ADVANCING RESEARCH TO PATIENTS - Diabetes Research...invasive surgery, has a large surface area, and more importantly, has the same blood supply and drainage characteristics of the

annual report 2015 >

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ADVANCINGRESEARCH TOPATIENTS

Message from the Director 2

Research Review 4

The Diabetes Education and Nutrition Service at the DRI 30

Faculty and Staff 33

Executive Officers’ Report 36

Financial Summary 38

To Our Donors 40

The Heritage Society 44

Boards of Directors 45

DRI Foundation Staff 49

ONE GOAL: A CURE

[diabetes research institute foundation] 2 3 [2015 annual report]

It’s my pleasure to share with you the many researchaccomplishments that took place at the DiabetesResearch Institute in the past year, including progressmade 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 newlocation for insulin producing cells (islets) to be transplantedinto 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 insulininjections – 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, andengineering new encapsulation materials to conformallycoat and protect transplanted islets from immune systemattack, 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 toconduct these important trials in multiple centers at thesame time, thus speeding the collection of data anddevelopment of meaningful therapeutic strategies.

• Ensuring a plentiful supply of cells for transplant

Read about the advances that DRI investigators have made in the area of cellular reprogramming andregeneration. 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 partnersand supporters around the world, are proud to present our research pipeline and report on the critically importantwork that is taking place for the benefit of those with T1D and their families. Advancing research to patients until thedisease is cured – this is our mission and this is our promise.

With warm regards,

Camillo Ricordi, M.D.

Stacy Joy Goodman Professor of SurgeryDistinguished Professor of MedicineProfessor of Biomedical Engineering,

Microbiology & ImmunologyDirector, Diabetes Research Institute

and Cellular Transplantation University of Miami

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

MESSAGEFROM THEDIRECTOR

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This particularly feared complication of type 1 diabetes, in whichpatients cannot sense that their blood sugar level is dropping todangerously low levels, can lead to seizures, loss of consciousnessand even death. Roughly 30 to 40 percent of those with type 1diabetes experience impaired awareness of hypoglycemia andthe 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 receivingthe donor cells, patients recover glucose awareness allowingthem to sense fluctuations in their blood sugar levels – quiteoften 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 injectionsfor more than 10 years. Others who have followed remain insulin-independent since undergoing the therapy as well.

For all of the advances in diabetes technologies, islettransplantation is the only procedure, outside of a full pancreastransplant, that has demonstrated the ability to restore naturalinsulin production in patients living with type 1 diabetes. But, as DRI researchers undeniably recognize, several challengesremain 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 tohouse the transplanted cells – researchers have known for yearsthat the liver, the current transplant site, is not ideal – there aretwo additional overarching issues: developing a reliable andplentiful supply of insulin-producing cells or regenerating theperson’s own islets; and solving the significant immune systemchallenges that initially caused the body’s attack on its own cells.

Overcoming these hurdles and discovering a biological cure fordiabetes is the sole mission at the Diabetes Research Institute.The strategic path to accomplishing this goal is being pursuedwith an intense focus on Advancing Research to Patients.

A DECADE OFFREEDOMFROM INSULINTHERAPY

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5 [2015 annual report] [diabetes research institute foundation] 4

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, thatwasn’t wearing an insulin pump attached to them everyday. And it’s miraculous. I mean it…it…it’s hard to put intowords…You guys learned things from every patient beforeme. I’m standing on their shoulders…They're [Patients tocome] going to be standing on my shoulders.”

Karla Edge, 55, diagnosed at age 6“It feels like a whole new way of life. It feels fantastic! It gives mechills just thinking about it – how my life was before compared tonow, it’s like freedom…there’s no longer that worry for me or myfamily…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.”

Chris Shuh, 64, diagnosed at age 30“The fact that it has worked so long is an incredible delight. To not worry about testing every time you walk out the door orhaving to test 10 times a day…I watched my only daughter getmarried, my husband and I are both retired and enjoying life…Today is my 64th birthday! And I’m happy to be alive!...The cureis coming. It will happen in your lifetime…do not dismay. The cure is coming!”

This past year, several of the DRI's islet transplant recipientsreached 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.

They are different ages, reside in different zip codes, and have lived for a varyingnumber of years with type 1 diabetes, but every patient who has had an islettransplant 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 unableto achieve optimal metabolic control without suffering repeated, life-threat-ening episodes of hypoglycemia unawareness.


Reaching the Biological Cure >

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.

Encapsulation

Structural Housing

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

Oxygen Delivery

Certain cells in the body that have beneficial properties can be added to

help promote long-term islet survival.

Co-delivery of “Helper” Cells

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.

Localized Drug Delivery

Restoring immune system balance to protect insulin-producing cells and prevent the re-

currence of the autoimmune process, which mistakenly destroys a person's own cells.

Re-educating the Immune SystemIdentifying, developing and/or regenerating a limitless supply of cells to sense glucose levels and produce insulin.

Increasing Cell Supply

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

Clinical Trials

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

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

Building upon decades of progress in islet transplantation, researchers are developing the DRIBioHub, 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 tofunction long term.

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 managethe 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.

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

overcome in order to reach a biological cure. These keyresearch areas, which are addressed through the BioHubstrategy, include: the Site – identifying an optimal location inthe body to house the insulin-producing cells; Sustainability– shielding insulin-producing cells from attack usingprotective barriers and, ultimately, rebalancing the immunesystem to prevent the recurrence of autoimmunity; andSupply – creating a reliable and plentiful supply of insulin-producing cells or regenerating a patient’s own cells.

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


To overcome this challenge, the DRI has exploredalternative sites within the body and has focused on theomentum, a highly vascularized tissue covering abdominalorgans. The omentum is easily accessed by minimallyinvasive surgery, has a large surface area, and moreimportantly, has the same blood supply and drainagecharacteristics of the pancreas – where islets are originallyfound before they are destroyed in type 1 diabetes.

After receiving approval from the Food and DrugAdministration (FDA) to proceed with a Phase I/II clinicaltrial 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. RodolfoAlejandro, identified several candidates who met thestringent selection criteria for the clinical trial and wereplaced on the waiting list for a matching organ.

In late August of 2015, DRI researchers successfullyperformed the unique procedure on the first patient, whobecame insulin independent within days of receiving thedonor cells – a record time for islet transplantation studies.

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

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

This was the first tissue-engineered transplant using a“biodegradable scaffold” implanted on the surface of theomentum. The technique was specifically developed tominimize the inflammatory reaction that typically occurswhen islets are implanted in the liver or in other siteswhere the cells have immediate contact with the blood.Researchers have observed that the inflammation, coupledwith other factors, leads to the loss of many of thetransplanted islets.

The DRI’s pilot trial will include up to six patients andinclude the immunosuppressive regimen currently used for clinical islet transplantation studies. At the end of twoyears, DRI researchers will assess whether two primaryendpoints have been met: the absence of severehypoglycemia 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 studiesaround the world, potentially ushering in a new era of islet transplantation and one in which more patients canbenefit from the therapy.

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

[ A press conference announcing the unprecedentedtransplant results was held three weeks after Wendy had the procedure. Pictured are (left to right) Dr. Pascal Goldschmidt, Dean, University of MiamiMiller School of Medicine; Joshua Rednik, DRIFPresident 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 IsletTransplantation; and Dr. David Baidal, AssistantProfessor of Medicine.

There are probably a million places that your averageteenager would choose to spend their 17th birthday, but ahospital room in Seoul, Korea, is certainly not one of them. But that’s where Wendy Peacock found herself that day afterexhibiting a variety of symptoms that ranged from severeweight 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 wasdiagnosed with type 1 diabetes.

Wendy was the only person in their community living withthe disease, so she and her family had no support systemaround them nor anyone to turn to for advice. And while shedidn’t know much about diabetes at the time, Wendy soonlearned that she would need to carefully plan her meals,monitor her glucose levels and take insulin shots for the restof her life. It was a “game changer,” she recalls. The followingyear, her father was re-assigned back in the U.S. and theymoved to Texas, where Wendy and her family have lived eversince. She went on to attend college and law school andworked hard to manage her diabetes. Over the years, Wendyremained in close proximity to her parents, which becameincreasingly necessary as she began suffering with severehypoglycemic episodes.

