximity to her parents, which became increasingly necessary as she began suffering with severe hypoglycemic episodes.

Soon the “lows” struck much more frequently, and as a single mother of a young son, John Paul, Wendy was having a difficult time caring for herself, let alone her child. She had no choice but to move in with her mom and dad so they could help look after both of them. “I’m good at taking care of my diabetes but sometimes it doesn’t matter what you do,” says Wendy. “One time I woke up and the paramedics were sitting on the floor. My son was crying, ‘Mommy’s sick.’ And I just don’t want him to see me that way. I need to be able to take care of my son.”

So Wendy set out to do just that. She recalled sometime back in 2002 seeing a news segment about an islet cell transplant and began researching information about the procedure.

“When I came across what they were doing at the DRI, it really resonated with me,” she said. Wendy contacted the Institute's Clinical Islet Transplant team and then flew to Miami to undergo some testing for that clinical islet transplant trial.

Since she was still producing some insulin at the time, she

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didn’t qualify for the study. Nevertheless, she continued to follow the research.

In 2014, Wendy again reached out to the DRI and learned about the pilot BioHub trial. No longer producing insulin, she underwent the screening process and was told she was a candidate for the procedure. Then she waited for a matching donor pancreas to become available. On Sunday morning, August 16, 2015, Wendy received the phone call that would change her life. That afternoon, she was on a plane headed to Miami, where DRI researchers performed the novel, minimally invasive islet transplant procedure two days later.

On Wednesday, September 9, just three weeks after her transplant, Wendy, together with Drs. Camillo Ricordi, Rodolfo Alejandro and others on the research and clinical team, announced at a press conference that she was free from insulin injections in record time following the implantation of islet cells within a biological (biodegradeable) scaffold. Wendy was producing her own insulin naturally for the first time since being diagnosed with type 1 diabetes that evening of her 17th birthday.

“The DRI team was monitoring me very closely and so every day they would reassess based on my blood sugar getting lower. Every day they would decrease the insulin almost incrementally. Every day it changed – less and less every day until finally…none,” she explained. After being free from insulin injections for a week, Wendy admittedly needed to adjust to her new life.

“In a way it’s still surreal. I think I’m still processing that I’m not taking insulin anymore. As any type 1 diabetic knows, you live on a very structured schedule. And everything was centered around checking my blood sugar, having my insulin injection, what time am I going to eat, do I have enough food with me, do I have glucose tablets,” said Wendy. “So I had to plan and structure everything about my day and so actually just the other morning, I was leaving to go to the hospital for labs and I was doing my mental checklist and – then I stopped, I was like, ‘Wow, I don’t have to plan that.’ And so that part I’ve already seen a big difference.”

Note: At the time of this printing, Wendy remains free from insulin therapy for 9 months.

CLINICAL TRIALS NEW CLINICAL TRIAL AIMS TO PRESERVE ISLET FUNCTION, HALT AUTOIMMUNITY

While the positive early results of the DRI’s new pilot clinical trial to test the omentum as a transplant site may ultimately demonstrate that it is preferable to the liver, researchers continue to focus on overcoming the challenges posed by the immune system. Currently, patients who receive an islet transplant must take life-long immunosuppressive drugs to prevent their body from rejecting the donor cells, as well as to halt the autoimmune attack that caused the onset of type 1 diabetes (T1D).

The DRI’s goal is to eliminate the chronic, long-term need for these drugs and to sustain the function of islets with naturally occurring mechanisms of the immune system.

While developing successful therapies has been difficult because type 1 diabetes is a multi-factorial disease, decades of research progress has yielded important insights about the need to attack the disease on many levels. The DRI team, led by Drs. Camillo Ricordi, DRI Director, and Jay Skyler, Deputy Director of Clinical Research and Academic Programs, is now poised to launch a new clinical study, known as the Diabetes Islet Preservation Immune Treatment (DIPIT) trial, which aims to target major areas that are critical for combatting type 1 diabetes.

DRI scientists have observed over time that islet transplant outcomes differ substantially in terms of the duration of insulin independence achieved by the recipients. They reviewed data from several islet transplant patients who have achieved long-term insulin independence (10 years or more) to identify factors that could be responsible for their extremely successful results. They found that those who have prolonged insulin independence were treated with a combination of drugs, including one that promotes the growth of myeloid-derived suppressor cells (MDSCs), a population of bone marrow (immune) cells that help create tolerance by suppressing the attack on transplanted islets.

When the MDSC-promoting drug was coupled with Exenatide, which is commonly used by patients with type 2 diabetes to enhance natural insulin production, the effect on islet survival and function was even better. The results of this DRI study combining MDSCs and Exenatide in islet transplant patients was presented in 2015 at the 75th Scientific Sessions of the American Diabetes Association.

These findings, together with other study results using different drug combinations, have led DRI researchers to believe that a cocktail of multiple agents will be successful for addressing three major challenges: halting the immune system attack, preserving the remaining islet function and, possibly, giving the body a chance to recover and regenerate its own islets.

The DIPIT trial will combine for the first time five different agents that have demonstrated significant benefits on transplanted islets when used alone or in small combinations of two or three of the drugs. This past year, the DRI team submitted an Investigational New Drug (IND) application to the Food and Drug Administration (FDA), and received approval to test the effects of this five-drug therapy in a Phase I/IIa clinical trial in a group of 42 patients, ages 18 – 35, who are within four months of diagnosis with type 1 diabetes.

All of the drugs have previously been used in patients for a variety of conditions, however, this is the first time that all five will be used simultaneously in a specifically designed trial. An important facet of this trial is that the immunosuppressive agent used for the induction therapy in this combination of drugs is ATG, and only used for two days. The other immune-modulating agents are given at varying time points. The table outlines the five-drug regimen, each agent’s function and the dosing schedule for the one-year duration.

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The multidisciplinary DRI team that will be conducting the DIPIT Trial includes (seated, left to right: Rodolfo Alejandro, M.D., Director of the Clinical Cell Transplant Program; Luca Inverardi, M.D., Deputy Director of Translational Research; Jay Skyler, M.D., Deputy Director of Clinical and Academic Programs; Camillo Ricordi, M.D., DRI Director; and Khemraj Hirani, Ph.D., Director of Regulatory Affairs and Quality Assurance. (Standing, left to right) David Baidal, M.D., Assistant Professor of Medicine; and Alberto Pugliese, M.D., Head of Immunogenetics.

Also serving on the DIPIT team are Lisa Rafkin, MS, RD, CDE, Associate Chair for Clinical Coordination, and Della Matheson, RN, CDE, Trial Coordinator, Type 1 Diabetes TrialNet Study at DRI/UM.

AGENT

FUNCTION

SCHEDULE

ATG (Thymoglobulin®)

Used as an induction therapy to halt autoimmunity by depleting the attack cells (autoreactive effector cells)

2 doses on days 1 and 2

GCSF (Filgrastim®) IL-2 (Proleukin®)

Exenatide (Byetta®)

Etanercept ( Enbrel®)

Promotes the growth of the desired immune suppressor cells, MDSCs, from the bone marrow

6 doses over 12 days

Typically used for type 2 diabetes to promote natural insulin function and has other benefits for healthy beta cell function and glucose metabolism

Weekly over one year

Promotes the expansion of regulatory T cells to help restore immune balance and prevent autoimmune destruction of the islets

First 5 days and then every 15 days for one year

An anti-inflammatory drug to eliminate inflammatory responses

Weekly over one year

The DIPIT trial will be conducted at the DRI and at multiple facilities throughout the United States.

The data from this study will also provide vital information for developing treatment strategies in people with long-standing type 1 diabetes.

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THE SITE DEVELOPING AND TESTING BIOHUB PLATFORMS WITHIN THE OMENTUM

THE OMENTUM SHOWS PROMISE AS AN ALTERNATIVE TRANSPLANT SITE Status: In its BioHub clinical trial, the DRI performed the first tissue-engineered transplant using a biodegradable scaffold implanted on the surface of the omentum. The technique, which has been designed to minimize the inflammatory reaction that is normally observed when islets are implanted in the liver or in other sites with immediate contact to the blood, has shown promising early results.

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The DRI has focused on the very vascularized omentum as an alternative implant site due to its large surface, easy access and physiologic drainage into the portal system.

These advantages provide the ability to more closely mimic the natural pancreas environment – housing the insulinproducing islets and other components to sustain the cells’ long term function.

The development of a biodegradable scaffold made up of the patient’s own plasma and a clotting promoter (thrombin) commonly used in surgical procedures, has demonstrated its effectiveness in early Phase I/II clinical trials currently underway at the DRI. This past year, the research team, led by Drs. Camillo Ricordi, DRI Director, Dora Berman-Weinberg, Research Associate Professor of Surgery, and Antonello Pileggi, former Director of Preclinical Cell Processing and Translational Models, and their team submitted this pioneering work for publication.

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The biodegradable scaffold is made by combining the donor islets with the patients own blood plasma and then adding thrombin, a commonly used, clinical-grade enzyme. Together, these substances create a gel-like material that holds the islets in place. The photo in the center shows a microscopic image of islets implanted within the biodegradable scaffold.

Additionally, the further development and testing of a silicone scaffold as an alternative BioHub platform, also engineered for implantation within the omentum, was pursued. In their attempts to advance this work to patients with diabetes, DRI researchers had submitted a preinvestigational New Drug (IND) application to the FDA, but were confronted with several regulatory hurdles. While the islet-loaded silicone platform has shown safety and the ability to achieve insulin independence in study models, the FDA requested further preclinical testing for safety and effectiveness before granting approval for clinical trials.

Dr. Norma Kenyon, Martin Kleiman Professor of Surgery, Medicine, Microbiology and Immunology and Senior Scientist, and Dr. Berman-Weinberg, and their teams performed biocompatibility and efficacy studies in experimental and preclinical models, the results of which will be assessed for re-submission to the FDA.

