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1 Encapsulation JDRF Encapsulation Research Progress Report 2015 PRESENTED TO Name Line One Name Line Two (optional - Delete this line if not needed) MARCH 12, 2015

2 Back to top IN THIS ISSUE INTRODUCTION 2 PROGRESS OVERVIEW 3 RESEARCH HIGHLIGHTS 5 WHAT S AHEAD 7 JDRF ENCAPSULATION PROGRAM FUNDING HIGHLIGHTS 8 Imagine... a future without insulin injections Thanks to donors support of JDRF s pioneering research, we know that it is possible to end an individual s dependence on injected insulin and achieve normal blood-glucose control by transplanting pancreatic islet cells into people living with type 1 diabetes T1D. Islet-cell transplantation has demonstrated the life-changing impact of cell-replacement therapy. Studies have shown that isletcell transplant recipients can achieve normalized blood-glucose control without the hourly ordeal of testing, carbohydrate counting, insulin-dosage calculation, and infusion of insulin by injection or pump for up to five years. Yet widespread use of islet transplantation is not possible because of two major obstacles a lack of available islets for transplantation and the need for transplant recipients to take immunosuppressive drugs to prevent the immune system from attacking the transplanted cells. Encapsulated cell therapies can overcome both obstacles. By wrapping either stem cell-derived islets or progenitor cells with the ability to mature into islets in a protective barrier before implanting them in the body, the encapsulated cells would sense a person s blood-glucose levels and produce insulin and other required hormones as needed. The protective barrier would shield them from the destructive immune responses associated with T1D and transplantation, and the implanted cells would be effective for months, possibly years, at a time before needing to be replaced. As currently envisioned, encapsulated cellreplacement therapies would involve an individual with T1D receiving one or more implants during a minimally invasive outpatient procedure. The implants would need to be periodically replaced. The JDRF Encapsulated Cell Therapy Research Program is a crucial link in our commitment to advance more effective treatment and disease-management options along the way to a cure for T1D. Encapsulation is a key technology platform that would make islet replacement safer and accessible to more individuals with T1D with the goal of making them insulin independent for months to years at a time. 2

3 Back to top Stem Cell Advances The potential for utilizing stem cells to create replacement beta cells (the portion of an islet-cell cluster responsible for producing insulin) that could be used to treat people with T1D was envisioned early on in the field of encapsulated beta cell therapy research. PROGRESS OVERVIEW JDRF launched the encapsulation program in Since that time, researchers have made substantial progress thanks to our multifaceted program of incentives, collaboration, and direct funding of research. The program comprises industry partnerships, support for academic research, and the JDRF Encapsulation Consortium. JDRF Encapsulation Consortium Structure LOCAL IMMUNOSUPPRESSION Mass. General Hospital Northwestern Univ. Georgia Tech Univ. Ecole Polytech (CH) Univ. British Columbia (CA) Univ. Louisville U. Miami/DRI NOVEL BIOMATERIALS MIT/Univ. Mass./Harvard/Joslin Kings College (UK) Northwestern Univ. Georgia Tech Univ. U. Alberta (CA) Emory Univ. Data & protocol sharing Cross-team comparisons Standardization Core facilities TRANSLATIONAL STUDIES Mass. General Hospital & Vanderbilt Univ. Univ. Minnesota Emory Univ. Univ. Alberta (CA) Living Cell Technology Co. MACRO DEVICE DESIGNS Univ. Miami/DRI Brighams & Womens Hosp. Univ. Alberta (CA) Univ. Twente (NL) Univ. Cal. San Francisco Univ. British Columbia (CA) STANDARDIZATION TOOLS Univ. California Irvine Vrije Univ. (BE) Fifteen years ago, on the heels of a major scientific breakthrough that isolated human embryonic stem cells (hesc), JDRF became one of the first organizations to fund research aimed at using hesc to create an unlimited supply of functioning beta cells that could be used to treat, or ultimately cure, T1D. Around this same time, JDRF became aware of a growing body of research suggesting that adult stem cells might also hold promise as a source for creating beta cells. As a result, the JDRF grantreview process has focused on funding a range of promising research using both embryonic and adult stem cells to create beta cells. In 2002, for example, JDRF partnered with the Swedish Research Council and the Swedish Diabetes Association and in 2003 joined forces with the United Kingdom s Wellcome Trust to fund several T1D-related stem cell-research projects. By 2004, JDRF was funding embryonic and adult human stem-cell research being conducted in 17 different laboratories around the globe. Today, this early research is proving relevant in the advancement of JDRFsupported encapsulated cell therapy research. For example: An hesc line developed in 2005 by CyThera with the help of JDRF funding is currently being used to create the encapsulated islets used in an experimental therapy being developed by ViaCyte the successor company to CyThera and a JDRF research partner. While JDRF has moved beyond funding basic stem-cell research, the promise of our previous investments is coming to bear in therapies such as the one being developed by ViaCyte. The JDRF Encapsulation Consortium brings together the world s leading scientists and research institutions to work together on solving critical remaining challenges to developing market-ready encapsulated cell therapies for the treatment of T1D. 3

