Transcript Slide 1
Can Type 1 Diabetes Be Prevented?
Della Matheson, RN, CDE Research Coordinator, Type 1 Diabetes TrialNet University of Miami, Diabetes Research Institute
Type 1 Diabetes Prevention in NOD
Mice
AAV murine IL-10 AAV rat preproinsulin gene (vLP-1) Adenovirus expressing mIL-4 Aerosol insulin Allogenic thymic macrophages Alpha Galactosylceramide Alpha-interferon (rIFN-alpha) Alpha/beta T cell receptor thymocytes Aminoguanidine Androgens Anesthesia Antioxidant MDL 29,311 Antisense GAD mRNA Azathioprine Anti-B7-1 Bacille Calmette Gue’rin (BCG) Baclofen Bee venom Biolistic-mediated IL-4 Blocking peptide of MHC class II Bone marrow transplantation Castration Anti-CD3 Anti-CD4 CD4+CD25+regulatory T cells Anti-CD8 Anti-CD28 MAb Cholera toxin B subunit-insulin protein Class I derived self-I-A beta(g7) (54-76) peptide Cold exposure Anti-complement receptor Complete Freund’s adjuvant Anti-CTLA-4 Cyclic nucleotide phosphodiesterases (PDEs) Cyclosporin Cyclosporin A DC deficient in NF-kappaB DC from pancreatic lymph node DC with IL-4 Deflazacort Deoxysperogualin Dexamethasone/progesterone/growth hormone/estradiol Diazoxide 1,25 dihydroxy Vitamin D3, KH1060 1,25 dihydroxycholecalciferol 1,25 dihydroxyl Vitamin D3 Elevated temperature Emotionality Encephalomyocarditis virus (ECMV) Essential fatty acid deficient diets FK506 FTY720 (myriocin) GAD 65 peptides in utero Anti-GAD monoclonal antibody Galactosylceramide Glucose (neonatal) Glutamic acid decarboxylase (intraperitoneal, intrathymic, intravenous, oral) Glutamic acid decarboxylase 65 Th2 cell clone Glutamic acid decarboxylase peptides (intraperitoneal, intrathymic, intravenous, oral) Gonadectomy Guanidinoethyldisulphide Heat shock protein 65 Heat shock protein peptide (p277) Hematopoietic stem cells encoding proinsulin Housing alone Human IGF-1 I-A beta g7(54-76) peptide Anti-I-A monoclonal antibodies Anti-ICAM-1 IgG2a antibodies Immobilization Inomide Anti-integrin alpha 4 Insulin (intraperitoneal, oral, subcutaneous, nasal) Insulin B chain (plasmid) Insulin B chain/B chain amino acids 9-23 (intraperitoneal, oral, subcutaneous, nasal) Insulin-like growth factor I (IGF-I) Anti-intercellular adhesion molecule-1 (ICAM-1) Interferon-alpha (oral) Interferon-gamma Anti-interferon-gamma Interferon-gamma receptor/IgG1 fusion protein Interleukin-1 Interleukin-4 Interleukin-4-Ig fusion protein Interleukin-4-plasmid Interleukin-10 Interleukin-10-plasmid DNA Interleukin-10-viral Interleukin 11-human Interleukin-12 Intrathymic administration of mycobacterial heat shock protein 65 Intrathymic administration of mycobacterial heat shock peptide p277 Islet cells-intrathymic L-Selectin (MEL-14) Lactate dehydogenase virus (LDH) Large multilamellar liposome Lazaroid Anti-leukocyte function associated antigen (LFA-1) Anti-LFA-1 Linomide (quinoline-3-carboxamide) Lipopolysaccharide-activated B cells Lisofylline Lymphocyte choriomeningitis virus (LCMV) Anti-lymphocyte serum Lymphoctyte vaccination Lymphocytic choriomeningitis virus Anti-L-selectin Lymphotoxin LZ8 MC1288 (20-epi-1,25-dihydroxyvitamin D3) MDL 29311 Metabolically inactive insulin analog Anti-MHC class I Anti-MHC class II MHC class II derived cyclic peptide Mixed allogeneic chimerism Mixed bone marrow chimeras Monosodium glutamate Murine hepatitis virus (MHV) Mycobacterium avium Mycobacterium leprae Natural antibodies Natural polyreactive autoantibodies Neuropeptide calcitonin gene-related peptide Nicotinamide Nicotine Ninjin-to (Ren-Shen-Tang), a Kampo (Japanese traditional) formulation NKT cells NY4.2 cells OK432 Overcrowding Pancreatectomy Pentoxifylline Pertussigen Poly [I:C] Pregestimil diet Prenatal stress Preproinsulin DNA Probucol Prolactin Rampamycin Recombinant vaccinia virus expressing GAD Reg protein Reg protein Rolipram Saline (repeated injection) Schistosoma mansoni Semi-purified diet (e.g., AIN-76) Short term chronic stress Silica Sirolimus/tacrolimus Sodium fusidate Soluble interferon-gamma receptor Somatostatin Non-specific pathogen free conditions Streptococcal enterotoxins Streptozotocin Sulfatide (3’sulfogalactosylceramide) Superantigens Superoxide dismutase-desferrioxamine Anti-T cell receptor TGF-beta 1 somatic gene therapy Th1 clone specific for hsp60 peptide Anti-thy-1 Thymectomy (neonatal) Tolbutamide Tolerogenic dendritic cells induced by vitamin D receptor ligands Top of the rack Treatment combined with a 10% w/v sucrose-supplemented drinking water Tumor necrosis factor-alpha TX527 (19-nor-14,20-bisepi-23-yne-1,25(OH)(2)D(3)) Vitamin E Anti-VLA-4