SUSTAINABILTY OVERCOMING THE CHALLENGES POSED BY THE IMMUNE SYSTEM IS ESSENTIAL FOR A PERMANENT BIOLOGICAL CURE FOR TYPE 1 DIABETES.

While identifying an optimal transplant site in the body and developing an unlimited supply of islets are key pieces of the puzzle, the need to reverse autoimmunity and prevent the rejection of transplanted cells without the need for harmful immunosuppressive drugs are leading priorities at the DRI. Much has been learned about the immune system in recent years, which has led researchers to develop new strategies using the body’s own cells and naturally occurring processes rather than the chronic use of toxic agents that prevent the immune system from reacting to foreign tissue.

One of the major research efforts underway is the ability to reset the immune system by restoring the balance between the cells responsible for clearing out unwanted “invaders” and the regulatory cells that turn on and off the soldier cells. In particular, there is mounting evidence that regulatory T cells (Tregs), which play a central role in maintaining self-tolerance – the immune system’s ability

to recognize and not attack the body’s own cells and tissues – are critical in this equation. However, in autoimmune conditions, like type 1 diabetes, there are not enough functioning Tregs to turn off the attacking group of immune cells. This loss of regulation, or “balance,” results in the continued destruction of the targeted insulin-producing cells. Restoring this immune system balance is key to reversing autoimmunity and is the focus of several strategies underway at the DRI and with collaborating centers.

Other research approaches are focused on protecting transplanted cells by encapsulating them within protective barriers that can be engineered to incorporate beneficial agents directly within the coating material.

These strategies and more that are aimed at sustaining long-term islet function constitute the lion’s share of DRI research initiatives aimed at developing a biological cure.

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REBALANCING THE IMMUNE SYSTEM WITH LOW-DOSE IL-2 Status: The DRI team has been working to obtain FDA approval for a clinical trial to test whether IL-2, used alone, can stimulate the regulatory effects of the immune system and sustain beta cell function, even after discontinuation of the therapy.

When administered in low doses, the naturally occurring molecule interleukin 2 (IL-2) has demonstrated the ability to selectively boost the number of desired regulatory T cells of the immune system.

In people with T1D and other autoimmune conditions, these vital regulatory cells are decreased and/or don’t function optimally. By promoting the expansion of these cells in the individual with autoimmune disease, low-dose IL-2 may provide a way to restore the balance and allow the body to heal itself.

In an early European trial in patients with the autoimmune condition alopecia, a type of hair loss that occurs when the immune system mistakenly attacks hair follicles, low-dose IL-2 was given over a period of time, resulting in the reversal of the condition and the regrowth of hair. Studies in T1D patients have begun with collaborators in France as well.

Dr. David Klatzmann and his team at Université Pierre et Marie Curie in Paris performed the first “safety” trial testing the low-dose IL-2 treatment in patients with new onset type 1 diabetes. No adverse events have been seen and the results of these collaborative studies were published this past year in Diabetes.

In addition, numerous studies conducted by Drs. Alberto Pugliese, Head of the DRI’s Immunogenetics Program, and Thomas Malek, Professor and Vice-Chair of Microbiology and Immunology, suggest that IL-2 may indeed be able to correct autoimmunity and improve symptoms of the disease.

Based on the strength of the preliminary data with low-dose IL-2, it will be part of the recently FDA-approved DIPIT clinical trial that will test a combination of five agents aimed at halting the autoimmune destruction of insulin-producing cells.

Overall, these studies, together with those performed using IL-2 for other autoimmune conditions, have provided a critical stepping stone for conducting additional trials to evaluate optimal dosing regimens and longer-term efficacy.

This past year, Drs. Pugliese and Malek, along with Dr. Jay Skyler, DRI Deputy Director of Clinical Research and Academic Programs, and their teams have been working to obtain FDA approval to test whether this agent can stimulate the regulatory effects of the immune system and sustain beta cell function even after discontinuation of the therapy.

If successful, this therapy may also be utilized in patients undergoing islet transplantation or other cell replacement therapies to block rejection and the recurrence of the autoimmune response that initially caused type 1 diabetes.

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“ADOPTING” TREGS TO RESET AUTOIMMUNITY Status: The DRI team has developed a unique protocol demonstrating that adoptive Treg therapy can reverse the disease and reset autoimmunity in experimental models, achieving disease remission in 100 percent of the recipients. Importantly, the therapy was directed specifically at halting the destruction of the beta cells while the remaining immune responses remained intact.

In addition to testing agents alone that can promote the growth of regulatory T cells, the DRI is also investigating methods to increase the levels of these beneficial cells through a process known as adoptive Treg therapy, possibly with the help of IL-2.

In the context of type 1 diabetes, adoptive Treg therapy means correcting for the deficiency of these cells by giving Tregs from one’s self or from another individual in order to reset the natural regulatory function of the immune system and prevent the attack on the insulin-producing beta cells.

Research has shown that mice that are genetically deficient in Tregs exhibit rapid, lethal autoimmunity.

Using this unique experimental model, Dr. Allison Bayer, Research Assistant Professor in the Department of Microbiology and Immunology, and her team have demonstrated that when additional Tregs are given to these recipient mice, autoimmunity is prevented and the mice live a normal, disease-free life. Importantly, tolerance to transplanted tissue is also achieved with this type of Treg treatment.

Dr. Bayer and her team have been investigating mechanisms by which successful adoptive Treg

therapy can be achieved for the reversal of autoimmunity in type 1 diabetes or to suppress islet transplant rejection.

Their recent studies have focused on manipulating the recipient’s immune system in order to recreate the biological environment that allows donor Tregs to survive long-term and induce tolerance to transplanted tissue.

Through studies in experimental models, Dr. Bayer has identified critical factors for successful adoptive Treg therapy, which includes creating adequate space for the new cells, minimizing competition for nutrients, and adding agents, particularly IL-2, to promote their growth, survival and function. Additionally, since Tregs regulate many different types of immune cells, it is vital to direct that regulation specifically to resetting the autoimmune response itself.

This past year, Dr. Bayer and her team have developed a strategy for adoptive Treg therapy in a mouse model of spontaneous autoimmune diabetes, which closely resembles the disease process in humans. Focusing on the critical factors for creating a supportive Treg environment defined by their previous research, they have demonstrated that adoptive Treg therapy can reverse the disease and reset the autoimmune response in this experimental model. In this model, the team achieved

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disease remission in 100 percent of the recipients, with many being monitored for up to 400 days disease free. In fact, the DRI team was able to use a 20-fold less quantity of Tregs in order to achieve this outcome as compared to other scientific studies.

to patients. This is a costly and inefficient process that also carries the risk of amplifying the “bad” cells that could destroy beta cells. Dr. Bayer’s approach may circumvent or reduce the need for a large-scale Treg expansion prior to adoptive transfer to patients.

The team then went on to perform an important experiment to determine whether the adoptive Treg therapy was, in fact, directed specifically at halting the destruction of the insulin-producing beta cells that led to disease “remission,” while leaving the remainder of the immune responses intact. The researchers transplanted mismatched skin onto the same recipient to challenge the immune system’s response to foreign tissue.

The result? The skin was rejected while the beta cell acceptance (tolerance) was maintained, demonstrating that the immune system functioned as it should and the adoptive transfer was successful at resetting the autoimmune response.

Moving forward, Dr. Bayer will be investigating additional methods to recreate the supportive Treg environment, the effects of this therapy on other immune responses, and how those responses will impact Treg growth, survival and function. The team has specifically designed the experimental studies to be more easily applied to patients using clinically approved agents with a known safety profile, and their ongoing research will help determine whether donor Tregs can be used successfully in the clinical setting and advance to patients living with type 1 diabetes.

Tregs are a relatively small population of cells. The ability to achieve these results by generating a smaller number of Tregs is quite significant. Currently, methods in use for clinical adoptive Treg therapy require several rounds of expansion for growing enough cells before they are given

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In recognition of this promising work, Dr. Bayer was one of only five investigators at the University of Miami School of Medicine, three being from the Diabetes Research Institute, to receive the prestigious 2015 Stanley J. Glaser Foundation Research Award. This generous support, together with funding provided by the DRI Foundation, will allow her to further pursue this avenue of research.

INDUCING TOLERANCE WITH POTENT IMMUNOSUPPRESSIVE CELLS Status: DRI findings reveal that treatments with agents that stimulate the production of myeloidderived suppressor cells (MDSCs), such as GCSF, together with Exenatide, which stimulates beta cell function, significantly delays or prevents islet loss in islet transplant patients.

One of the five agents being proposed in the DIPIT clinical trial, GCSF (Filgrastim), is included for its ability to promote the growth of myeloid-derived suppressor cells (MDSCs), a population of immune system cells that have powerful immunological benefits.

Several studies have shown that cancerous tumors are able to evade destruction by the immune system by recruiting MDSCs to surround the malignant cells.

DRI researchers want to use this same immune mechanism to stop the autoimmune attack on the body’s own insulin-producing cells or to newly transplanted islets. The goal is to eliminate the need for anti-rejection drugs using the body’s own natural protection.

To test this theory, Dr. Luca Inverardi, the DRI’s Deputy Director of Translational Research, and his team performed a series of studies in experimental models to learn whether giving this agent to the recipients at the time of an islet transplant could prolong the survival of the insulin-producing cells. The results demonstrated that the induction of MDSCs did, in fact, delay the rejection of the transplanted islets.

That resulting data led the researchers to question whether MDSCs play a role in delaying or preventing rejection in people who received islet transplants. The team analyzed the duration of islet survival in the DRI’s cohort of islet transplant recipients. Striking findings emerged from their study. They observed that treatments with GCSF together with Exenatide, which stimulates

beta cell function, are associated with a significant delay or prevention of islet loss in a major proportion of islet transplant recipients who received this treatment.