Soon the “lows” struck much more frequently, and as a singlemother of a young son, John Paul, Wendy was having adifficult time caring for herself, let alone her child. She had nochoice but to move in with her mom and dad so they couldhelp look after both of them. “I’m good at taking care of mydiabetes but sometimes it doesn’t matter what you do,” saysWendy. “One time I woke up and the paramedics were sittingon the floor. My son was crying, ‘Mommy’s sick.’ And I justdon’t want him to see me that way. I need to be able to takecare of my son.”

So Wendy set out to do just that. She recalled sometime backin 2002 seeing a news segment about an islet cell transplantand began researching information about the procedure.“When I came across what they were doing at the DRI, it reallyresonated with me,” she said. Wendy contacted the Institute'sClinical Islet Transplant team and then flew to Miami toundergo some testing for that clinical islet transplant trial.Since she was still producing some insulin at the time, she

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

In 2014, Wendy again reached out to the DRI and learnedabout the pilot BioHub trial. No longer producing insulin, sheunderwent the screening process and was told she was acandidate for the procedure. Then she waited for a matchingdonor pancreas to become available. On Sunday morning,August 16, 2015, Wendy received the phone call that wouldchange her life. That afternoon, she was on a plane headed toMiami, where DRI researchers performed the novel, minimallyinvasive islet transplant procedure two days later.

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

“The DRI team was monitoring me very closely and so everyday they would reassess based on my blood sugar gettinglower. Every day they would decrease the insulin almostincrementally. Every day it changed – less and less every dayuntil finally…none,” she explained. After being free frominsulin 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’mnot taking insulin anymore. As any type 1 diabetic knows, you live on a very structured schedule. And everything wascentered around checking my blood sugar, having my insulininjection, what time am I going to eat, do I have enough foodwith me, do I have glucose tablets,” said Wendy. “So I had toplan and structure everything about my day and so actuallyjust the other morning, I was leaving to go to the hospital for labs and I was doing my mental checklist and – then Istopped, 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 frominsulin therapy for 9 months.

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

CLINICAL TRIALS

“Through all of the emotions that I’ve experienced throughout thisprocess, 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!”

WENDY PEACOCK: FIRST PATIENT IN BIOHUB TRIALREMAINS FREE FROM INSULIN THERAPY


[While the positive early results of the DRI’s new pilot clinical trial to test the omentum asa transplant site may ultimately demonstrate that it is preferable to the liver, researcherscontinue 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 autoimmuneattack that caused the onset of type 1 diabetes (T1D).

CLINICAL TRIALS

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 inpeople with long-standing type 1 diabetes.

AGENT FUNCTION SCHEDULE

ATG (Thymoglobulin®) Used as an induction 2 doses on days 1 and 2 therapy to halt autoimmunity by depleting the attack cells (autoreactive effector cells)

GCSF (Filgrastim®) Promotes the growth of the 6 doses over 12 days desired immune suppressor cells, MDSCs, from the bone marrow

IL-2 (Proleukin®) Promotes the expansion of First 5 days and then every regulatory T cells to help restore 15 days for one year immune balance and prevent autoimmune destruction of the islets

Exenatide (Byetta®) Typically used for type 2 Weekly over one year diabetes to promote natural insulin function and has other benefits for healthy beta cell function and glucose metabolism

Etanercept ( Enbrel®) An anti-inflammatory drug to Weekly over one year eliminate inflammatory responses

The multidisciplinary DRI team that will be conducting theDIPIT 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; CamilloRicordi, M.D., DRI Director; and Khemraj Hirani, Ph.D., Director of Regulatory Affairs and Quality Assurance. (Standing, left toright) David Baidal, M.D., Assistant Professor of Medicine; andAlberto Pugliese, M.D., Head of Immunogenetics.

NEW CLINICAL TRIAL AIMS TO PRESERVE ISLET FUNCTION, HALT AUTOIMMUNITY

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.

The DRI’s goal is to eliminate the chronic, long-term needfor these drugs and to sustain the function of islets withnaturally occurring mechanisms of the immune system.While developing successful therapies has been difficultbecause type 1 diabetes is a multi-factorial disease, decadesof research progress has yielded important insights aboutthe need to attack the disease on many levels. The DRIteam, led by Drs. Camillo Ricordi, DRI Director, and Jay Skyler, Deputy Director of Clinical Research andAcademic Programs, is now poised to launch a new clinicalstudy, known as the Diabetes Islet Preservation ImmuneTreatment (DIPIT) trial, which aims to target major areas that are critical for combatting type 1 diabetes.

DRI scientists have observed over time that islet transplantoutcomes differ substantially in terms of the duration ofinsulin independence achieved by the recipients. Theyreviewed data from several islet transplant patients whohave achieved long-term insulin independence (10 years ormore) to identify factors that could be responsible for theirextremely successful results. They found that those whohave prolonged insulin independence were treated with a combination of drugs, including one that promotes thegrowth of myeloid-derived suppressor cells (MDSCs), apopulation of bone marrow (immune) cells that help createtolerance by suppressing the attack on transplanted islets.

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

These findings, together with other study results usingdifferent drug combinations, have led DRI researchers tobelieve that a cocktail of multiple agents will be successfulfor addressing three major challenges: halting the immunesystem attack, preserving the remaining islet function and,possibly, giving the body a chance to recover and regenerateits own islets.

The DIPIT trial will combine for the first time five differentagents that have demonstrated significant benefits on transplanted islets when used alone or in smallcombinations 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 firsttime that all five will be used simultaneously in aspecifically designed trial. An important facet of this trial is that the immunosuppressive agent used for theinduction therapy in this combination of drugs is ATG, and only used for two days. The other immune-modulatingagents 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.


The DRI has focused on the very vascularized omentum asan alternative implant site due to its large surface, easyaccess and physiologic drainage into the portal system.These advantages provide the ability to more closely mimicthe natural pancreas environment – housing the insulin-producing 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, hasdemonstrated its effectiveness in early Phase I/II clinicaltrials currently underway at the DRI.

This past year, the research team, led by Drs. CamilloRicordi, DRI Director, Dora Berman-Weinberg, ResearchAssociate Professor of Surgery, and Antonello Pileggi, former Director of Preclinical Cell Processing andTranslational Models, and their team submitted thispioneering work for publication.

Additionally, the further development and testing of asilicone scaffold as an alternative BioHub platform, alsoengineered for implantation within the omentum, waspursued. In their attempts to advance this work to patientswith diabetes, DRI researchers had submitted a pre-investigational New Drug (IND) application to the FDA, but were confronted with several regulatory hurdles. Whilethe islet-loaded silicone platform has shown safety and theability to achieve insulin independence in study models, the FDA requested further preclinical testing for safety andeffectiveness before granting approval for clinical trials. Dr. Norma Kenyon, Martin Kleiman Professor of Surgery,Medicine, Microbiology and Immunology and SeniorScientist, and Dr. Berman-Weinberg, and their teamsperformed biocompatibility and efficacy studies inexperimental and preclinical models, the results of which will be assessed for re-submission to the FDA.

The biodegradable scaffold is made by combining the donor islets with the patients own blood plasma and then addingthrombin, 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 ofislets implanted within the biodegradable scaffold.

THE SITE

DEVELOPING AND TESTING BIOHUB PLATFORMS WITHIN THE OMENTUM

[

THE OMENTUM SHOWS PROMISE AS ANALTERNATIVE TRANSPLANT SITE

Status: In its BioHub clinical trial, the DRI performed the first tissue-engineered transplantusing a biodegradable scaffold implanted on thesurface of the omentum. The technique, whichhas been designed to minimize the inflammatoryreaction that is normally observed when islets are implanted in the liver or in other sites withimmediate contact to the blood, has shownpromising early results.


When administered in low doses, the naturally occurringmolecule 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, thesevital regulatory cells are decreased and/or don’t functionoptimally. By promoting the expansion of these cells in theindividual with autoimmune disease, low-dose IL-2 mayprovide a way to restore the balance and allow the body to heal itself.

In an early European trial in patients with the autoimmunecondition alopecia, a type of hair loss that occurs when theimmune system mistakenly attacks hair follicles, low-dose IL-2was 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 etMarie Curie in Paris performed the first “safety” trial testingthe low-dose IL-2 treatment in patients with new onset type 1diabetes. 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. AlbertoPugliese, Head of the DRI’s Immunogenetics Program, andThomas 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 usingIL-2 for other autoimmune conditions, have provided a criticalstepping stone for conducting additional trials to evaluateoptimal 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 canstimulate 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 patientsundergoing islet transplantation or other cell replacementtherapies to block rejection and the recurrence of theautoimmune response that initially caused type 1 diabetes.