Discovery of Insulin Auto-Antibodies
Canadian-European Cyclosporin Study Remissions Azathioprine & Steroids
Skyler, Diabetes 1988; 37:1574-1582 Silverstein et al NEJM 1988;319:599-604
Natural History of Type 1 Diabetes
PUTATIVE ENVIRONMENTAL TRIGGER GENETIC PREDISPOSITION CELLULAR (T CELL) AUTOIMMUNITY INSULITIS BETA CELL INJURY HUMORAL AUTOANTIBODIES (ICA, IAA, Anti-GAD 65 , IA 2 Ab, ZnT8 ) LOSS OF FIRST PHASE INSULIN RESPONSE (IVGTT) GLUCOSE INTOLERANCE (OGTT) “PRE” DIABETES CLINICAL ONSET DIABETES TIME
ADA Position Statement: 1990
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Sufficient data exist to warrant intervention studies for prevention of T1D
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Intervention for prevention should be attempted only in the context of defined clinical trials
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Intervention studies are best accomplished by randomized controlled studies
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A registry of intervention studies should be maintained, and all planned studies should be reported to a coordinating body
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Screening of high risk populations is encouraged
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Risk assessment, counseling, and follow-up must be offered.
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Studies must be evaluated on the basis of potential risks vs. benefits; children should not be excluded, on the basis of age alone, from a therapeutic study that may benefit them by preventing diabetes
How Risk is Determined
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Step 1: Screening antibody testing Step 2: Monitoring OGTT HbA1c HLA (DQA0102, DQB0602) Risk Score (age, BMI, C-peptide)
DPT-1 – Time to Diabetes By Number of Antibodies 1.0
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P- Value< 0.001
(Log Rank Test) Number at Risk 24151 1718 405 378 147 22297 1401 297 255 95 0 n = 26799 1 17049 1045 229 192 61 2 11807 743 163 130 40 9052 557 118 78 30 7439 457 91 49 22 3 4 Years Followed 5 STRATA: 0 1 2 6198 371 66 31 16 6 3 7 3524 199 35 14 8 0 1 2 3 4 8 4
Combined DPT-1 Parenteral & Oral Insulin Trials 1.0
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Indeterminate: BG > 200 mg/dl at 30, 60, or 90 min 0.6
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Normal Glucose Tolerance 0.4
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Number at Risk 57 64 26 536 42 51 20 499 0 1 23 35 16 410 2 STRATA: 16 19 9 308 3 9 6 7 220 Comb IFG + (IGT or Indet) 3 2 3 110 Indeterminate only 1 1 43 Indet Only 2 1 1 IGT only 4 5 6 Years Followed 7 8 IGT Only Comb IFG+(IGTor Indet) IGT Only Indet Only NGT 9 NGT 10
DPT-1 Objective
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To determine of antigen based therapy (specifically insulin) could prevent or delay onset of T1D
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Parenteral Insulin In Subjects with High Risk: > 50% 5 year risk Oral Insulin In Subjects with Moderate Risk: 25-50% risk
The DPT·1 Funnel
103,391 Relatives Screened 97,635 Eligible Samples 97,273 Samples Analyzed 3483 Samples ICA+ (3.58%) 711 Subjects Randomized
DPT-1 Parenteral Study – Time to Diabetes By Treatment 1.0
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P- Value= 0.796
(Log Rank Test) Number at Risk 169 170 144 131 0 1 96 101 69 69 39 40 13 14 1 Intervention Observation 2 STRATA: Treated Control 3 4 Years Followed Intervention 5 6 Observation 7
DPT-1 Oral Insulin Trial Time to Diabetes By Treatment 1.0
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(Log Rank Test) Number at Risk 0.1
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186 186 174 170 0 1 STRATA : 146 137 2 Treated Control 110 102 85 71 3 4 Years Followed Oral Insulin 40 37 23 12 5 Oral Placebo 6 Oral Insulin Oral Placebo 7
DPT-1 Oral Study - Time to Diabetes - By Treatment Subset: IAA Confirmed > 80 nU/ml 1.0
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(Log Rank Test) Number at Risk 130 133 122 121 0 1 104 96 2 STRATA: Diabetes Care 2005; 28:1068-76 Projected 4.5 – 5 year delay Treated Control 86 69 66 46 40 32 23 12 3 4 Years Followed Oral Insulin 5 Oral Placebo 6 Oral Insulin Oral Placebo 7
Insulin Effect Most Evident in Subjects with Baseline IAA ≥ 300
Oral Insulin Placebo 0 1
Projected 10 year delay
Log-rank P=0.01
Peto Pr. P=0.01
Hazard Ratio: 0.41 (0.21, 0.80)
N=63 (Ins.) and 69 (Plac.)