These patients experienced a longer duration of insulin independence compared to the untreated patients.

Armed with these findings, the team has submitted a paper to the medical journal PLOS ONE. The use of GCSF, which has been a widely used clinical treatment for neutropenia in cancer patients, is considered safe and has not been linked to increased risk of disease occurrence. For this reason, in vivo (in a living organism) MDSC induction using GCSF might represent a powerful tool to prevent rejection of transplanted islet cells in patients with type 1 diabetes, and/or delay or prevent the onset of the disease in those at risk.

The DRI team also has strong data suggesting that the co-administration of both GCSF and low-dose IL-2 can significantly delay or prevent the onset of the disease in experimental models of autoimmune (type 1) diabetes.

Dr. Inverardi presented these significant findings related to the use of GCSF alone and in combination with other agents at the American Diabetes Association’s 75th Scientific Session in June 2015.

The data obtained in the murine models and the results observed in the human patients have a potentially powerful impact in helping to define the testing of these treatments in clinical trials.

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TARGETING ISLET CELLS IN VIVO Status: A special class of molecules, called aptamers, is being used to target islet cells in vivo for the purpose of delivering location markers as well as protective agents directly to the cells in the pancreas or in a DRI BioHub. Researchers have developed and tested this new technology by "mapping" the proteins on both the islet's surface and non-islet tissue and continue to test various combinations of aptamers to determine which best bind to the specific islet surface proteins.

As a way to overcome the inability to observe islets in their native pancreas or after transplantation, researchers are developing strategies to visualize and quantify beta cells in vivo (within a living organism). New advances in imaging and nanotechnology are allowing scientists to test a special class of molecules which are, essentially, the chemical equivalent of antibodies but have more advantages. Known as aptamers, these tiny strands of nucleic acids – similar to RNA but more resistant – are able to hone in and bind to specific targets on the cells. These molecules are very small in size, have low production costs, and have the key advantage of binding to cell markers without causing an immune response. These unique features make aptamers particularly attractive for delivering desired molecules or agents to islet cells within the body or in a DRI BioHub. Drs. Luca Inverardi, Paolo Serafini, Assistant Professor of Microbiology and Immunobiology, Alessia Zoso, Scientist, and Giacomo Lanzoni, Assistant Scientist, have screened billions of aptamers and identified those that target only the beta cells in both mouse models and humans.

This past year, the researchers tested this novel technology by attaching fluorescent markers to the aptamers, and then delivering the fluorescence to the living insulin-producing cells, thereby “tagging” them. After binding to the targeted islet/beta cell, sophisticated scanners pick up the signal from the fluorescently labeled islets, providing valuable information as to the quantity of living islets/beta cells and their location. The team is also adapting this technology for its use with clinical instruments, such

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as Magnetic Resonance Imaging (MRI), that is routinely used in the clinic setting. The same aptamer technology will also allow the delivery of anti-inflammatory and/or anti-rejection agents directly to the desired cells instead of shutting down the entire immune system with systemic immunosuppression.

In subsequent steps, the team optimized the aptamers by combining multiple “strands” to further increase their ability to bind to pancreatic islets and deliver the desired agents. Known as tetrameric aptamers, or tetraptamers, this four-strand design resulted in increased binding ability, while also minimizing the quantity of aptamers needed for imaging analyses.

The researchers will next begin screening the combinatorial tetraptamers with the goal of selecting the "bundled" aptamers with the highest binding efficiency to islet cells. The team will attach markers to "light up" the islets to determine the success of the islet targeting. This process will allow researchers to assess the number, size and location of the islets. Additional objectives are to use them to deliver therapeutic agents thereby locally protecting islets from immune attack, as well as to promote cell expansion and/or cell regeneration.

[

The DRI team has optimized the aptamers by combining four "strands" to further increase their ability to bind to islets.

NATURAL KILLER CELLS: RESTORING BALANCE, REVERSING AUTOIMMUNITY Status: DRI study data show that there are defects in a population of immune cells, natural killer (NK) cells, which are the first responders of the immune system, that could be caused by virus manipulation.

Additional studies indicate that the build-up of folic acid could be a major contributor to these cellular defects.

The immune system is broadly divided into two categories: the first-responding innate immune system and the learned response or adaptive immune system. The innate immune system is the arm that detects and immediately deals with any invaders, such as bacteria and viruses.

The primary cell of the innate immune system is the natural killer or NK cell, and as the name suggests, these cells, also called NK effectors (NKeff), are the attackers of the innate immune system. But this is just one arm of the NK cell population. The NK regulatory arm (NKregs) keeps immune responses from getting out of control.

Research has shown that many viruses have developed the ability to incapacitate and hide from the innate immune response, particularly targeting the natural killer effector cells, in order to remain essentially unchallenged. This manipulation creates an immune-privileged environment for the viruses to survive an attack by the NKeff cells, the first responders. DRI researchers believe that when the innate system cannot properly act upon the viruses due to that manipulation, the downstream immune system – the adaptive immune system – needs to launch an abnormally strong response. This response is likely what leads to the typical inflammation that is associated with type 1 diabetes, as well as all autoimmune conditions.

Recent data collected by Drs. Chris Fraker, Research Assistant Professor of Surgery and Cell Transplantation and a member of the DRI’s Biomedical and Tissue Engineering team, and Allison Bayer, Research Assistant Professor of Microbiology and Immunology, working together with Dr. Alberto Pugliese, Head of Immunogenetics, and Della Matheson, RN, CDE, Trial

Coordinator for DRI/University of Miami Clinical Center for the Type 1 Diabetes TrialNet Study, and their teams, has demonstrated highly significant differences in the innate immune system make-up (NK cells) between those with longstanding type 1 diabetes compared to those without diabetes. The subjects with T1D have significantly reduced NKeff populations and significantly increased NKreg populations, supporting the idea of viral manipulation, among other indications.

The data indicate that there are defects in the NK cells of type 1 diabetes patients. One potential cause of this defect could be a dysfunction in a particular cell pathway (folate pathway) due to the build-up of folic acid, which is toxic to NK immune function. Previous research, coupled with the DRI’s preliminary findings, indicate that specific enzymes within the folate pathway are significantly different in those with type 1 diabetes.

NK cell deficiency can potentially lead to susceptibility of the type of chronic and latent viral infection that has been implicated in type 1 diabetes. The researchers have submitted for grant support to pursue the links between the role of NK cells and viral infections in T1D development and the cellular folate metabolism pathway that is important in cell division, protein manufacture, and immune cell function.

In recognition of this promising work, Dr. Fraker was a recipient of the 2015 Stanley J. Glaser Foundation Research Award from the University of Miami Miller School of Medicine. This generous support, together with funding from the DRI Foundation and additional grant support, will allow him to further pursue this research initiative.

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DEVELOPING IMMUNE-MODULATORY AGENTS TO PREVENT OR REVERSE DIABETES Status: The DRI team has demonstrated that blocking a particular molecule, Smad7, that is involved in controlling inflammation and immune responses, can reverse hyperglycemia (high blood sugar) and prevent the onset of type 1 diabetes in experimental models.

Another strategy underway at the DRI involves designing new classes of drugs that can reverse or prevent type 1 diabetes by regulating (modulating) the signals between immune cells.

treatment of Crohn’s disease, the major form of inflammatory bowel disease (IBD), with very promising results, and the corresponding agent (Mongersen) has been acquired by a major pharmaceutical company.

The goal is to identify therapeutic agents that are safer and more effective than existing treatments and can be used as an ongoing therapy to prevent T1D in those who are likely to develop it, to reverse it in new-onset patients, and ultimately, in those receiving islet transplants.

Dr. Peter Buchwald, Director of the DRI’s drug discovery team, believes that this type of approach is likely to succeed within the foreseeable future, just as new drugs successfully treated many other diseases in the 20th Century.

Along these lines, the drug discovery team at the DRI has obtained very encouraging results in studies with experimental models of type 1 diabetes demonstrating the reversal, as well as prevention, of the disease using an antiSmad7 agent. In the challenging model of reversal, in which treatment is only started after the onset of hyperglycemia (high blood sugar), more than half of the Smad7 agent treated diabetic models reverted to normal blood sugar levels and adequate insulin secretion, and this was maintained even long after the treatment was discontinued. They also found results suggesting that by targeting this pathway, one could not only control the autoimmune destruction of the islet cells, but possibly even support the regeneration of islets.

Dr. Buchwald and his team have honed in on a recently identified cell signaling pathway that is involved in controlling inflammation and immune responses. In certain autoimmune diseases, a particular protein known as Smad7 can be upregulated and “interfere” with normal signaling, leading to the dysregulation of the immune response.

Inhibiting Smad7 has been shown to be effective in certain autoimmune diseases. A corresponding oral therapy is currently being studied in advanced clinical trials for the

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Ongoing work is supported by the pharmaceutical company owning the Smad7 agent since it is interested in exploring its potential for type 1 diabetes. Some of the DRI team’s work on Smad7 had been presented at the 2015 ADA Scientific Sessions in Boston, MA. In the next phase of their research, Dr. Buchwald and his team will focus on confirming the safety and efficacy of their Smad7-targeting agent and on elucidating its mechanism of action.

AN EYE ON MACROPHAGES Status: Using their “Living Window” eye model, DRI researchers have shown that macrophages, immune cells that attack invaders and protect “self” cells, can change their “type” within the local environment.

The team is working to gain a clearer understanding of these macrophages in order to develop new therapies to prevent islet rejection.

In 2008, DRI researchers developed a novel method for obtaining real-time imaging of functioning islets transplanted within the anterior chamber of the eye.