SUSTAINABILTY

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

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.

While identifying an optimal transplant site in the bodyand developing an unlimited supply of islets are key pieces of the puzzle, the need to reverse autoimmunityand prevent the rejection of transplanted cells without the need for harmful immunosuppressive drugs areleading priorities at the DRI.

Much has been learned about the immune system inrecent years, which has led researchers to develop newstrategies using the body’s own cells and naturallyoccurring processes rather than the chronic use of toxicagents that prevent the immune system from reacting to foreign tissue.

One of the major research efforts underway is the abilityto reset the immune system by restoring the balancebetween 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 inmaintaining 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, inautoimmune conditions, like type 1 diabetes, there are not enough functioning Tregs to turn off the attackinggroup of immune cells. This loss of regulation, or “balance,”results in the continued destruction of the targetedinsulin-producing cells. Restoring this immune systembalance is key to reversing autoimmunity and is the focusof several strategies underway at the DRI and withcollaborating centers.

Other research approaches are focused on protectingtransplanted cells by encapsulating them withinprotective barriers that can be engineered to incorporatebeneficial agents directly within the coating material.

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

“ADOPTING” TREGS TO RESET AUTOIMMUNITY

Status: The DRI team has developed a uniqueprotocol demonstrating that adoptive Treg therapycan reverse the disease and reset autoimmunity inexperimental models, achieving disease remission in 100 percent of the recipients. Importantly, thetherapy was directed specifically at halting thedestruction of the beta cells while the remaining immune responses remained intact.


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

In the context of type 1 diabetes, adoptive Treg therapymeans correcting for the deficiency of these cells by givingTregs from one’s self or from another individual in order to reset the natural regulatory function of the immunesystem and prevent the attack on the insulin-producingbeta cells.

Research has shown that mice that are geneticallydeficient in Tregs exhibit rapid, lethal autoimmunity. Using this unique experimental model, Dr. Allison Bayer,Research Assistant Professor in the Department ofMicrobiology and Immunology, and her team havedemonstrated that when additional Tregs are given tothese recipient mice, autoimmunity is prevented and themice live a normal, disease-free life. Importantly, toleranceto transplanted tissue is also achieved with this type of Treg treatment.

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

therapy can be achieved for the reversal of autoimmunityin 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 thebiological environment that allows donor Tregs to survivelong-term and induce tolerance to transplanted tissue.

Through studies in experimental models, Dr. Bayer hasidentified critical factors for successful adoptive Tregtherapy, which includes creating adequate space for thenew cells, minimizing competition for nutrients, andadding agents, particularly IL-2, to promote their growth,survival and function. Additionally, since Tregs regulatemany different types of immune cells, it is vital to direct that regulation specifically to resetting theautoimmune 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 closelyresembles the disease process in humans. Focusing on the critical factors for creating a supportive Tregenvironment defined by their previous research, they have demonstrated that adoptive Treg therapy can reversethe disease and reset the autoimmune response in thisexperimental model. In this model, the team achieved

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

The team then went on to perform an importantexperiment to determine whether the adoptive Tregtherapy was, in fact, directed specifically at halting thedestruction of the insulin-producing beta cells that led to disease “remission,” while leaving the remainder of theimmune responses intact. The researchers transplantedmismatched skin onto the same recipient to challenge the immune system’s response to foreign tissue.The result? The skin was rejected while the beta cellacceptance (tolerance) was maintained, demonstratingthat the immune system functioned as it should and theadoptive transfer was successful at resetting theautoimmune response.

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 forclinical adoptive Treg therapy require several rounds ofexpansion for growing enough cells before they are given

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

Moving forward, Dr. Bayer will be investigating additionalmethods to recreate the supportive Treg environment, theeffects of this therapy on other immune responses, andhow those responses will impact Treg growth, survival and function. The team has specifically designed theexperimental studies to be more easily applied to patientsusing clinically approved agents with a known safetyprofile, and their ongoing research will help determinewhether donor Tregs can be used successfully in the clinicalsetting and advance to patients living with type 1 diabetes.

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

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 ofdelivering location markers as well as protective agentsdirectly to the cells in the pancreas or in a DRI BioHub.Researchers have developed and tested this new technologyby "mapping" the proteins on both the islet's surface andnon-islet tissue and continue to test various combinations of aptamers to determine which best bind to the specificislet surface proteins.

INDUCING TOLERANCE WITH POTENTIMMUNOSUPPRESSIVE CELLS

Status:DRI findings reveal that treatments withagents that stimulate the production of myeloid-derived suppressor cells (MDSCs), such as GCSF,together with Exenatide, which stimulates beta cell function, significantly delays or prevents islet loss in islet transplant patients.


As a way to overcome the inability to observe islets in theirnative pancreas or after transplantation, researchers aredeveloping strategies to visualize and quantify beta cells in vivo (within a living organism). New advances in imagingand nanotechnology are allowing scientists to test a specialclass of molecules which are, essentially, the chemicalequivalent of antibodies but have more advantages. Knownas aptamers, these tiny strands of nucleic acids – similar toRNA but more resistant – are able to hone in and bind tospecific targets on the cells. These molecules are very small in size, have low production costs, and have the keyadvantage of binding to cell markers without causing animmune response. These unique features make aptamersparticularly attractive for delivering desired molecules oragents to islet cells within the body or in a DRI BioHub.

Drs. Luca Inverardi, Paolo Serafini, Assistant Professor ofMicrobiology and Immunobiology, Alessia Zoso, Scientist, and Giacomo Lanzoni, Assistant Scientist, have screenedbillions of aptamers and identified those that target onlythe beta cells in both mouse models and humans.

This past year, the researchers tested this novel technologyby attaching fluorescent markers to the aptamers, and thendelivering the fluorescence to the living insulin-producingcells, thereby “tagging” them. After binding to the targetedislet/beta cell, sophisticated scanners pick up the signalfrom the fluorescently labeled islets, providing valuableinformation as to the quantity of living islets/beta cells and their location. The team is also adapting thistechnology for its use with clinical instruments, such

as Magnetic Resonance Imaging (MRI), that is routinelyused in the clinic setting. The same aptamer technologywill also allow the delivery of anti-inflammatory and/oranti-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 theirability to bind to pancreatic islets and deliver the desiredagents. 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 thecombinatorial tetraptamers with the goal of selecting the"bundled" aptamers with the highest binding efficiency toislet cells. The team will attach markers to "light up" theislets to determine the success of the islet targeting. Thisprocess will allow researchers to assess the number, sizeand location of the islets. Additional objectives are to use them to deliver therapeutic agents thereby locallyprotecting islets from immune attack, as well as to promote cell expansion and/or cell regeneration.

The DRI team has optimizedthe aptamers by combiningfour "strands" to furtherincrease their ability to bindto islets.

[

One of the five agents being proposed in the DIPIT clinicaltrial, GCSF (Filgrastim), is included for its ability to promotethe growth of myeloid-derived suppressor cells (MDSCs), a population of immune system cells that have powerfulimmunological 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 immunemechanism to stop the autoimmune attack on the body’s own insulin-producing cells or to newlytransplanted 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 DeputyDirector of Translational Research, and his team performeda series of studies in experimental models to learnwhether 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 questionwhether MDSCs play a role in delaying or preventingrejection in people who received islet transplants. Theteam analyzed the duration of islet survival in the DRI’scohort of islet transplant recipients. Striking findingsemerged from their study. They observed that treatmentswith 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 islettransplant recipients who received this treatment. These patients experienced a longer duration of insulinindependence compared to the untreated patients.Armed with these findings, the team has submitted apaper to the medical journal PLOS ONE.

The use of GCSF, which has been a widely used clinicaltreatment for neutropenia in cancer patients, is consideredsafe and has not been linked to increased risk of diseaseoccurrence. For this reason, in vivo (in a living organism)MDSC induction using GCSF might represent a powerfultool to prevent rejection of transplanted islet cells inpatients 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 cansignificantly delay or prevent the onset of the disease inexperimental models of autoimmune (type 1) diabetes.