4 continued from page 3 Progress Overview Back to top We have made tremendous strides in the following areas: Identifying multiple sources of potential cells to use in encapsulation devices: Porcine (or Xeno) islets derived from specific pathogen-free pig herds Human embryonic stem cell-derived (hesc) islets Research and development of potential encapsulation materials: Alginate (seaweed-derived) encapsulation materials Chitosan (shellfish-derived) encapsulation materials Microcapsules (individually encapsulated replacement cells) Macro-encapsulation devices (encapsulates multiple replacement cells) Multiple research teams testing potential devices in clinical trials: Porcine islets in alginate capsules Human islets in alginate microcapsules hesc-derived replacement cells in a macro device In many ways, charting a path towards encapsulated cell therapy is akin to navigating a maze: there are multiple starting points, but only a few will get you to your destination. 4

5 Back to top RESEARCH HIGHLIGHTS In many ways, charting a path toward encapsulated cell therapy is akin to navigating a maze: there are multiple starting points but only a few will get you to your destination, and some routes are more direct than others. Since we have no way of knowing which route(s) will get us to our goal, JDRF s dynamic plan calls for supporting research into a variety of cell-source therapies, encapsulation materials, and device prototypes. These research projects are in various stages of execution, including preclinical animal testing and early-phase clinical testing with human volunteers. The following are highlights of JDRF-supported encapsulated cell therapy research that is opening the door to exciting breakthroughs in T1D treatment. ROBERT S. LANGER, PH.D. For the past eight years, Dr. Langer s JDRF-funded research has focused on developing the best biomaterials for encapsulating replacement cells. Improving alginate encapsulation material is among his endeavors. While alginate capsules can form a barrier that protects implanted islets from attacking T-cells, the capsules themselves don t always escape detection by the immune system. When that happens, scar tissue can form around the implanted capsules, preventing them from properly releasing insulin. To overcome this problem, Dr. Langer, along with his co-investigator Dan Anderson, Ph.D., and their team of researchers at the Massachusetts Institute of Technology and Boston Children s Hospital, has been working on a variety of ways to help alginate capsules remain safe from detection or attack by the immune system. His team has used a highthroughput method to generate thousands of novel materials, some of which have shown superior biocompatibility compared to existing alginate preparations. Another solution involves embedding encapsulation devices with anti-inflammatory drugs that are released the first few days after implantation takes place when the immune system is most active. In the coming months, Dr. Langer anticipates publishing his findings. JONATHAN LAKEY, PH.D JDRF is currently supporting the work of Dr. Lakey, director of research and surgery at University of California-Irvine, to create a standard for developing encapsulated cell therapy devices. Dr. Lakey s work aims to sort out which cell sources and encapsulation technologies work best together; establish a threshold for device efficacy; and provide device developers guidance in selecting cell formulations and encapsulation materials for their products. To facilitate his efforts, Dr. Lakey has established agreements with several companies to assess their developing technology. He is currently working, for example, with Cellartis AB/Novo Nordisk to test the efficacy and safety of the company s hesc cell preparation when combined with various encapsulation approaches. Dr. Lakey is also collaborating with Islet Sheet Medical to determine the biocompatibility and immune-protection properties of its Alginate Sheet a thin macro-encapsulation product. What he learns through these and other collaborations will ultimately inform his efforts to develop standards for encapsulated cell therapy devices. MARK POZNANSKY, M.D., PH.D. Dr. Poznansky, director of the Vaccine and Immunology Center at Massachusetts General Hospital, is investigating ways to enhance encapsulation materials ability to protect islets from T-cell attacks without crippling an implant recipient s entire immune system. With the help of JDRF funding, Dr. Poznansky has been leading research into CXCL12, a naturally occurring protein that can repel immune cells. His team is testing whether incorporation of this protein into alginate encapsulation materials can provide islets better protection against immune system attacks. Dr. Poznansky s research has already demonstrated that diabetic mice that received replacement cells encapsulated in an alginate material laced with the CXCL12 protein were protected from immune damage and lived significantly longer in a non-diabetic state than mice receiving encapsulated cells without CXCL12. Dr. Poznansky s next steps include optimizing the CXCL12 formulation and designing a large-animal study to test the product s efficacy and safety. 5

