Jessica Dunne, PhD, Director, Discovery Research Prevention of t1d Jessica Dunne, PhD, Director, Discovery Research October 21, 2014

Protecting Future Generations From T1D Prevention is as Important as a Cure Dramatic rise especially among young children Children born to a family with a close relative who has T1D have a greater risk of developing the disease Only prevention can alter this trend and protect future generations from T1D Another reason why JDRF’s prevention research and development program is so important to people affected by the disease is the fact that a child born to a family with a close relative who has T1D is 10 times more likely to get the disease than a child born to an average family. Prevention R&D is urgent to have a means of avoiding siblings of those with the disease of getting it or to stop future generations of children born to parents or grandparents with T1D from getting the disease. Clearly there is an important genetic component to T1D that drives this increased risk in close relatives; that genetic risk combined with environmental factors is what ultimately leads to the disease. Only prevention therapies can eliminate the concern about developing T1D in these close relatives of those with T1D. 2 2

Cases/100,000/yr in Children 0–14 yr Incidence and Prevalence of T1D Increasing and Occurring at Earlier Age Cases/100,000/yr in Children 0–14 yr 3

Projected Number of Youth < 20 Years With T1D: Increased Incidence Scenario Number of US youth with T1D projected to increase 3.3-fold by 2050 Highest among NHW youth (7.04/1000 in 2050) Largest relative increase among Hispanic youth (6.6-fold increase) US health care systems need to be prepared All NHW Hispanic AA Imperatore, et al. Diabetes Care, 35(12), 2515, 2012

T1D Natural History: A Framework for Prevention Risk of developing T1D can be identified T1D develops with a relatively predictable course with variable rate of progression Interventions can be developed to arrest progression Genetic Risk Environmental Etiologies Beta Cell Autoimmunity Beta Cell Loss 100% 0% Functional Beta Cell Mass At Risk Pre-Symptomatic Recent Onset Established Diabetes Time Glucose Intolerance Clinical Symptoms Adapted from Eisenbarth 5

Risk of T1D in relatives of individuals with T1D Identical Twin: 30-70% Multiple Affected First Degree Relatives: 20-50% Sibling: 8% (but if HLA risk genes identical:30-70%) Offspring Father: 5% Mother: 3% If no Family Hx- General Population: 0.4% (but if HLA risk genes: 4%) (Only 10-15% of newly diagnosed cases of T1D have a relative with T1D) 6

? Enteroviruses The most common viruses in man; frequent infection in early childhood Cause both mild and severe infections, such as meningitis, encephalitis, paralysis (poliomyelitis) myocarditis, chronic cardiomyopathies pancreatitis, hand foot and mouth disease More than 100 different types Vaccine has been developed against one enterovirus group (polioviruses) 7

Enteroviruses and Type 1 Diabetes Islet cell damage in fatal enterovirus infections Enterovirus detection in new onset T1D pancreas (nPOD- V, DiViD) T1D Genetics: IFIH1 gene affects response to enterovirus Viral infection (type 1 interferon) signature pattern detected prior to onset of T1D autoimmunity Viral antibodies first detected around time of T1D autoimmunity 8

The Hygiene Hypothesis Lack of early childhood exposure to infectious agents, symbiotic microorganisms (e.g., gut flora), and parasites increases susceptibility to T1D by suppressing natural development of the immune system. Disappearing microbiota 9

The Gut Microbiome in T1D Metabolism Synthesis of vitamins Digestion of harmful compounds Energy production Fermentation of non-digestibile substances Protection Stimulation of immune system Antimicrobial effect Physical barrier against pathogenic bacteria 10

JDRF Gut Microbiome Program Key Messages JDRF is supporting several promising vaccine projects, including vaccines to induce normal micro-organisms in the GI tract The JDRF Microbiome Consortium was created in 2011 to engage the community, create collaborations and drive the field forward Important JDRF Microbiome Consortium findings: The gut microbiome is fairly stable after the age of 3 The gut microbiome differs in children who go on to develop T1D from those that don’t There is some evidence that this change precedes the onset of autoimmunity The gut microbiome has small ecosystems or networks and the interactions between these networks is important in determining function The gut microbiome changes with age, diet, vitamins, antibiotic use, etc., and laying down an early foundation may be important This slides is a summary of the key messages to communicate about the JDRF prevention R&D program that were reviewed in this presentation. 11

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Encapsulated cell replacement therapy Albert Hwa, PhD, Director, Discovery Science October 21, 2014

Pancreas and Islet Transplant Can “Cure” T1D Solid black – UMN TCD+TNFa blocker Solid gray – CITR TCD+TNFa blocker White – whole pancreas txn mention benefit of islet txns, severe hypo population, risk benefit ratio is acceptable “Cures” Type 1 Diabetes Limited by supply of healthy donor islets, pancreases Long term use of powerful immunosuppressive drugs

Encapsulated Cell Replacement Therapy Beta Cell Source Replenishable Appropriately functional Scalable, consistent production Encapsulation System Prevents immune rejection Supports long term cell survival and function Allows appropriate insulin kinetics

JDRF Encapsulation Program Goals Purpose To support the development of implantable encapsulated beta cell products to safely provide normal glucose control to individuals living with T1D Ultimate Goal Implantable, replenishable beta cell products with encapsulation technology and no immunosuppression, capable of delivering insulin independence

Local Immunosuppression Standardization Tools JDRF Encapsulation Consortium MIT/Univ. Mass./Harvard/Joslin Kings College (UK) Northwestern Univ. Georgia Tech Univ. U. Alberta (CA) Emory Univ. Novel Biomaterials Mass. General Hospital Northwestern Univ. Georgia Tech Univ. Univ. British Columbia (CA) Univ. Louisville U. Miami/DRI Local Immunosuppression Univ. Miami/DRI Brighams & Womens Hosp. Univ. Albeta (CA) Univ. Twente (NL) Univ. Cal. San Francisco Univ. British Columbia (CA) Beta-O2 Macro Device Designs Data & protocol sharing Cross-team comparisons Standardization Core facilities JDRF Mass General Hospital Univ. Minnesota Emory Univ. Univ. Alberta (CA) Univ. Illinois Chicago Late-stage Studies Univ. California Irvine Vrije Univ. (BE) Standardization Tools

2004 award to Cythera to derive additional lines

Beta O2 - ßAir device Pilot trial showed long-term cell function and survival; decrease in HbA1c Follow up trial with 8 patients

Living Cell Technologies – encapsulated pig islets High health status pigs No xeno-relevant viruses, bacteria and parasites. Herd now bred in documented bio-isolation. Three year health records and regular monitoring. Alginate-based microcapsules JDRF sponsored part of New Zealand clinical trial, as approved by the NZ regulatory authority Auckland Islands, New Zealand. Relate some history of the pig colony – helps folks remember and is interesting/humorous Define PERV? YES – help them to see that xeno isn’t a slam dunk – there are many considerations not just those found in the encapsulation technology Living Cell Technologies, Ltd. 20

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