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

The data obtained in the murine models and the resultsobserved in the human patients have a potentiallypowerful impact in helping to define the testing of thesetreatments in clinical trials.

21 [2015 annual report]

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.

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

The goal is to identify therapeutic agents that are safer and more effective than existing treatments and can beused 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 discoveryteam, 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.

Dr. Buchwald and his team have honed in on a recentlyidentified cell signaling pathway that is involved incontrolling inflammation and immune responses. In certainautoimmune diseases, a particular protein known as Smad7can be upregulated and “interfere” with normal signaling,leading to the dysregulation of the immune response.Inhibiting Smad7 has been shown to be effective in certainautoimmune diseases. A corresponding oral therapy iscurrently being studied in advanced clinical trials for the

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

Along these lines, the drug discovery team at the DRI has obtained very encouraging results in studies withexperimental models of type 1 diabetes demonstrating thereversal, as well as prevention, of the disease using an anti-Smad7 agent. In the challenging model of reversal, in whichtreatment is only started after the onset of hyperglycemia(high blood sugar), more than half of the Smad7 agenttreated diabetic models reverted to normal blood sugarlevels and adequate insulin secretion, and this wasmaintained even long after the treatment wasdiscontinued. They also found results suggesting that bytargeting this pathway, one could not only control theautoimmune destruction of the islet cells, but possibly even support the regeneration of islets.

Ongoing work is supported by the pharmaceuticalcompany owning the Smad7 agent since it is interested in exploring its potential for type 1 diabetes. Some of theDRI 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 onconfirming the safety and efficacy of their Smad7-targetingagent and on elucidating its mechanism of action.

The immune system is broadly divided into two categories: the first-responding innate immune system and the learned response or adaptive immunesystem. 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 thenatural killer or NK cell, and as the name suggests, thesecells, also called NK effectors (NKeff), are the attackers ofthe innate immune system. But this is just one arm of theNK cell population. The NK regulatory arm (NKregs) keepsimmune responses from getting out of control.

Research has shown that many viruses have developed theability to incapacitate and hide from the innate immuneresponse, particularly targeting the natural killer effectorcells, in order to remain essentially unchallenged. Thismanipulation creates an immune-privileged environmentfor the viruses to survive an attack by the NKeff cells, thefirst responders. DRI researchers believe that when theinnate system cannot properly act upon the viruses due tothat manipulation, the downstream immune system – theadaptive immune system – needs to launch an abnormallystrong response. This response is likely what leads to thetypical inflammation that is associated with type 1diabetes, as well as all autoimmune conditions.

Recent data collected by Drs. Chris Fraker, ResearchAssistant Professor of Surgery and Cell Transplantation and a member of the DRI’s Biomedical and TissueEngineering team, and Allison Bayer, Research AssistantProfessor of Microbiology and Immunology, workingtogether with Dr. Alberto Pugliese, Head ofImmunogenetics, and Della Matheson, RN, CDE, Trial

Coordinator for DRI/University of Miami Clinical Center forthe Type 1 Diabetes TrialNet Study, and their teams, hasdemonstrated highly significant differences in the innateimmune system make-up (NK cells) between those withlongstanding type 1 diabetes compared to those withoutdiabetes. The subjects with T1D have significantly reducedNKeff populations and significantly increased NKregpopulations, supporting the idea of viral manipulation,among other indications.

The data indicate that there are defects in the NK cells oftype 1 diabetes patients. One potential cause of this defectcould be a dysfunction in a particular cell pathway (folatepathway) due to the build-up of folic acid, which is toxic toNK immune function. Previous research, coupled with theDRI’s preliminary findings, indicate that specific enzymeswithin the folate pathway are significantly different inthose 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 havesubmitted for grant support to pursue the links betweenthe role of NK cells and viral infections in T1D developmentand the cellular folate metabolism pathway that isimportant in cell division, protein manufacture, andimmune cell function.

In recognition of this promising work, Dr. Fraker was arecipient of the 2015 Stanley J. Glaser Foundation ResearchAward from the University of Miami Miller School ofMedicine. This generous support, together with fundingfrom the DRI Foundation and additional grant support, will allow him to further pursue this research initiative.

DEVELOPING IMMUNE-MODULATORY AGENTSTO PREVENT OR REVERSE DIABETES

Status: The DRI team has demonstrated thatblocking a particular molecule, Smad7, that isinvolved in controlling inflammation and immuneresponses, can reverse hyperglycemia (high bloodsugar) and prevent the onset of type 1 diabetes inexperimental models.

[diabetes research institute foundation] 20


In 2008, DRI researchers developed a novel method for obtaining real-time imaging of functioning isletstransplanted within the anterior chamber of the eye.Known as the “Living Window,” this unique site allowsresearchers 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 SignalTransduction, and Midhat Abdulreda, Assistant Professor of Surgery, and their team are using the Living Window to actually view and characterize the immune reactionsthat lead to islet destruction with the goal of developingstrategies to intervene and inhibit the attack.

Research has shown that inflammation is a major cause of post-transplant islet rejection and studies with anti-inflammatory agents are currently underway to addressthis issue. A special population of immune cells calledmacrophages play a key role in this inflammatoryresponse. The “good” M2-like macrophages help tomaintain 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 aftertransplantation. Their study showed for the first time thatthe infiltrating macrophages “change type” locally withinthe transplant environment. These findings open the door for approaches that can intervene with this process, both locally and systemically, to deplete “bad” M1-likemacrophages and promote “good” M2-like macrophageswithin the transplanted islets themselves. The researchersare now focused on pursuing specific target receptors onthe 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 ScientificSessions in Boston, MA, and at the 2015 IPITA Conference in Melbourne, Australia.

In recognition of this innovative research using theanterior chamber of the eye to observe cell processes ina living organism, Dr. Abdulreda was a recipient of twocompetitive NIH-sponsored grants, the National ResearchService Award (NRSA) and a Research Career Development(K01) award. Dr. Abdulreda was also a recipient of theUniversity of Miami’s prestigious 2015 Stanley J. GlaserFoundation Research Award.

AN EYE ON MACROPHAGES

Status:Using their “Living Window” eye model, DRIresearchers have shown that macrophages, immunecells that attack invaders and protect “self” cells, canchange their “type” within the local environment.The team is working to gain a clearer understandingof these macrophages in order to develop newtherapies to prevent islet rejection.

The encapsulation of islet cells has been researchedextensively 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, thematerials 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 IsletImmunoengineering Laboratory, and her team havepioneered a cell encapsulation method to “wrap” singleislets within an ultra-thin protective barrier that conformsto the unique size and shape of each islet cell. The team’snovel conformal coating method has been designed to specifically address what are considered to be thelimitations of traditional cell encapsulation strategies. By minimizing the space between the islet cell membraneand the coating – up to 10-fold – critical oxygen andnutrient delivery is enhanced.

While the design of the coating materials is challenging –destructive immune system cells need to be screened outwhile oxygen, nutrients, glucose and insulin need to gainfree access through the coating material – Dr. Tomei andher team have been developing and testing severalcombinations of biocompatible polymers – the coatingmaterial used – and have been successful in identifying a particular polymer that has demonstrated safety andefficacy in experimental models.

In preliminary findings, the team was able to protecttransplanted islets from rejection while maintainingnormal blood sugar levels in the study models.

The data suggest that diabetes was reversed in less thanone week and the islets continued to function long-termwithout the use of any anti-rejection drugs. During thecourse of these experiments, the team also investigatedwhether the choice of the transplant site whereencapsulated islets are placed would have any effect onachieving normal blood sugar levels. Some of the team’sinitial findings were published in several peer-reviewedjournals, including Biotechnology and Bioengineeringand Expert Opinion Biological Therapeutics.

In next steps, Dr. Tomei and her team will build upon thesestriking results in study models of diabetes that closelyresemble the disease process in humans. They will furthertest materials that can be approved for human use withthe goal of advancing this work to safety and efficacystudies 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 developingtechnologies for the targeted delivery of immuno-modulatory agents within the transplant site, which cannot only further protect the islets from immune attack, but potentially reduce the quantities of cells required tonormalize blood glucose levels. The polymer material thatis used to encapsulate the islets makes it possible totether, or attach, bioactive compounds to the capsulesurface or within the coatings themselves that mayenhance graft survival. The team will be testing this approach in experimental models by implanting these coated islets within the DRI BioHub biodegradablescaffold platform.

