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

2. 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

3. 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

4. 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

5. 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

6. 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

7. ? 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

8. 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

9. 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

10. 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

11. 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

12. THANK YOU

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

14. 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

15. 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

16. 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

17. 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

18. 2004 award to Cythera to derive additional lines

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

20. 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

21. Comments and Questions

22. THANK YOU