Known as the “Living Window,” this unique site allows researchers to study insulin-producing cells in a living experimental model and witness a variety of cell interactions.

Drs. Per-Olof Berggren, Head of Cell Biology and Signal Transduction, and Midhat Abdulreda, Assistant Professor of Surgery, and their team are using the Living Window to actually view and characterize the immune reactions that lead to islet destruction with the goal of developing strategies to intervene and inhibit the attack.

Research has shown that inflammation is a major cause of post-transplant islet rejection and studies with antiinflammatory agents are currently underway to address this issue. A special population of immune cells called macrophages play a key role in this inflammatory response. The “good” M2-like macrophages help to maintain a balanced islet-friendly environment, but “bad” M1-like macrophages are the cells that contribute to tissue damage and rejection after transplantation.

Drs. Berggren and Abdulreda are working to gain a clearer understanding of the functions of M1 and M2 macrophages in order to develop therapies that can prevent islet rejection and promote survival after transplantation.

Last year, the team obtained important data about the macrophages that penetrate the islets after transplantation. Their study showed for the first time that the infiltrating macrophages “change type” locally within the transplant environment. These findings open the door for approaches that can intervene with this process, both locally and systemically, to deplete “bad” M1-like macrophages and promote “good” M2-like macrophages within the transplanted islets themselves. The researchers are now focused on pursuing specific target receptors on the surface of the macrophages to promote the survival of the transplanted cells.

The results of the DRI team’s studies were presented at the American Diabetes Association’s 75th Scientific Sessions in Boston, MA, and at the 2015 IPITA Conference in Melbourne, Australia.

In recognition of this innovative research using the anterior chamber of the eye to observe cell processes in a living organism, Dr. Abdulreda was a recipient of two competitive NIH-sponsored grants, the National Research Service Award (NRSA) and a Research Career Development (K01) award. Dr. Abdulreda was also a recipient of the University of Miami’s prestigious 2015 Stanley J. Glaser Foundation Research Award.

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ISLET ENCAPSULATION: ENGINEERING PROTECTIVE BARRIERS Status: Preliminary results suggest that the DRI’s unique conformal coating technology can protect transplanted islets from rejection while maintaining normal blood sugar levels without the use of immunosuppression in experimental models.

The encapsulation of islet cells has been researched extensively as a potential therapy for type 1 diabetes.

However, there has been limited success in translating this approach to patients due to a number of issues, including the size of the capsules themselves, the materials used to coat the cells, and the inability to provide the encapsulated islets with enough oxygen to keep them healthy and functioning long term.

Dr. Alice Tomei, Director of the DRI’s Islet Immunoengineering Laboratory, and her team have pioneered a cell encapsulation method to “wrap” single islets within an ultra-thin protective barrier that conforms to the unique size and shape of each islet cell. The team’s novel conformal coating method has been designed to specifically address what are considered to be the limitations of traditional cell encapsulation strategies.

By minimizing the space between the islet cell membrane and the coating – up to 10-fold – critical oxygen and nutrient delivery is enhanced.

While the design of the coating materials is challenging – destructive immune system cells need to be screened out while oxygen, nutrients, glucose and insulin need to gain free access through the coating material – Dr. Tomei and her team have been developing and testing several combinations of biocompatible polymers – the coating material used – and have been successful in identifying a particular polymer that has demonstrated safety and efficacy in experimental models.

In preliminary findings, the team was able to protect transplanted islets from rejection while maintaining normal blood sugar levels in the study models.

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The data suggest that diabetes was reversed in less than one week and the islets continued to function long-term without the use of any anti-rejection drugs. During the course of these experiments, the team also investigated whether the choice of the transplant site where encapsulated islets are placed would have any effect on achieving normal blood sugar levels. Some of the team’s initial findings were published in several peer-reviewed journals, including Biotechnology and Bioengineering and Expert Opinion Biological Therapeutics.

In next steps, Dr. Tomei and her team will build upon these striking results in study models of diabetes that closely resemble the disease process in humans. They will further test materials that can be approved for human use with the goal of advancing this work to safety and efficacy studies in preclinical models to obtain regulatory approval.

These studies will form the basis for advancing this work to clinical trials in patients with type 1 diabetes.

A second phase of their research involves developing technologies for the targeted delivery of immunomodulatory agents within the transplant site, which can not only further protect the islets from immune attack, but potentially reduce the quantities of cells required to normalize blood glucose levels. The polymer material that is used to encapsulate the islets makes it possible to tether, or attach, bioactive compounds to the capsule surface or within the coatings themselves that may enhance graft survival. The team will be testing this approach in experimental models by implanting these coated islets within the DRI BioHub biodegradable scaffold platform.

SUPPLY DEVELOPING A RELIABLE AND PLENTIFUL SUPPLY OF INSULIN-PRODUCING CELLS – OR REGENERATING ONE'S OWN CELLS – IS ONE OF THE KEY FACTORS FOR ACHIEVING A BIOLOGICAL CURE.

The documented, long-term results of islet transplantation clearly demonstrate the ability of this cell replacement therapy to restore natural insulin production and normalize blood sugar levels in people with type 1 diabetes. However, the widespread application of this therapy to the millions who can benefit is limited due to several factors. Chief among them is the need for patients to take life-long immunosuppressant drugs to not only prevent the body from rejecting the donor cells, but to halt the autoimmune attack that caused the onset of the disease. Additionally, there is a dire shortage of donor islet cells available for transplant.

Currently, islets used for transplantation come from the pancreases of deceased donors. With organ donation in the United States at critically low levels – about 1,300 pancreases were available last year – there is clearly not enough supply to treat the millions of children and adults living with diabetes.

As the DRI’s immunology teams work to overcome the challenges posed by the immune system, other teams are developing strategies to create a reliable supply of insulinproducing cells – even by regenerating cells within the patient’s own body – that may ultimately circumvent the need for transplantation altogether.

Scientists have discovered that different cell populations within the pancreas can regenerate the endocrine, or insulin-producing, cells through reprogramming, replication, or stimulation of immature pancreatic cells known as progenitors. Rather than educating a stem cell from its earliest stages of development, pancreatic progenitors can potentially offer a shortcut. For this reason, several cell sources that have been investigated throughout the past decade and a half are no longer a primary focus for the development of beta cell replacement strategies.

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REPROGRAMMING THE NON-ENDOCRINE CELLS OF THE PANCREAS WITH A SINGLE, FDA-APPROVED AGENT Status: The DRI has successfully converted the non-endocrine cells of the pancreas into new, glucoseresponsive islet-like clusters using a single agent, BMP-7, which is already approved by the FDA for clinical use. Their published findings demonstrated for the first time that non-endocrine cells can be reprogrammed to respond to blood glucose without the use of any genetic manipulation.

Pancreatic islets constitute only about 2 percent of the organ. The remaining 98 percent is the acinar or non-endocrine pancreatic tissue (NEPT), which, after islet isolation, is routinely discarded since the exocrine function in those with diabetes continues to work normally (by producing digestive enzymes).

It has been known for some time that one of the interesting features of the NEPT is its ability to be reprogrammed into other cell types or tissues. However, conventional approaches to cell reprogramming entail genetic modification, which poses health risks to patients and has other drawbacks.

Drs. Juan Dominguez-Bendala, Director of Stem Cell Development for Translational Research, and Ricardo Pastori, Director of Molecular Biology, and their teams have pioneered the use of a novel, non-invasive means of cell reprogramming, which is expected to have a shorter path for testing in clinical transplantation trials.

This past year, the team has successfully converted the NEPT of the pancreas into new, glucose-responsive islet-like clusters using a single agent BMP-7 (bone morphogenetic protein-7), which is already approved by the Food and Drug Administration (FDA) for clinical use. Their findings, which were published in Diabetes, demonstrated for the first

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time that non-endocrine cells can be reprogrammed to respond to blood glucose without the use of any genetic manipulation.

The cells generated in this manner produced insulin levels between 50 and 250 times higher than previously published by other teams, which used genetically engineered viruses plus treatment with additional agents that are known to cause unpredictable genetic patterns in cells.

The DRI’s process represents a safer and more efficient method to increase the limited supply of insulin-producing cells for transplant. The relative simplicity of the approach, coupled with its high efficiency, makes it a prime candidate for translation to people living with type 1 diabetes.

The promise of this technology also lies in its regenerative potential in targeting the native pancreas in vivo after researchers can restore self-tolerance and halt autoimmunity. Enabling the insulin-producing cells to regenerate within the patient’s body may eliminate the need to transplant donor cells altogether and address the challenge of foreign-tissue rejection.

GENERATING INSULIN-PRODUCING CELLS FROM THE BILIARY TREE Status: The DRI team observed progenitor cells along the largest biliary and pancreatic ducts, which have shown the ability to mature into insulin-producing cells. The team has also developed an in vitro protocol that stimulates the efficient conversion of these biliary tree progenitor cells into insulinproducing cells that respond to glucose.

The use of BMP-7 is also being tested to induce progenitor cells found inside and outside of the pancreas to develop into insulin-producing cells. Recently, scientists have discovered a unique population of stem cells and progenitor cells (immature cells) in the biliary tree, a network of drainage ducts that connects the liver and pancreas to the intestine. The DRI’s Drs. Luca Inverardi, Giacomo Lanzoni, and Juan Dominguez-Bendala have been collaborating with Dr. Lola Reid from the University of North Carolina, a recognized expert in liver development and regeneration, who discovered these cells. DRI scientists have been interested in these cells because they are pancreatic “precursors,” which means they have already started down the path to become pancreatic cells. The team’s previous research has demonstrated that these stem cells in the biliary tree can mature into both liver and pancreatic cells, including insulin-producing cells.