ISLET ENCAPSULATION: ENGINEERING PROTECTIVE BARRIERS

Status: Preliminary results suggest that the DRI’sunique conformal coating technology can protecttransplanted islets from rejection while maintainingnormal blood sugar levels without the use ofimmunosuppression in experimental models.

Currently, islets used for transplantation come from thepancreases of deceased donors. With organ donation inthe United States at critically low levels – about 1,300pancreases were available last year – there is clearly notenough supply to treat the millions of children and adultsliving with diabetes.

As the DRI’s immunology teams work to overcome thechallenges posed by the immune system, other teams aredeveloping strategies to create a reliable supply of insulin-producing cells – even by regenerating cells within thepatient’s own body – that may ultimately circumvent theneed for transplantation altogether.

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

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.


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, glucose-responsive islet-like clusters using a single agent,BMP-7, which is already approved by the FDA forclinical use. Their published findings demonstrated for the first time that non-endocrine cells can bereprogrammed to respond to blood glucose withoutthe use of any genetic manipulation.

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


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 isletisolation, is routinely discarded since the exocrine functionin those with diabetes continues to work normally (byproducing digestive enzymes).

It has been known for some time that one of theinteresting features of the NEPT is its ability to bereprogrammed into other cell types or tissues. However,conventional approaches to cell reprogramming entailgenetic modification, which poses health risks to patientsand has other drawbacks.

Drs. Juan Dominguez-Bendala, Director of Stem CellDevelopment for Translational Research, and RicardoPastori, 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 theNEPT of the pancreas into new, glucose-responsive islet-likeclusters using a single agent BMP-7 (bone morphogeneticprotein-7), which is already approved by the Food and DrugAdministration (FDA) for clinical use. Their findings, whichwere published in Diabetes, demonstrated for the first

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 previouslypublished by other teams, which used geneticallyengineered viruses plus treatment with additional agents that are known to cause unpredictable geneticpatterns in cells.

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

The promise of this technology also lies in its regenerativepotential in targeting the native pancreas in vivoafter researchers can restore self-tolerance and haltautoimmunity. Enabling the insulin-producing cells toregenerate within the patient’s body may eliminate theneed to transplant donor cells altogether and address the challenge of foreign-tissue rejection.


The use of BMP-7 is also being tested to induce progenitorcells found inside and outside of the pancreas to developinto insulin-producing cells. Recently, scientists havediscovered a unique population of stem cells andprogenitor cells (immature cells) in the biliary tree, anetwork of drainage ducts that connects the liver andpancreas to the intestine. The DRI’s Drs. Luca Inverardi,Giacomo Lanzoni, and Juan Dominguez-Bendala have beencollaborating with Dr. Lola Reid from the University ofNorth Carolina, a recognized expert in liver developmentand regeneration, who discovered these cells. DRI scientistshave been interested in these cells because they arepancreatic “precursors,” which means they have alreadystarted down the path to become pancreatic cells. Theteam’s previous research has demonstrated that thesestem cells in the biliary tree can mature into both liver and pancreatic cells, including insulin-producing cells.

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

This past year, the team developed an in vitro protocol that stimulates the commitment of biliary tree progenitorcells to develop into islet cells. During these experiments,however, the maturation was only partial in that insulin-producing cells were obtained, but they did not releaseinsulin in a glucose responsive way. In order to stimulatethe maturation of these cells into cells that would respondto glucose, the researchers combined these progenitor cellswith a particular type of mesenchymal stromal cell (MSC).Strikingly, the combination of these cells enabled theprogenitors to mature into glucose-responsive insulin-producing cells.

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

GENERATING INSULIN-PRODUCING CELLS FROMTHE BILIARY TREE

Status: The DRI team observed progenitor cells alongthe largest biliary and pancreatic ducts, which haveshown the ability to mature into insulin-producingcells. The team has also developed an in vitroprotocol that stimulates the efficient conversion of these biliary tree progenitor cells into insulin-producing cells that respond to glucose.

ASSESSING ISLET QUANTITY AND FUNCTION

Status:DRI researchers together with representativesfrom Biorep Technologies developed an automateddigital system for assessing the quality and functionof transplanted islets, as well as new technologies formeasuring insulin release, both of which are moreeffective than other existing methodologies.

A major obstacle of current islet transplant procedures isthe lack of reliable, reproducible, and standardized methodsto assess the quantity and functionality of isolated isletsbefore they are transplanted. Over the past several years,DRI scientists have been working closely with engineersfrom Miami-based Biorep Technologies to develop a fullyautomated digital image analysis (DIA) islet cell counter.This new technology, which includes both the hardwareand software needed for automated islet counting, wasdeveloped, tested, and calibrated in a joint effort, and afinalized version was recently delivered to the DRI.

Dr. Peter Buchwald and his team have tested thisequipment’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 betterdocumented islet mass quantification than the currently used manual counting procedure, and thecorresponding paper has been accepted for publication in Cell Transplantation.

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


RESEARCH REVIEW

TRIALNET

Sponsored by the National Institutes of Health (NIH), Type 1Diabetes TrialNet is an international network of researcherswho are exploring ways to prevent, delay and reverse theprogression of type 1 diabetes. The studies are conducted bythe Type 1 Diabetes TrialNet Study Group, which is housed at the DRI under the direction of Dr. Jennifer Marks, TrialNetClinical 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 ofthe studies that TrialNet has conducted, and a third organized by the Immune Tolerance Network with TrialNetparticipation, have identified drugs with promise of benefit.

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

In addition, there are currently two studies underway aimedat beta cell preservation in those newly diagnosed with type 1 diabetes. TrialNet has launched a study utilizing low-dose thymoglobulin and granulocyte colony stimulating factor (GCSF). This unique approach combines two immuno-modulatory 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, incollaboration 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 definitiveknowledge about the disease and the mechanisms of theimmune system that trigger an attack on insulin-producingbeta 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 collectingblood samples from those with T1D due to the scarce access researchers had to pancreas and other disease-related tissues.

To overcome this challenge, in 2007 JDRF seeded thecreation of the Network for Pancreatic Organ Donors withDiabetes (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 howthe 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 researchareas 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 nPODrecently took place in Miami and was co-hosted by Dr.Pugliese together with Dr. Atkinson. Throughout the four-day conference, Dr. Pugliese gave several presentations and chaired a number of panels and committees.

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MULTICENTER INITIATIVES

CLINICAL ISLET TRANSPLANTATION CONSORTIUM

The Clinical Islet Transplantation (CIT) Consortium is aglobal network of clinical centers and a data coordinatingcenter established in 2004 to conduct studies of islettransplantation in patients with type 1 diabetes. The CITConsortium was created by the National Institutes of Health(NIH). Two NIH Institutes – the National Institute of Diabetesand Digestive and Kidney Diseases (NIDDK) and the NationalInstitute of Allergy and Infectious Diseases (NIAID), sponsorthe 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 thepancreas, in people whose own islets have been destroyed bythe autoimmune process that characterizes type 1 diabetes.

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

DIABETES PREVENTION PROGRAM (DPP)

The National Institute of Diabetes and Digestive and KidneyDiseases (NIDDK) in February awarded a five-year, $1.7 milliongrant to Dr. Ronald Goldberg, Associate Director of MedicalAffairs and Co-Director of the DRI Clinical Laboratory, and histeam, which initiates Phase 3 of the Diabetes PreventionProgram Outcomes Study (DPPOS). The DPP and its OutcomeStudy, DPPOS, conducted at 27 sites around the U.S. includingthe DRI, has now received continuous funding from the NIHsince it was initiated in 1994. The DPP was the first multi-ethnic study to show that lifestyle change in the form of alow-fat, weight-reducing diet combined with an exerciseprogram, substantially reduced the development of type 2 diabetes in high risk subjects with prediabetes. In addition, DPP showed that metformin, one of the mostwidely used medications for treatment of diabetes alsoreduced the likelihood of diabetes development. The DPPOSthen demonstrated that these effects were durable over the subsequent 10 years of follow-up. It also provided earlyinformation on whether these interventions reduced thelikelihood 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 theseinterventions 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 trialtesting the effects of metformin has made this aspect of thestudy the centerpiece of the new DPPOS Phase 3 trial. This isbecause of the increasing recognition that metformin mayprotect against the development of cardiovascular diseaseand 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 otherdiabetes complications, it will continue to examine whether a long-standing lifestyle program has benefits on these andother complications, as the participants age.