6 continued from page 5 Research Highlights Back to top JDRF s dynamic plan calls for supporting research into a variety of cellsource therapies, encapsulation materials, and device prototypes. This work is opening the door to exciting breakthroughs in T1D treatment. TIMOTHY KIEFFER, PH.D. Dr. Kieffer, diabetes research group leader and a professor at the University of British Columbia, is conducting JDRFsupported preclinical studies testing the safety and efficacy of a prototype device being developed by BetaLogics, a Johnson & Johnson company focused on encapsulated cell therapy. In previous studies, Dr. Kieffer and his team demonstrated that BetaLogics cell-development protocol could successfully coax hescs into becoming islet-like cells that produce insulin and control blood glucose once implanted into small-animal models. In forthcoming studies, Kieffer s research will focus on assessing how well the BetaLogics encapsulation device can provide immune protection and prevent cell escape. The information gleaned from these studies will help BetaLogics refine its proto-type device and move it toward human clinical trials. DANIEL PIPELEERS, M.D., PH.D. JDRF is currently funding Dr. Pipeleers work to assess whether encapsulated cells function longest and best when implanted as microcapsules where individual cells are encapsulated and injected into a recipient s body or as a macro device where all of the beta cells are encapsulated in a single device and placed into the body. Dr. Pipeleers, who is director of the Diabetes Research Center at Brussels Free University, will use encapsulated cells from ViaCyte (which is developing a macro-encapsulation device) and Beta-Cell NV (which is developing microcapsule technology to compare the two approaches. The research team will perform both preclinical and clinical trials to assess the safety and efficacy of the two technologies. The findings will help define conditions and quality-control criteria for development of large-scale production of encapsulated cell implants. DOUG MELTON, PH.D. JDRF-supported Harvard University researcher Doug Melton, Ph.D., has developed a method for fully converting human stem cells into insulin-producing beta cells while still in the lab. Previous lab methods were only able to convert stem cell to immature beta cells, which then required weeks to months to mature into insulin-producing cells. Dr. Melton s new method, which will significantly speed the conversion process, is an important advance towards potential large-scale, rapid production of human beta cells. Current sources of human beta cells are largely limited to cadaver donors. Once perfected, however, Dr. Melton s conversion method could exponentially increase the availability of human beta cells, speeding delivery of novel encapsulated cell therapies and accelerating basic research on a cure for the disease. JDRF recently awarded a new multimillion dollar research grant to Dr. Melton for scaling up production of beta cells using his new method. Dr. Melton will also begin working with other members of the JDRF Encapsulation Consortium to conduct animal tests of experimental encapsulation products using this new source of beta cells. 6

7 continued from page 6 Research Highlights Back to top ViaCyte s experimental encapsulated cell therapy for treatment of T1D combines an islet precursor-cell formulation known as VC-01 and its Encaptra encapsulation device. VIACYTE JDRF began funding development of ViaCyte s encapsulated cell therapy research in 2011, and since then a total of $13 million in funding has been committed by JDRF provided certain milestones are achieved. ViaCyte has created a unique cell-replacement product called VC-01, which in preclinical trials proved capable of controlling blood-glucose levels in diabetic mice. The company uses various lab techniques to grow and coax hescs into precursor islet cells. The precursor cells are placed into ViaCyte s encapsulation device called Encaptra to create the implantable cell-replacement product. In studies, VC-01 cells that were implanted in animal models developed into fully functioning islets that secrete insulin and other blood glucose-controlling hormones. The novel device allows oxygen and other nutrients to feed the developing islets while protecting them from an immune-system attack. In July 2014, ViaCyte announced that it submitted an investigational new drug application to the FDA. In August, the FDA gave ViaCyte the green light to begin the first ever clinical evaluation of a stem cellderived replacement therapy for people with T1D. The study will focus on assessing the safety of VC-01, but other information will be collected that may also provide hints of its benefit. WHAT S AHEAD ViaCyte Chief Scientific Officer Kevin D Amour explains his company s developing approach to encapsulated cell therapy for the treatment of T1D. Click on the video above or go to to see this clip. JDRF has transformed beta cell encapsulation from a sleepy field into a vibrant, dynamic one, with multiple products at every phase of the pipeline. But there is much more to be done. The JDRF Encapsulation Consortium has identified the following priorities for its ongoing work. Developing new biomaterials and new device designs Exploring micro- and macro-encapsulation and hybrid device designs Understanding the limitations of current designs Improving long-term function and testing in large animals Advancing encapsulation devices into clinical trials As we guide these first-generation products through testing and to market, we are also supporting the discovery and development of better materials and designs that will enable longer product lifespans, easier implantation, and better compatibility with human tissue. Your support will help to ensure the continuation and expansion of the type of groundbreaking encapsulated cell-therapy research that will be instrumental in taking us from Type One to Type None. 7

8 Back to top FUNDING HIGHLIGHTS The following chart highlighting the JDRF-funded research projects covered in this progress report represents a portion of the encapsulated cell therapy research made possible through your generous support. RESEARCHER/PARTNER PROJECT TOTAL JDRF FUNDING Robert S. Langer, Ph.D. Advanced Biomaterials and Delivery of Systems for Islet Encapsulation $9,820,440 Jonathan Lakey, Ph.D. Identifying Key Parameters for Encapsulated Islet Transplantation $1,026,940 Mark Poznansky, M.D., Ph.D. A Novel Encapsulant Incorporating CXCL12 that Protects the Islet Graft $502,000 Timothy Kieffer, Ph.D. Treatment of Diabetes with Human Pancreatic Precursor Cells $725,656 Daniel Pipeleers, M.D., Ph.D. Biology of Encapsulated Beta Cell Implants in Diabetes Patients $1,980,000 Doug Melton, Ph.D Physiology of SC-Derived Human Beta Cells $4,000,000 ViaCyte Cell Therapy for Diabetes $13,000,000 8