This past year, the team developed an in vitro protocol that stimulates the commitment of biliary tree progenitor cells to develop into islet cells. During these experiments, however, the maturation was only partial in that insulinproducing cells were obtained, but they did not release insulin in a glucose responsive way. In order to stimulate the maturation of these cells into cells that would respond to glucose, the researchers combined these progenitor cells with a particular type of mesenchymal stromal cell (MSC).

Strikingly, the combination of these cells enabled the progenitors to mature into glucose-responsive insulinproducing cells.

The DRI team is planning to expand these findings and test the potential of these cells in experimental models of type 1 diabetes.

Upon further investigation, the team observed a series of niches of progenitor cells along the largest biliary and pancreatic ducts. These cells appear to have the critical characteristics that could enable them to respond to BMP-7 and mature into insulin-producing cells. The researchers are now working to generate functional beta cells from these biliary tree stem cells and pancreatic progenitor cells.

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ASSESSING ISLET QUANTITY AND FUNCTION Status: DRI researchers together with representatives from Biorep Technologies developed an automated digital system for assessing the quality and function of transplanted islets, as well as new technologies for measuring insulin release, both of which are more effective than other existing methodologies.

Dr. Peter Buchwald and his team have tested this equipment’s capabilities to ensure that it provides accurate counts, and they showed that the machine is more effective than any other existing DIA approach.

It can provide faster, more objective, and better documented islet mass quantification than the currently used manual counting procedure, and the corresponding paper has been accepted for publication in Cell Transplantation.

A major obstacle of current islet transplant procedures is the lack of reliable, reproducible, and standardized methods to assess the quantity and functionality of isolated islets before they are transplanted. Over the past several years, DRI scientists have been working closely with engineers from Miami-based Biorep Technologies to develop a fully automated digital image analysis (DIA) islet cell counter.

This new technology, which includes both the hardware and software needed for automated islet counting, was developed, tested, and calibrated in a joint effort, and a finalized version was recently delivered to the DRI.

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The DRI team also worked with Biorep to develop an advanced perifusion system for measuring glucosestimulated insulin release (GSIR), a critical technology for assessing the effects of different factors on islet function, such as varying glucose and oxygen levels, as well as the size of the islets themselves. The perifusion system is also critical for measuring the rate of response that encapsulated islets have to sensing glucose and releasing insulin. This past year, Dr. Buchwald and his team used this technology to compare the glucose responsiveness of free, non-encapsulated islets with those of islets encapsulated using the technology available at the DRI. Results demonstrated that capsule thickness is important and thinner capsules can provide more physiological response. These findings were published last year in Biomedical Engineering Online.

RESEARCH REVIEW

MULTICENTER INITIATIVES

TRIALNET Sponsored by the National Institutes of Health (NIH), Type 1 Diabetes TrialNet is an international network of researchers who are exploring ways to prevent, delay and reverse the progression of type 1 diabetes. The studies are conducted by the Type 1 Diabetes TrialNet Study Group, which is housed at the DRI under the direction of Dr. Jennifer Marks, TrialNet Clinical Center Principal Investigator.

TrialNet has conducted several studies aimed at slowing the immune system’s attack on insulin-producing cells in people newly diagnosed with type 1 diabetes. Two of the studies that TrialNet has conducted, and a third organized by the Immune Tolerance Network with TrialNet participation, have identified drugs with promise of benefit.

Currently, TrialNet is focused on altering the immune system attack in order to delay or prevent type 1 diabetes in relatives found to be at risk for the disease. Three prevention studies are ongoing – using oral insulin, the immune co-stimulation blocking drug abatacept, and a monoclonal antibody targeting activation of the immune system.

In addition, there are currently two studies underway aimed at beta cell preservation in those newly diagnosed with type 1 diabetes. TrialNet has launched a study utilizing lowdose thymoglobulin and granulocyte colony stimulating factor (GCSF). This unique approach combines two immunomodulatory therapies designed to work in concert with one another with the hope of creating a more profound and durable effect on beta cell preservation. Also, in collaboration with the Immune Tolerance Network, TrialNet has begun a study using a monoclonal antibody, tocilizumab, to block pro-inflammatory immune cells.

JDRF nPOD (NETWORK FOR PANCREATIC ORGAN DONORS WITH DIABETES) To combat type 1 diabetes, researchers need definitive knowledge about the disease and the mechanisms of the immune system that trigger an attack on insulin-producing beta cells in order to prevent its onset and, ultimately, find a cure. Historically, this knowledge had been lacking because studies in patients have been limited to collecting blood samples from those with T1D due to the scarce access researchers had to pancreas and other diseaserelated tissues.

To overcome this challenge, in 2007 JDRF seeded the creation of the Network for Pancreatic Organ Donors with Diabetes (JDRF nPOD), a global network that procures and distributes pancreatic tissue from organ donors with type 1 diabetes to further study the key immunological, histological, viral and metabolic questions related to how the disease develops. The DRI’s Dr. Alberto Pugliese, Head of Immunogenetics, and the University of Florida’s Dr. Mark Atkinson, Director of the UF Diabetes Institute, serve as Co-Executive Directors of nPOD, together with a multidisciplinary team of diabetes investigators.

Since its inception, nPOD has reviewed and ultimately approved more than 145 projects, covering many research areas relevant to T1D. Results obtained from studies of nPOD specimens are now regularly presented at virtually all major diabetes scientific meetings and many studies have been published. The 8th Annual Meeting of nPOD recently took place in Miami and was co-hosted by Dr. Pugliese together with Dr. Atkinson. Throughout the fourday conference, Dr. Pugliese gave several presentations and chaired a number of panels and committees.

To learn more visit: TrialNet www.diabetestrialnet.org nPOD www.jdrfnpod.org CIT Consortium www.citisletstudy.org Diabetes Prevention Program .www.dppos.org

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CLINICAL ISLET TRANSPLANTATION CONSORTIUM The Clinical Islet Transplantation (CIT) Consortium is a global network of clinical centers and a data coordinating center established in 2004 to conduct studies of islet transplantation in patients with type 1 diabetes. The CIT Consortium was created by the National Institutes of Health (NIH). Two NIH Institutes – the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and the National Institute of Allergy and Infectious Diseases (NIAID), sponsor the Consortium. DRI Director Dr. Camillo Ricordi serves as Chairman of the CIT Consortium Steering Committee.

Studies conducted by the CIT Consortium focus on improving the safety and long-term success of methods for transplanting islets, the insulin-producing cells of the pancreas, in people whose own islets have been destroyed by the autoimmune process that characterizes type 1 diabetes.

Recently, the Consortium announced the results of its Phase 3 multicenter clinical study suggesting that islet transplantation offers a potentially life-saving treatment for the most severe cases of type 1 diabetes in which patients experience hypoglycemia unawareness, a life-threatening complication that can lead to seizures, loss of consciousness and even death. The findings open the door for islet transplantation to be an FDA-approved therapy for those patients who experience this dangerous complication of type 1 diabetes.

DIABETES PREVENTION PROGRAM (DPP) The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) in February awarded a five-year, $1.7 million grant to Dr. Ronald Goldberg, Associate Director of Medical Affairs and Co-Director of the DRI Clinical Laboratory, and his team, which initiates Phase 3 of the Diabetes Prevention Program Outcomes Study (DPPOS). The DPP and its Outcome Study, DPPOS, conducted at 27 sites around the U.S. including the DRI, has now received continuous funding from the NIH since it was initiated in 1994. The DPP was the first multiethnic study to show that lifestyle change in the form of a low-fat, weight-reducing diet combined with an exercise program, substantially reduced the development of type 2 diabetes in high risk subjects with prediabetes.

In addition, DPP showed that metformin, one of the most widely used medications for treatment of diabetes also reduced the likelihood of diabetes development. The DPPOS then demonstrated that these effects were durable over the subsequent 10 years of follow-up. It also provided early information on whether these interventions reduced the likelihood of diabetic complications. Among women, the DRI team found that the lifestyle intervention decreased the overall prevalence of microangiopathy (eye, nerve and kidney complications) which was more common in those who developed diabetes versus those who did not.

This is important since it suggests that not only do these interventions prevent the development of diabetes, but that they may prevent or slow the development of its complications should they develop.

The fact that DPPOS is the longest running clinical trial testing the effects of metformin has made this aspect of the study the centerpiece of the new DPPOS Phase 3 trial. This is because of the increasing recognition that metformin may protect against the development of cardiovascular disease and cancer, two conditions that contribute substantially to ill-health and mortality in people with diabetes. Not only will Phase 3 test the effects of metformin on these and other diabetes complications, it will continue to examine whether a long-standing lifestyle program has benefits on these and other complications, as the participants age.

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THE DIABETES EDUCATION AND NUTRITION SERVICE AT THE DRI

The Diabetes Education and Nutrition Service at the DRI’s Eleanor and Joseph Kosow Diabetes Treatment Center continues to use collaboration, innovation, integration and evaluation as the driving forces behind its patient initiatives.

Assuming the directorship of the Diabetes Education and Nutrition Service this past year was Della Matheson, RN, CDE, who has been with the DRI for almost three decades and brings a unique expertise in clinical research and diabetes management perspectives to her new role. Together with several newly hired specialists, including dietitians and certified diabetes educators, the team has been able to meet the increasing demand for patient education and medical nutrition therapy at the DRI, thanks in large part to a generous gift from longtime benefactor Betty Dunn, who together with her late husband Lowell, has continued to support these critical services for children and adults living with diabetes.

An American Diabetes Association-recognized program, the Diabetes Education and Nutrition Service is highly respected for its expertise and excellence, which has resulted in more and more patients being referred to this DRI program. Its patient base largely comes from the DRI Kosow Clinic and University of Miami Miller School of Medicine departments (including Pediatric Endocrinology, Family Medicine, and Internal Medicine).