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


THE DIABETES EDUCATION AND NUTRITION SERVICE AT THE DRI

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

Assuming the directorship of the Diabetes Educationand Nutrition Service this past year was Della Matheson,RN, CDE, who has been with the DRI for almost threedecades and brings a unique expertise in clinicalresearch and diabetes management perspectives to hernew role. Together with several newly hired specialists,including dietitians and certified diabetes educators, theteam has been able to meet the increasing demand forpatient education and medical nutrition therapy at the DRI, thanks in large part to a generous gift fromlongtime 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 highlyrespected for its expertise and excellence, which hasresulted in more and more patients being referred tothis DRI program. Its patient base largely comes from theDRI Kosow Clinic and University of Miami Miller Schoolof Medicine departments (including PediatricEndocrinology, Family Medicine, and Internal Medicine).

However, a growing number of community providers arereferring their patients to the DRI Education Departmentfor both individual sessions and group classes. In aregion that is disproportionately affected by diabetes,the closure of three large, community-based diabeteseducation programs over the past several years hasmade the services provided by the DRI even more crucial for patients and their families; the DRI EducationDepartment is unique among programs in South Floridain that it accepts referrals from physicians outside of its own practice.

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

Of those served, approximately 50 percent fall into thecategory in which there is no available reimbursementfor education services; this includes patients who are un-insured or insured through Medicare/Medicaid. With this financial burden, the DRI EducationDepartment would certainly suffer from fiscal instability without the generous support of donors. The contributions made by these philanthropists

Thanks to the generous support of the Lowell S. Dunn andBetty 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 adequatestaff 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 professionaland community outreach initiatives, including but notlimited 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

• 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 alsocoordinated three clinical experience training programsduring the past year which involved up-skilling industryrepresentatives on the medical and education standardsfor diabetes care. Over 100 representatives attended,with outstanding program satisfaction ratings across all programs offered.

Moving into the coming year, the DRI DiabetesEducation and Nutrition Service will continue to updateits very successful educational curriculum to maintainthe current class schedule (e.g., Healthy Me, DiabetesMade Simple, Pump Training and the highly acclaimedMastering Your Diabetes program). Mastering YourDiabetes (MYD) now has incorporated continuousglucose monitoring into the program so that everyparticipant has the opportunity to wear a diagnosticCGM (continuous glucose monitor) throughout theprogram. In addition, a new session has been added tohelp patients to understand how to use this dynamicform of diabetes monitoring to better “think likea 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., ahigh school to college/working life paradigm to betterfacilitate these young people as they move into thisnext, and more independent, phase of their lives.

[ The DRI's Diabetes Education and NutritionService team (left to right) Lory Gonzalez, ARNP,CDE, Amy Kimberlain, RD, LD/N, and DirectorDella Matheson, RN, CDE.


DIABETES RESEARCH INSTITUTE FACULTY AND STAFF

Camillo Ricordi, M.DStacy Joy Goodman Professor of SurgeryDistinguished Professor of MedicineProfessor of Biomedical Engineering,

Microbiology, and ImmunologyDirector, Diabetes Research Institute

and Cellular Transplantation

Dr. Midhat AbdulredaAssistant Professor of Surgery

Dr. Ashutosh AgarwalAssistant Professor of

Biomedical Engineering

Dr. Rodolfo AlejandroProfessor of MedicineDirector, Clinical Cell Transplant

Program (CCTP)

Dr. David Baidal Assistant Professor of Medicine

Dr. Allison BayerResearch Assistant Professor of

Microbiology and Immunology

Dr. Per-Olof BerggrenMary Lou Held Visiting ScientistAdjunct Professor of SurgeryDirector, Rolf Luft Research Center

Stockholm, Sweden

Dr. Dora Berman-WeinbergResearch Associate Professor of Surgery

Dr. Ernesto Bernal-MizrachiProfessor of Medicine Chief, Division Endocrinology, Diabetes,

and Metabolism Deputy Director of Beta Cell Biology and

Signal Transduction

Dr. Peter BuchwaldAssociate Professor of Molecular &

Cellular Pharmacology Director, Drug Discovery Program

Dr. Juan Dominguez-BendalaResearch Associate Professor of SurgeryDirector, Stem Cell Development for

Translational Research

Dr. Chris FrakerResearch Assistant Professor of Surgery

Dr. Hermes FlorezProfessor of Public Health Sciences

and MedicineDirector, Division of Epidemiology

and Population HealthGRECC Director, Miami VA

Healthcare System

Dr. Ronald GoldbergProfessor of MedicineDirector, Diabetes Prevention Program (DPP)

Dr. Luca InverardiResearch Professor of MedicineDirector, Immunobiology of Islet

TransplantationDeputy Director of Translational Research

Dr. Norma S. KenyonMartin Kleiman Professor of SurgeryDirector, Wallace H. Coulter Center for

Translational Research Chief Innovation Officer, University of Miami

Dr. Elina LinetskyResearch Assistant Professor of Surgery

Dr. Thomas MalekProfessor of Microbiology and Immunology Interim Chair of Microbiology

and Immunology

Dr. Jennifer MarksProfessor of Medicine

Dr. Armando MendezResearch Associate Professor of MedicineDirector, Advanced Technology PlatformsDirector, Clinical Chemistry Lab

Dr. Shari Messinger CayetanoAssociate Professor of Biostatistics Director, Biostatistics

Dr. Bresta MirandaAssistant Professor of MedicineInterim-Director, Eleanor and Joseph Kosow

Diabetes Treatment Center

Dr. Ricardo PastoriResearch Professor of MedicineDirector, Molecular Biology Laboratory

Dr. Maria del Pilar SolanoAssistant Professor of Medicine

Dr. Alberto PuglieseProfessor of MedicineDirector, Immunogenetics

Dr. Lisa Rafkin MervisResearch Assistant Professor of Medicine

Dr. Paolo SerafiniAssistant Professor of Microbiology

and Immunobiology

Dr. Jay SkylerProfessor of MedicineDeputy Director of Clinical Research

and Academic Programs

Dr. Alice TomeiAssistant Professor of Biomedical Engineering

Voluntary DRI ProfessorsDr. Sara FarnettiVoluntary Assistant Professor of Surgery

Dr. Daniel MintzVoluntary Professor of Medicine

Dr. Cherie StablerAdjunct Associate Professor

of Biomedical Engineering

Faculty

"There have been tremendousadvancements in research towardour ultimate goal of achieving abiological cure."

– DRI Director Dr. Camillo Ricordi


DIABETES RESEARCH INSTITUTE FACULTY AND STAFF

Image Analysis FacilityDr. Maria Bulina, Sr. Manager Research

Support, Director

Immunobiology of IsletTransplantationDr. Luca Inverardi, Research Professor

of Medicine, DirectorDr. Paolo Serafini, Assistant Professor of

Microbiology and Immunobiology Dr. Alessia Zoso, ScientistDr. Giacomo Lanzoni, Assistant Scientist

Immunogenetics ProgramDr. Alberto Pugliese, Research Professor

of Medicine, DirectorDr. Sirlene Cechin, Associate ScientistDr. Isaac Snowhite, Associate ScientistGloria Allende, Sr. Research Associate 2

Islet PhysiologyDr. Per-Olof Berggren, Adjunct Professor

of Surgery, Director Dr. Midhat Abdulreda, Assistant Professor

of Surgery Alexander Shishido, Research Associate 1Dr. Maged Hossameldin, Research Scholar

Microbiology and Immune ToleranceDr. Tom Malek, Professor of Microbiology

and Immunology Dr. Allison Bayer, Assistant Professor of

Microbiology and Immunology Cecilia Cabello Kindelan, Supervisor

Research LabAlexander Sands, Research Associate 1

Molecular BiologyDr. Ricardo Pastori, Research Professor

of Medicine, DirectorDr. Dagmar Klein, Scientist

Fast Track ProgramDr. Camillo Ricordi, Stacy Joy Goodman

Professor of Surgery, DirectorDr. Diego Correa, Director and Scientist Dr. Simona Corrao, Post-Doctoral Associate Xiumin Xu, Director, DRI-China,