However, a growing number of community providers are referring their patients to the DRI Education Department for both individual sessions and group classes. In a region that is disproportionately affected by diabetes, the closure of three large, community-based diabetes education programs over the past several years has made the services provided by the DRI even more crucial for patients and their families; the DRI Education Department is unique among programs in South Florida in that it accepts referrals from physicians outside of its own practice.

In total, the DRI education team has served over 8,000 individual patients with approximately 4,000 separate patient visits occurring this year. Services are provided primarily at the DRI Education Department at the University of Miami Medical campus, however, access to dietary counseling has expanded to include the opportunity for patients to see a dietitian at the Kendall, FL, offices of the University of Miami's UHealth services twice per month.

Of those served, approximately 50 percent fall into the category in which there is no available reimbursement for education services; this includes patients who are un-insured or insured through Medicare/Medicaid.

With this financial burden, the DRI Education Department would certainly suffer from fiscal instability without the generous support of donors.

The contributions made by these philanthropists

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[

The DRI's Diabetes Education and Nutrition Service team (left to right) Lory Gonzalez, ARNP, CDE, Amy Kimberlain, RD, LD/N, and Director Della Matheson, RN, CDE.

Thanks to the generous support of the Lowell S. Dunn and Betty L. Dunn Family Foundation, the Diabetes Education and Nutrition Service at the Diabetes Research Institute continues to provide a variety of educational programs to individuals, groups, and families affected by diabetes.

provide individual patient scholarships and subsidies to the DRI Education Program that ensure adequate staff to accomplish its goal of providing comprehensive diabetes self-management education to all persons in the community regardless of financial means.

The DRI team continues to be involved in professional and community outreach initiatives, including but not limited to: • UM campus and community health services, including expansion sites throughout South Florida • Lectures for UM Medical Students, Residents, and Fellows about diabetes education principles and practices; importance of multidisciplinary team in management of patients with type 1 and type 2 diabetes • Mentorship and observation experiences to allied health professionals interested in pursuing careers as diabetes educators • Local professional presentations through American Diabetes Association and American Association of Diabetes Educators of Florida • University of Miami Grand Rounds • Diabetes Research Institute Foundation – PEP (Parents Empowering Parents) Squad and ‘Top Tips’ articles

31

[2015 annual report]

• Newspaper and television interviews for The Miami Herald, Univision, Today’s Dietitian, US News & World Report, among other media outlets The DRI Diabetes Education and Nutrition Service also coordinated three clinical experience training programs during the past year which involved up-skilling industry representatives on the medical and education standards for diabetes care. Over 100 representatives attended, with outstanding program satisfaction ratings across all programs offered.

Moving into the coming year, the DRI Diabetes Education and Nutrition Service will continue to update its very successful educational curriculum to maintain the current class schedule (e.g., Healthy Me, Diabetes Made Simple, Pump Training and the highly acclaimed Mastering Your Diabetes program). Mastering Your Diabetes (MYD) now has incorporated continuous glucose monitoring into the program so that every participant has the opportunity to wear a diagnostic CGM (continuous glucose monitor) throughout the program. In addition, a new session has been added to help patients to understand how to use this dynamic form of diabetes monitoring to better “think like a pancreas.”

The Education Service is also developing a “Transitions” program for teens exiting pediatric care/parental care to adult care/self-management responsibilities, i.e., a high school to college/working life paradigm to better facilitate these young people as they move into this next, and more independent, phase of their lives.

"There have been tremendous advancements in research toward our ultimate goal of achieving a biological cure." – DRI Director Dr. Camillo Ricordi

[diabetes research institute foundation] 32

DIABETES RESEARCH INSTITUTE FACULTY AND STAFF Faculty Camillo Ricordi, M.D

Dr. Chris Fraker

Dr. Ricardo Pastori

Stacy Joy Goodman Professor of Surgery Distinguished Professor of Medicine Professor of Biomedical Engineering, Microbiology, and Immunology Director, Diabetes Research Institute and Cellular Transplantation

Research Assistant Professor of Surgery

Research Professor of Medicine Director, Molecular Biology Laboratory

Dr. Hermes Florez Dr. Maria del Pilar Solano

Assistant Professor of Surgery

Professor of Public Health Sciences and Medicine Director, Division of Epidemiology and Population Health GRECC Director, Miami VA Healthcare System

Dr. Ashutosh Agarwal

Dr. Ronald Goldberg

Dr. Lisa Rafkin Mervis

Assistant Professor of Biomedical Engineering

Professor of Medicine Director, Diabetes Prevention Program (DPP)

Research Assistant Professor of Medicine

Dr. Rodolfo Alejandro

Dr. Luca Inverardi

Dr. Midhat Abdulreda

Professor of Medicine Director, Clinical Cell Transplant Program (CCTP)

Dr. David Baidal Assistant Professor of Medicine

Dr. Allison Bayer Research Assistant Professor of Microbiology and Immunology

Dr. Per-Olof Berggren Mary Lou Held Visiting Scientist Adjunct Professor of Surgery Director, Rolf Luft Research Center Stockholm, Sweden

Dr. Dora Berman-Weinberg Research Associate Professor of Surgery

Dr. Ernesto Bernal-Mizrachi Professor of Medicine Chief, Division Endocrinology, Diabetes, and Metabolism Deputy Director of Beta Cell Biology and Signal Transduction

Dr. Peter Buchwald Associate Professor of Molecular & Cellular Pharmacology Director, Drug Discovery Program

Dr. Juan Dominguez-Bendala Research Associate Professor of Surgery Director, Stem Cell Development for Translational Research

33 [2015 annual report]

Research Professor of Medicine Director, Immunobiology of Islet Transplantation Deputy Director of Translational Research

Dr. Norma S. Kenyon Martin Kleiman Professor of Surgery Director, Wallace H. Coulter Center for Translational Research Chief Innovation Officer, University of Miami

Dr. Elina Linetsky Research Assistant Professor of Surgery

Assistant Professor of Medicine

Dr. Alberto Pugliese Professor of Medicine Director, Immunogenetics

Dr. Paolo Serafini Assistant Professor of Microbiology and Immunobiology

Dr. Jay Skyler Professor of Medicine Deputy Director of Clinical Research and Academic Programs

Dr. Alice Tomei Assistant Professor of Biomedical Engineering

Voluntary DRI Professors Dr. Sara Farnetti

Dr. Thomas Malek

Voluntary Assistant Professor of Surgery

Professor of Microbiology and Immunology Interim Chair of Microbiology and Immunology

Dr. Daniel Mintz

Dr. Jennifer Marks

Dr. Cherie Stabler

Professor of Medicine

Adjunct Associate Professor of Biomedical Engineering

Dr. Armando Mendez Research Associate Professor of Medicine Director, Advanced Technology Platforms Director, Clinical Chemistry Lab

Dr. Shari Messinger Cayetano Associate Professor of Biostatistics Director, Biostatistics

Dr. Bresta Miranda Assistant Professor of Medicine Interim-Director, Eleanor and Joseph Kosow Diabetes Treatment Center

Voluntary Professor of Medicine

DIABETES RESEARCH INSTITUTE FACULTY AND STAFF Administrative Dr. Mitra Zehtab, MBA, Deputy Director and Chief Operating Officer Dora Cardenal, Director, Accounting Angie Arzani, Sr. Manager, Finance Sabrina Boulazreg, Sr. Manager, Business Operations

Edmundo Caldera, Administrative Assistant

Ligia Delgado,

Clinical Cell Transplant Program (CCTP)

Eleanor and Joseph Kosow Diabetes Treatment Center

Dr. Rodolfo Alejandro, Professor of

Faculty

Medicine, Director

Dr. David Baidal, Assistant Professor

Dr. Rodolfo Alejandro,

of Medicine

Professor of Medicine

Ana Alvarez Gil, ARNP Alina Cuervo, Sr. Medical Biller Stephanie Calle, Research Assistant Dr. Nathalia Padilla, Research Scholar

Dr David Baidal, Assistant Professor of Medicine

Dr. Ronald B. Goldberg, Professor of Medicine

Dr. Jennifer Marks, Professor of Medicine Dr. Bresta Miranda, Assistant Professor

Sr. Accounting Assistant

Mabel Luis, Executive Assistant Grace Perez, Sr. Buyer Juan Perez-Scholz, Manager, Sponsored Programs

Ilvis Torres, Senior Administrative Assistant

Medical Development Gary Kleiman, Sr. Development Director, Major Gifts

Aimee Siegel-Harris, Manager, Donor Relations

Biomedical Engineering Dr. Chris Fraker, Research Assistant

Clinical Research Center

of Clinical of Medicine, Interim-Director

Dr. Bresta Miranda, Assistant Professor of Medicine, Interim-Director

Dr. Maria del Pilar Solano, Assistant Professor of Clinical of Medicine

Dr. Jay Sosenko, Professor of Medicine Dr. Jay S. Skyler, Professor of Medicine

Burlett Masters, Research Support Specialist

Ada Konwai, Sr. Research Assistant

DRI Education Program Diabetes Prevention Program (Type 2)

Della Matheson, Director Lory Gonzalez, Nurse Educator Amy Kimberlain, Dietitian Dina Bardales, Supervisor, Patient Care

Dr. Ronald B. Goldberg, Professor of Medicine, Director

Juliet Ojito, Nurse Specialist, Research Jeanette Gonzalez-Calles,

Flow Cytometry Lab

Research Associate 2 Bertha Veciana, Sr. Medical Assistant

Dr. Oliver Umland, Scientist

Professor of Surgery

Dr. Mohammad Tootoonchi, Post-Doctoral Associate

Clinical Chemistry Lab Dr. Armando Mendez, Research Associate Professor of Medicine, Director Esperanza Perez, Supervisor, Medical Technology Rosa Hernandez, Research Associate 1 Elsa Cribeiro, Sr. Research Assistant Zackary Barnes, Sr. Research Assistant

Drug Discovery Program (DPP)

Histology

Dr. Peter Buchwald, Associate Professor

Kevin Johnson, Sr. Research Associate 3

of Molecular and Cellular Pharmacology, Director Dr. Konstantin Levay, Assistant Scientist Dr. Jinshui Chen, Sr. Research Associate 1

Alejandro Tamayo Garcia, Research Associate 1

Damir Bojadzic, Research Assistant

Human Cell Processing (cGMP) Facility Dr. Camillo Ricordi, Stacy Joy Goodman Professor of Surgery

Dr. Luca Inverardi, Research Professor of Medicine

Dr. Elina Linetsky, Research Assistant Professor of Surgery

Dr. Raj Hirani, Director of Regulatory Support Dr. Alejandro Alvarez-Garcia, Associate Scientist

Dr. Xiao Jing Wang, Associate Scientist

Luis Roque, Quality Assurance Auditor Carmen Castillo, Sr. Research Assistant

[diabetes research institute foundation] 34

Image Analysis Facility

Fast Track Program

Dr. Maria Bulina, Sr. Manager Research

Dr. Camillo Ricordi, Stacy Joy Goodman

Support, Director

Immunobiology of Islet Transplantation Dr. Luca Inverardi, Research Professor of Medicine, Director

Dr. Paolo Serafini, Assistant Professor of Microbiology and Immunobiology Dr. Alessia Zoso, Scientist Dr. Giacomo Lanzoni, Assistant Scientist

Immunogenetics Program Dr. Alberto Pugliese, Research Professor of Medicine, Director

Dr. Sirlene Cechin, Associate Scientist Dr. Isaac Snowhite, Associate Scientist Gloria Allende, Sr. Research Associate 2

Islet Physiology Dr. Per-Olof Berggren, Adjunct Professor of Surgery, Director

Dr. Midhat Abdulreda, Assistant Professor of Surgery

Professor of Surgery, Director Dr. Alice Tomei, Assistant Professor of Dr. Diego Correa, Director and Scientist Biomedical Engineering and Director Dr. Simona Corrao, Post-Doctoral Associate Dr. Diana Velluto, Assistant Scientist Xiumin Xu, Director, DRI-China, Dr. Maria Abreu, Post-Doctoral Associate Collaborative Human Cell Vita Manzoli, Sr. Research Associate 1 Transplant Program

Marta Garcia Contreras, Sr. Research Associate 1

Pre-Clinical Cell Processing and Translational Models Dr. Armando Mendez, Research Associate Professor of Medicine, Director

Dr. Joel Szust, Scientist and Core Director Yelena Gadea, Sr. Veterinary Technician Greycy Vega, Research Assistant

Natalia Sanders, Research Associate 1

Professor of Surgery, Director

Dr. Dora Berman-Weinberg, Research Associate Professor

Dr. Dongmei Han, Scientist Waldo Diaz, Sr. Manager,

Alexander Rabassa, Sr. Research Associate 3 James Geary, Sr. Veterinary Tech Reiner Rodriguez-Lopez, Veterinary Technician

Dr. Allison Bayer, Assistant Professor of Microbiology and Immunology Research Lab

Alexander Sands, Research Associate 1

Molecular Biology Dr. Ricardo Pastori, Research Professor of Medicine, Director

Dr. Dagmar Klein, Scientist

35

[2015 annual report]

Biomarkers and Mechanisms Panel and Chair of the Genetics Working Group Dr. Jay Sosenko, Associate Chair of Ethics and Epidemiology Dr. Lisa Rafkin-Mervis, Associate Chair of Clinical Coordination Dr. David Baidal, Co-Investigator Della Matheson, Lead Trial Coordinator

Dr. Norma Sue Kenyon, Martin Kleiman

and Immunology

Cecilia Cabello Kindelan, Supervisor

Dr. Jennifer Marks, Principal Investigator Dr. Alberto Pugliese, Vice-Chair of the

Dr. Carlos Blaschke,

Research Support

Dr. Tom Malek, Professor of Microbiology

Diabetes TrialNet

Pre-Clinical Research

Research Laboratory Alexander Shishido, Research Associate 1 Melissa Willman, Sr. Manager, Dr. Maged Hossameldin, Research Scholar

Microbiology and Immune Tolerance

Tissue Engineering and Encapsulation Technologies

Stem Cell Development for Translational Research Dr. Juan Dominguez-Bendala, Research Associate Professor of Surgery, Director Silvia Alvarez Cubela, Manager, Research Laboratory Dr. Fabiola Placeres, Research Scholar

Clinical Research Coordinator Irene B. Santiago, Sr. Administrative Assistant

EXECUTIVE OFFICERS' REPORT

>

During the past fiscal year, the Diabetes Research Institute Foundation continued its mission to raise the funds necessary to support the Diabetes Research Institute, located at the University of Miami’s Miller School of Medicine. Our sole objective is to assist the Institute’s scientists in their work to find a biological cure for type 1 diabetes. At the outset of this fiscal year, we were eagerly awaiting the start of the DRI’s BioHub pilot clinical trial. That trial was part of the first-ever study to test a new transplant site in the body – the omentum – onto which researchers would engineer a biodegradable scaffold to house insulin-producing cells.

[diabetes research institute foundation] 36

Having completed the comprehensive preparedness plan that is typical for patient studies and screening, the DRI’s clinical islet transplant team selected the first few trial candidates who met their strict selection criteria. Then, we waited for word of a donor pancreas to match one of the patients’ blood types.

Early Sunday morning, August 9, 2015, we received word that one of the patients, Wendy Peacock, from San Antonio, TX, was en route to Miami. Soon thereafter, she would become the first person to undergo this pioneering procedure. The good news continued. Within days, Wendy was producing her own insulin. In fact, the donor islets were working so well that the transplant team was able to completely discontinue her insulin therapy after only a few weeks. Not only was Wendy free from insulin injections for the first time in 26 years, but she was off exogenous insulin in record time, making these the best islet transplant results ever achieved.

We are all encouraged by these promising early outcomes – ones that may ultimately define the optimal “Site” in the body for transplanted islets. We remain keenly aware, however, that this is not the ultimate cure; and a tremendous amount of work is left to be done. Identifying an alternative transplant site to the liver is just one of the strategic areas under investigation at the Institute in the development of the DRI BioHub. We firmly believe that the DRI is on the path to a cure, but we know that the next set of steps we must take to develop a plentiful “Supply” of insulin-producing cells and, in particular, to address the challenges posed by the immune system – the “Sustainability” pillar – remain.

We know that the need to overcome the challenges of the immune system – the ability to protect transplanted insulinproducing cells – is top of mind to all of you and to every person living with diabetes. It is also top of our minds at the Diabetes Research Institute Foundation because many of us are personally affected by this disease. And we know that we will not be able to fully create a biological cure for type 1 diabetes without overcoming these hurdles.

One of our most long-standing and loyal supporters, North America’s Building Trades Unions (NABTU), approved a new $6 million pledge, having fulfilled their previous five-year commitment for $5 million. We are grateful to Sean McGarvey, NABTU President, and all of the hard-working men and women of the building trades for this extraordinary commitment.

Their impact on and friendship to the DRI and Foundation over more than four decades cannot be overstated.

We’d like to extend special thanks to the Inserra Family for their considerable, ongoing generosity. That exemplary support combines with major gifts from Paola and Piero Gandini, Liana’s Dream Foundation, and so many others.

Add in funds raised at events like the Empire Ball, the Donaldson Organization Golf Outing, the Crystal Ball, Dreams in the City, the Love and Hope Ball, and a relatively new event, Out of the Kitchen with celebrity chef Sam Talbot. Not to be forgotten is the incredible support from our many activities with Walgreens in South Florida. There are too many other important events to mention, and they have helped us to provide meaningful resources to our DRI scientists.

While we pause to thank each and every donor and volunteer, we must also acknowledge that the work we have yet to do will take significant additional financial resources. The cost of research, human trials, and ultimately finding a biological cure for type 1 diabetes is staggering. Money from everyone who cares about this disease is needed so that the DRI, the only place that is solely focused on finding a biological cure, can indeed achieve that goal.

You can make a difference in how and when we get there. All of us can. And, at this exciting juncture, when we see tangible results from our efforts, we cannot waiver. As we sincerely thank you for all you have done to support this work, we must continue to ask for your ongoing support. All of those who live with type 1 diabetes are counting on us.

Sincerely,

For that reason, the majority of the research projects now underway at the DRI focus on resolving these issues. These key initiatives, together with the exciting translational research of clinical trials, comprise the lion’s share of where the Diabetes Research Institute Foundation’s financial support is channeled.

Because there is so much exciting and highly promising work being done by Dr. Camillo Ricordi and his entire team, the need to raise the significant amount of money required to fuel their research is critically important. Many of the members of our DRI family gave generously, renewed their commitments, and helped to provide the resources necessary for moving the science forward. Several million dollars alone were provided through the estates of generous individuals, like Shirley Harris, Lillian Redlich, and others, who not only provided for the DRI during their lifetime, but made the selfless decision to help find a cure for generations to come by supporting the DRIF through their estate plans

37

[2015 annual report]

William J. Fishlinger

Joshua W. Rednik

Chairman

President and CEO

FINANCIAL SUMMARY

>

Research Funding is Critical The Diabetes Research Institute has become the world leader it is today as a result of the substantial funding provided by the Diabetes Research Institute Foundation (DRIF). This funding stream is at the heart of the DRI's ability to make significant strides toward a cure. Supported by your donations, the DRIF ensures that our scientists can jump-start new ideas while continuing innovative, cure-focused research projects. Our mission – to provide the DRI with the funding necessary to cure diabetes now – is testament to the belief that tomorrow is not soon enough to cure this disease.