Collaborative Human Cell Transplant Program

Marta Garcia Contreras, Sr. Research Associate 1

Pre-Clinical Cell Processing and Translational ModelsDr. Armando Mendez, Research Associate

Professor of Medicine, Director Dr. Joel Szust, Scientist and Core DirectorYelena Gadea, Sr. Veterinary TechnicianGreycy Vega, Research Assistant

Pre-Clinical Research Dr. Norma Sue Kenyon, Martin Kleiman

Professor of Surgery, DirectorDr. Dora Berman-Weinberg,

Research Associate ProfessorDr. Dongmei Han, ScientistWaldo Diaz, Sr. Manager,

Research LaboratoryMelissa Willman, Sr. Manager,

Research SupportAlexander Rabassa, Sr. Research Associate 3James Geary, Sr. Veterinary TechReiner Rodriguez-Lopez,

Veterinary Technician

Stem Cell Development forTranslational ResearchDr. Juan Dominguez-Bendala,

Research Associate Professor of Surgery, Director

Silvia Alvarez Cubela, Manager, Research Laboratory

Dr. Fabiola Placeres, Research Scholar

Tissue Engineering and Encapsulation Technologies Dr. Alice Tomei, Assistant Professor of

Biomedical Engineering and Director Dr. Diana Velluto, Assistant Scientist Dr. Maria Abreu, Post-Doctoral Associate Vita Manzoli, Sr. Research Associate 1

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

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-InvestigatorDella Matheson, Lead Trial CoordinatorDr. Carlos Blaschke,

Clinical Research CoordinatorNatalia Sanders, Research Associate 1

Irene B. Santiago, Sr. Administrative Assistant

AdministrativeDr. Mitra Zehtab,MBA, Deputy Director and Chief

Operating OfficerDora Cardenal, Director, Accounting Angie Arzani, Sr. Manager, FinanceSabrina Boulazreg, Sr. Manager,

Business OperationsEdmundo Caldera,

Administrative AssistantLigia Delgado,

Sr. Accounting Assistant Mabel Luis, Executive AssistantGrace Perez, Sr. Buyer Juan Perez-Scholz, Manager,

Sponsored ProgramsIlvis Torres,

Senior Administrative Assistant

Medical DevelopmentGary Kleiman, Sr. Development

Director, Major GiftsAimee Siegel-Harris, Manager,

Donor Relations

Biomedical Engineering Dr. Chris Fraker, Research Assistant

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 TechnologyRosa Hernandez, Research Associate 1Elsa Cribeiro, Sr. Research AssistantZackary Barnes, Sr. Research Assistant

Clinical Cell Transplant Program(CCTP)Dr. Rodolfo Alejandro, Professor of

Medicine, Director Dr. David Baidal, Assistant Professor

of Medicine Ana Alvarez Gil, ARNPAlina Cuervo, Sr. Medical BillerStephanie Calle, Research AssistantDr. Nathalia Padilla, Research Scholar

Clinical Research CenterDr. Bresta Miranda, Assistant Professor

of Medicine, Interim-Director Burlett Masters,

Research Support SpecialistAda Konwai, Sr. Research Assistant

Diabetes Prevention Program (Type 2)

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

Juliet Ojito, Nurse Specialist, ResearchJeanette Gonzalez-Calles,

Research Associate 2 Bertha Veciana, Sr. Medical Assistant

Drug Discovery Program (DPP)Dr. Peter Buchwald, Associate Professor

of Molecular and Cellular Pharmacology, Director

Dr. Konstantin Levay, Assistant Scientist Dr. Jinshui Chen, Sr. Research Associate 1Alejandro Tamayo Garcia,

Research Associate 1Damir Bojadzic, Research Assistant

Eleanor and Joseph Kosow Diabetes Treatment Center

FacultyDr. Rodolfo Alejandro,

Professor of Medicine Dr David Baidal, Assistant Professor

of Medicine Dr. Ronald B. Goldberg,

Professor of MedicineDr. Jennifer Marks, Professor of MedicineDr. Bresta Miranda, Assistant Professor

of Clinical of Medicine, Interim-Director Dr. Maria del Pilar Solano, Assistant

Professor of Clinical of MedicineDr. Jay Sosenko, Professor of MedicineDr. Jay S. Skyler, Professor of Medicine

DRI Education ProgramDella Matheson, Director Lory Gonzalez, Nurse EducatorAmy Kimberlain, Dietitian Dina Bardales, Supervisor, Patient Care

Flow Cytometry LabDr. Oliver Umland, Scientist

HistologyKevin Johnson, Sr. Research Associate 3

Human Cell Processing (cGMP) FacilityDr. Camillo Ricordi, Stacy Joy Goodman

Professor of SurgeryDr. Luca Inverardi, Research Professor

of Medicine Dr. Elina Linetsky, Research Assistant

Professor of SurgeryDr. Raj Hirani, Director of Regulatory Support Dr. Alejandro Alvarez-Garcia,

Associate ScientistDr. Xiao Jing Wang, Associate ScientistLuis Roque, Quality Assurance Auditor Carmen Castillo, Sr. Research Assistant


Having completed the comprehensive preparedness plan that is typical for patient studies and screening, the DRI’sclinical islet transplant team selected the first few trialcandidates 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 thatone of the patients, Wendy Peacock, from San Antonio, TX, wasen 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 thetransplant team was able to completely discontinue her insulintherapy after only a few weeks. Not only was Wendy free frominsulin injections for the first time in 26 years, but she was offexogenous insulin in record time, making these the best islettransplant results ever achieved.

We are all encouraged by these promising early outcomes –ones that may ultimately define the optimal “Site” in the bodyfor transplanted islets. We remain keenly aware, however, thatthis is not the ultimate cure; and a tremendous amount ofwork is left to be done. Identifying an alternative transplantsite to the liver is just one of the strategic areas underinvestigation at the Institute in the development of the DRI BioHub.

We firmly believe that the DRI is on the path to a cure, but weknow that the next set of steps we must take to develop aplentiful “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 theimmune system – the ability to protect transplanted insulin-producing cells – is top of mind to all of you and to everyperson living with diabetes. It is also top of our minds at theDiabetes Research Institute Foundation because many of usare personally affected by this disease. And we know that wewill not be able to fully create a biological cure for type 1diabetes without overcoming these hurdles.

For that reason, the majority of the research projects nowunderway at the DRI focus on resolving these issues. These keyinitiatives, together with the exciting translational research ofclinical trials, comprise the lion’s share of where the DiabetesResearch Institute Foundation’s financial support is channeled.

Because there is so much exciting and highly promising workbeing done by Dr. Camillo Ricordi and his entire team, the needto raise the significant amount of money required to fuel theirresearch is critically important. Many of the members of ourDRI family gave generously, renewed their commitments, andhelped to provide the resources necessary for moving thescience forward. Several million dollars alone were providedthrough the estates of generous individuals, like Shirley Harris,Lillian Redlich, and others, who not only provided for the DRIduring their lifetime, but made the selfless decision to helpfind a cure for generations to come by supporting the DRIFthrough their estate plans

One of our most long-standing and loyal supporters, NorthAmerica’s Building Trades Unions (NABTU), approved a new $6 million pledge, having fulfilled their previous five-yearcommitment for $5 million. We are grateful to Sean McGarvey,NABTU President, and all of the hard-working men and womenof the building trades for this extraordinary commitment. Their impact on and friendship to the DRI and Foundationover more than four decades cannot be overstated.

We’d like to extend special thanks to the Inserra Family fortheir considerable, ongoing generosity. That exemplary support combines with major gifts from Paola and PieroGandini, Liana’s Dream Foundation, and so many others. Add in funds raised at events like the Empire Ball, theDonaldson Organization Golf Outing, the Crystal Ball, Dreamsin the City, the Love and Hope Ball, and a relatively new event,Out of the Kitchen with celebrity chef Sam Talbot. Not to beforgotten is the incredible support from our many activitieswith Walgreens in South Florida. There are too many otherimportant events to mention, and they have helped us toprovide 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 dowill take significant additional financial resources. The cost ofresearch, human trials, and ultimately finding a biological curefor type 1 diabetes is staggering. Money from everyone whocares about this disease is needed so that the DRI, the onlyplace that is solely focused on finding a biological cure, canindeed achieve that goal.