[diabetes research institute foundation] 38

Diabetes Research Institute Foundation Statement of Activities for the Year ended June 30, 2015

Diabetes Research Institute Statement of Activities

Support and Revenue

Support and Revenue

Contributions Reimbursement Contracts Special Events, Net of Expenses Investment Income Total Support and Revenue

8,309,457 224,997 3,316,644 636,275 $12,487,373

Expenses and Fund Balances Program Services Research (Provided to the Diabetes Research Institute) Community Education Total Program Services

6,570,828

42%

5,246,751

33%

2,060,833

13%

Kosow Center

620,308

4%

University of Miami

302,649

2%

Corporate Grants

742,065

5%

155,318

1%

National Institutes of Health JDRF Grants

American Diabetes Association/ American Heart Assocation Grants 6,570,828 773,232

Total Support

Expenditures 852,477 1,980,958

Total Support Services

$2,833,435

Change in Net Assets

2,309,878

Research Grants Research and Clinical Support Total Expenditures

Net Assets, Beginning of Year

24,850,703

Net Assets, End of Year

$27,160,581

Fundraising Percentage Fundraising Expense as a Percentage of Support and Revenue

39

[2015 annual report]

$15,698,752 100%

$7,344,060

Support Services Administration and General Fundraising

Diabetes Research Institute Foundation

16%

14,228,058 922,957 $15,151,015

TO OUR DONORS

>

To Our Generous Donors with Deepest Gratitude...

We wish to gratefully acknowledge all of our donors whose continuous support has allowed DRI scientists to pioneer new cell-based initiatives, discover groundbreaking pathways, and Advance Research to Patients.

Our entire DRI family is extraordinary. The passionate commitment to cure this disease is ever-present and, for that reason, many new donors have joined us. We sincerely appreciate every single gift, no matter the size. Your generous contributions and tireless efforts make the DRI's progress possible.

[diabetes [diabetes research research institute institute foundation] foundation]408

“On behalf of all of us affected by this horrible disease, thank you to everyone helping to support the DRI's work toward a cure."

– Lindsey Inserra (left)

>

> “It can almost bring a tear to my eye…what these guys are doing: Dedicating their lives to finding a cure for people like me all over the world. To me, it’s pure magic.”

– Sam Talbot (second from right)

>

41 [2015 annual report]

“Thanks to everyone involved in the D.A.D.s Day program and the Labor of Love and more, the NABTU has been able to provide the Diabetes Research Institute Foundation with the crucial dollars to fund research toward our ultimate goal...curing diabetes.”

>

– NABTU President Sean McGarvey (center)

pic 37

“There really can’t be a better cause than curing diabetes.”

– Peter DiCapua (third from left)

[diabetes research institute foundation] 42

>

“This is truly one of those unique events where fun and seriousness combine effortlessly with a focus on doing good in support of diabetes research.”

– Ricardo Salmon (right)

>

“I have been deeply involved with the DRI for well over a decade...I am so proud to be a part of an organization that is working to find a cure for millions worldwide."

– Delia DeRiggi-Whitton (left) 43 [2015 annual report]

>

HERITAGE SOCIETY The Heritage Society of the Diabetes Research Institute Foundation recognizes individuals who have generously made provisions in their estate plans, through life insurance, charitable remainder trusts and gift annuities, or other deferred giving vehicles to ensure that critical funding for the Diabetes Research Institute continues into the future.

Over the years, planned giving programs have enabled many donors to make substantial gifts to the DRI in ways that have complemented their individual financial objectives. Heritage Society members have chosen to create their own personal legacies and perpetuate their philanthropic goals for all those affected by diabetes.

We are exceptionally grateful to all of our Heritage Society donors, who demonstrate the passion and vision to advance a cure beyond their lifetime.

[

“I made my bequest to do what I could so that young people in the future might have a better chance of leading healthier, more normal lives."

- David Papier

“I feel like I am part of the DRI family, and we all share a common goal. If I don’t live to see a cure, I want to continue to contribute after I’m gone.”

- Jeanine Forman-Ham

“Making a gift to support the DRI allowed me to pay tribute to my beloved wife Ethel, whose brother, uncle and cousin suffered from diabetes. I truly believe that if you give, you get back a lot of satisfaction.”

- Marvin Oltchick

“We do everything we can now, but we can do so much more in our wills.

Jake is the future, and we’re investing in our future – by leaving a legacy.”

- Irene and Sy Cohen

[diabetes research institute foundation] 44

NATIONAL BOARD OF DIRECTORS Chairman William J. Fishlinger Immediate Past Chairman Harold G. Doran, Jr. President and CEO Joshua W. Rednik Treasurer John C. Doscas Secretary Bonnie Inserra

45 [2015 annual report]

Directors Diane Beber Marlene Berg Ronald Maurice Darling, Jr. Piero Gandini Marc S. Goldfarb Esther E. Goodman Marc S. Goodman Arthur Hertz Glenn Kleiman Eleanor Kosow Sandra Levy Sean F. McGarvey Sheila F. Natbony, D.O. Ramon Poo Charles Rizzo

Ricardo Salmon David Sherr Bruce A. Siegel Kathy Simkins Jill Viner Bruce Waller

REGIONAL BOARDS OF DIRECTORS Florida Region Directors Sari Addicott Bernard Beber, M.D. Diane Beber* Crystal Blaylock Sanchez Sabrina R. Gallo Bruce Fishbein Joel S. Friedman Rene W. Guim Javier Holtz Norman Kenyon, M.D.

Vito La Forgia Sandra Levy* Ramon Poo* Cristina Poo Deborah Rand Michelle Robinson Rosa Schechter James Sensale Jacci Seskin Don Strock Richard P. Tonkinson Stephen Wagman Rita Weinstein

[diabetes research institute foundation] 46

Northeast Region Co-chairs Marc S. Goldfarb* Bruce A. Siegel* Executive Committee William J. Fishlinger* Marc S. Goodman* Barbara Hatz Bonnie Inserra* Meryl R. Lieberman John R. Luebs Allan L. Pashcow Charles Rizzo*

*Also member of National Board of Directors

47

[2015 annual report]

Directors Samantha Shanken Baker Gregory H. Besner John Carrion Diane L. Cohen Delia DeRiggi-Whitton Peter L. DiCapua Kim Dickstein Douglas R. Donaldson Iris Feldman Joan Fishlinger Lindsey Inserra-Hughes Louise Pashcow Hon. C. Raymond Radigan Ricardo Salmon* Thomas P. Silver Jonathan Tepper Bruce Waller* Roberta Waller Wendy Waller

HONORARY BOARD Lynne and Martin Baron Bernard Beber, M.D. Barbara and H. Tod Berman* Juan Elias Calles Paul Cejas John Drury Annie and Nathan* Esformes Linda and Jay Finkelstein Bernard Fogel, M.D. Edward T. Foote, ll* Jeanine Forman Ham Samuel J. Fox Lisa and Mark M. Freedman C. Thomas Gallagher Douglas Gallagher Gladys and Martin Gelb Linda and Barry Gibb Dwina Gibb Yvonne Gibb Lawrence E. Glick Jay N. Goldberg Bella Goldstein Jane and Jerrold* Goodman Senator Bob Graham Lawrence Howard, M.D. Fana and Abel Holtz Lola and Donald Jacobson Martin P. Klein Harvey M. Krueger Robert Leichtung Sidney Levy Charlotte and Eugene* Milgram Martha Mishcon Marge Kleiman Mintz

Stephen Muss Judy and John P. Newell, lll Edward James Olmos Allan L. Pashcow Michelle Robinson Blanche Rosenblatt Donna Shalala Serena and Leon J. Simkins Oscar Sotolongo Ferne and Daniel Toccin Dottie and Jack S. Weiss Lenny Wolfe Sonja Zuckerman * Deceased

[diabetes research institute foundation] 48

DRI FOUNDATION STAFF Joshua W. Rednik

Ketty Charles

President and Chief Executive Officer

Accounting Clerk

Jeffrey Young

Marisol McKay

Northeast Region Anthony E. Childs

Chief Financial Officer

Data Entry Clerk

Lori Weintraub, APR

Natalie Nichols

Senior Vice President

Receptionist

Tom Karlya

Eddy Garcia

Vice President

Courier

Director, Northeast Region

Gloria Keyloun Administrative Assistant

Manhattan Staff Amy Epstein

Jill Shapiro Miller Vice President of Gift Planning

Lauren Schreier Senior Director of Marketing and Communications

Barbara Singer Director of Special Projects

Karen Paraboo Administration and Technology Manager

Director of Special Events

Florida Region Sheryl Sulkin

Jill Salter Development Manager

Director of Special Events

Tricia Pellizzi Nicole Otto

Special Events Coordinator

Associate Director of Special Events

Dena Kawecki Special Events Manager

Sarah Mehan

Jericho Staff Lily Scarlett Director of Special Events

Special Events Coordinator

Joelle Parra Communications and Social Media Manager

Mary Revie Executive Assistant

Laurie Cummings Communications Assistant

Oneida Osuna Accounting Assistant

49 [2015 annual report]

Melinda Megale Events Manager

National Office Florida Region 200 South Park Road Suite 100 Hollywood, FL 33021 Telephone 954.964.4040 Toll-free 1.800.321.3437 Fax 954.964.7036

Northeast Region Jericho Office 410 Jericho Turnpike Suite 201 Jericho, NY 11753 Telephone 516.822.1700 Fax 516.822.3570 Manhattan Office 259 West 30th Street Suite 402 New York, NY 10001 Telephone 212.888.2217 Fax 212.888.2219

DiabetesResearch.org