You can make a difference in how and when we getthere. All of us can. And, at this exciting juncture, whenwe see tangible results from our efforts, we cannotwaiver. As we sincerely thank you for all you have doneto support this work, we must continue to ask for yourongoing support. All of those who live with type 1diabetes are counting on us.

Sincerely,

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

EXECUTIVEOFFICERS'REPORT

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Joshua W. RednikPresident and CEO

William J. FishlingerChairman

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


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

Support and Revenue

Contributions 8,309,457 Reimbursement Contracts 224,997Special Events, Net of Expenses 3,316,644 Investment Income 636,275

Total Support and Revenue $12,487,373

Expenses and Fund Balances

Program ServicesResearch (Provided to the Diabetes

Research Institute) 6,570,828 Community Education 773,232

Total Program Services $7,344,060

Support ServicesAdministration and General 852,477 Fundraising 1,980,958

Total Su pport Services $2,833,435

Change in Net Assets 2,309,878

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 16%

Diabetes Research Institute Statement of Activities

Support and Revenue

Diabetes Research Institute Foundation 6,570,828 42%

National Institutes of Health 5,246,751 33%

JDRF Grants 2,060,833 13%

Kosow Center 620,308 4%

University of Miami 302,649 2%

Corporate Grants 742,065 5%

American Diabetes Association/ American Heart Assocation Grants 155,318 1%

Total Support $15,698,752 100%

Expenditures

Research Grants 14,228,058

Research and Clinical Support 922,957

Total Expenditures $15,151,015

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FINANCIALSUMMARY


>


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 appreciateevery single gift, no matter the size. Your generous contributions and tireless efforts make the DRI's progress possible.

TO OURDONORS

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“It can almost bringa tear to my eye…what these guys are doing: Dedicating theirlives to finding a cure for peoplelike me all over the world. To me,it’s pure magic.”

– Sam Talbot (second from right)

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

– Lindsey Inserra (left)

>

>

“Thanks to everyone involvedin the D.A.D.s Day program and the Labor of Love and more, theNABTU has been able to provide the Diabetes Research InstituteFoundation with the crucial dollars to fund research toward ourultimate goal...curing diabetes.”

– NABTU President Sean McGarvey (center)

pic 37

[diabetes research institute foundation] 42 43 [2015 annual report]

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

– Peter DiCapua(third from left)

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

– Ricardo Salmon (right) >

“I have been deeplyinvolved 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) >


HERITAGESOCIETY

ChairmanWilliam J. Fishlinger

Immediate Past ChairmanHarold G. Doran, Jr.

President and CEOJoshua W. Rednik

TreasurerJohn C. Doscas

SecretaryBonnie Inserra

DirectorsDiane Beber Marlene Berg Ronald Maurice Darling, Jr.Piero GandiniMarc S. GoldfarbEsther E. Goodman Marc S. GoodmanArthur Hertz Glenn Kleiman Eleanor Kosow Sandra LevySean F. McGarvey Sheila F. Natbony, D.O. Ramon Poo Charles Rizzo

Ricardo Salmon David SherrBruce A. SiegelKathy Simkins Jill Viner Bruce Waller

NATIONAL BOARDOF DIRECTORS

The Heritage Society of the Diabetes Research Institute Foundation recognizesindividuals who have generously made provisions in their estate plans, throughlife insurance, charitable remainder trusts and gift annuities, or other deferredgiving vehicles to ensure that critical funding for the Diabetes Research Institutecontinues into the future.

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

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

[ “I made my bequest to do what I could so that youngpeople in the future might have a better chance of leadinghealthier, more normal lives."- David Papier

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

“Making a gift to support the DRI allowed me to paytribute to my beloved wifeEthel, whose brother, uncleand cousin suffered fromdiabetes. I truly believe that if you give, you get back alot of satisfaction.”- Marvin Oltchick

“We do everything we cannow, but we can do so much more in our wills. Jake is the future, and we’reinvesting in our future – byleaving a legacy.” - Irene and Sy Cohen


Northeast Region

Co-chairsMarc S. Goldfarb*Bruce A. Siegel*

Executive CommitteeWilliam J. Fishlinger*Marc S. Goodman*Barbara HatzBonnie Inserra*Meryl R. LiebermanJohn R. LuebsAllan L. PashcowCharles Rizzo*

Directors Samantha Shanken Baker Gregory H. BesnerJohn CarrionDiane L. CohenDelia DeRiggi-WhittonPeter L. DiCapuaKim DicksteinDouglas R. DonaldsonIris FeldmanJoan FishlingerLindsey Inserra-Hughes Louise PashcowHon. C. Raymond RadiganRicardo Salmon*Thomas P. Silver Jonathan TepperBruce Waller*Roberta WallerWendy Waller

Florida Region

DirectorsSari AddicottBernard Beber, M.D. Diane Beber* Crystal Blaylock SanchezSabrina R. GalloBruce FishbeinJoel S. FriedmanRene W. GuimJavier Holtz Norman Kenyon, M.D.

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

*Also member of National Board of Directors

REGIONAL BOARDSOF DIRECTORS


DRI FOUNDATIONSTAFF

Lynne and Martin BaronBernard Beber, M.D.Barbara and H. Tod Berman*Juan Elias CallesPaul CejasJohn DruryAnnie and Nathan* EsformesLinda and Jay FinkelsteinBernard Fogel, M.D.Edward T. Foote, ll*Jeanine Forman HamSamuel J. FoxLisa and Mark M. FreedmanC. Thomas GallagherDouglas GallagherGladys and Martin GelbLinda and Barry GibbDwina GibbYvonne GibbLawrence E. GlickJay N. GoldbergBella GoldsteinJane and Jerrold* GoodmanSenator Bob GrahamLawrence Howard, M.D.Fana and Abel HoltzLola and Donald JacobsonMartin P. KleinHarvey M. KruegerRobert LeichtungSidney LevyCharlotte and Eugene* MilgramMartha MishconMarge Kleiman Mintz

Stephen MussJudy and John P. Newell, lllEdward James OlmosAllan L. PashcowMichelle RobinsonBlanche RosenblattDonna ShalalaSerena and Leon J. SimkinsOscar SotolongoFerne and Daniel ToccinDottie and Jack S. WeissLenny WolfeSonja Zuckerman

* Deceased

HONORARYBOARD


Joshua W. RednikPresident and Chief Executive Officer

Jeffrey YoungChief Financial Officer

Lori Weintraub, APR Senior Vice President

Tom Karlya Vice President

Jill Shapiro Miller Vice President of Gift Planning

Lauren Schreier Senior Director of Marketing and Communications

Barbara Singer Director of Special Projects

Karen ParabooAdministration and Technology Manager

Joelle ParraCommunications and Social Media Manager

Mary RevieExecutive Assistant

Laurie Cummings Communications Assistant

Oneida OsunaAccounting Assistant

Ketty CharlesAccounting Clerk

Marisol McKay Data Entry Clerk

Natalie Nichols Receptionist

Eddy GarciaCourier

Florida RegionSheryl SulkinDirector of Special Events

Nicole Otto Associate Director of Special Events

Dena KaweckiSpecial Events Manager

Sarah MehanSpecial Events Coordinator

Northeast RegionAnthony E. ChildsDirector, Northeast Region

Gloria KeylounAdministrative Assistant

Manhattan StaffAmy EpsteinDirector of Special Events

Jill Salter Development Manager

Tricia PellizziSpecial Events Coordinator

Jericho StaffLily Scarlett Director of Special Events

Melinda MegaleEvents Manager

DiabetesResearch.org

National OfficeFlorida Region 200 South Park RoadSuite 100Hollywood, FL 33021 Telephone 954.964.4040 Toll-free 1.800.321.3437 Fax 954.964.7036

Northeast RegionJericho Office410 Jericho TurnpikeSuite 201Jericho, NY 11753Telephone 516.822.1700Fax 516.822.3570

Manhattan Office259 West 30th StreetSuite 402New York, NY 10001Telephone 212.888.2217Fax 212.888.2219

Documents

ADVANCING RESEARCH TO PATIENTS - Diabetes Research...invasive surgery, has a large surface area, and more importantly, has the same blood supply and drainage characteristics of the