2 3 Years 4 5 6
endit
European Nicotinamide Diabetes Intervention Trial
Overall Treatment Effect: Intention To Treat Analysis
Nicotinamide
0 0 N = 549 Placebo Nicotinamide 275 274 1 2 3 4
Years since randomisation
245 260 232 232 205 208 184 171 5
NIDDK NIAID NICHDNCRR JDRF ADA
TrialNet Sites in North America
14 Clinical Centers + 200 North American Affiliates
TrialNet International Sites
+ 25 International Affiliates Turku, Finland Malmo, Swedem Bristol, UK Melbourne, Australia Milan, Italy Munich, Germany
Other NIH Funded Consortiums
Immune Tolerance Network TRIGR Study
(Trial to Reduce IDDM in the Genetically At Risk) breastfeeding/hydrolyzed
formula vs standard formula; 2,160 babies to be followed x 10 years; results expected in 2017 TEDDY
(Environmental Triggers and Determinants of Type 1 Diabetes) 7,801 babies: 788 first degree relatives with genetic risk (10% risk), 7013 non relatives with genetic risk (3%)
2836 families (11,626) sib pairs 493 families (1479): trio’s 968 Controls
Risk: Low (no antibodies) •Natural History (Screening C
NIP Pilot
Natural History of Progression to Type 1 Diabetes Risk: Low To Moderate (antibodies present Normal OGTT) •Natural History (Monitoring)
ORAL INSULIN CTLA-4IG Helminths
Genetic & Mechanistic Studies
ANTI CD3
Risk: High (multiple antibodies &/or abnormal OGTT) New Onset Studies: • MMF/DZB •AntiCD20 •CTLA-4 Ig •GAD-alum •Anti-IL1β •Metabolic Control (DirectNet) •Thymo (ITN) •IL-2/Rapa completed (ITN) •AntiCD3 (ITN) •Alefacept (ITN) not yet Diabetes Diagnosed
Strategies for Interdicting Type 1 Diabetes
Immunosuppressive Agents: Inhibit or Prevent Activity of the Immune System: Cyclosporin Azathiaprine √ √ MMF/DZB Thymoglobulin (ATG) IL2 /Rapamycin Anti-CD20 (Rituximab) CTLA-4Ig (Abatacept) Anti-CD3 (Teplizumab) √ √ √ Not yet reported: Alefacept (anti-CD2)
APC ß cell TH 0 cell TH 2 Protective Cytokines IL-4, IL-4, IL10 Beta cell survival
How Immunosuppressive Agents Work APC TH 0 cell TH 1 TH 2 ß cell Death IL-1, TNF ą, TN ß, IFN-y 02, H202, NO Cytotoxic M Ø & T Cells Destructive Cytokines
Other Strategies for Interdicting Type 1 Diabetes
Antigen-Specific Therapies
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rhGAD65 with Alum (Diamyd)
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Oral Insulin
√ Probiotic Therapy
Helminths (TSO)
Protective T cells APC T H 0 cell ß cell Death IL-1, TNF ą, TN ß, IFN-y 02, H202, NO Cytotoxic M Ø & T Cells T H 1 T H2 Destructive Cytokines IFN-y, IL-2
Choosing the Right Therapy
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The Benefit vs. Risk Ratio must be appropriate to the degree of risk for development of type 1 diabetes
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Must have proven efficacy
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Must be able to include children
Anti-CD3 (Teplizumab)
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High Risk: > 75% Risk for development of type 1 diabetes over the next 5 years
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140-170 participants ; follow-up 4-6 years
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1:1 randomization; Teplizumab: Control
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14 Day Infusion (51mcg/m2 -826mcg/m2 day 4 13)
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Ages: 8-45 of 633 participants in studies using AntiCD3, 378 were children
Risk: AntiCD3
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Lymphopenia (low WBC): 15% with 2% graded as severe
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Infections 49.5% with 48.6% mild to moderate
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Cytokine Release Syndrome: 5.7% with 85% mild moderate chills, fever, headache, nausea, vomiting, achiness
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Rash 42-62%
hOKT3g1(Ala-Ala) in new onset Type 1 diabetes
160 140 120 100 80 60 40 20 0 Drug Control C-peptide 0 6 12 Month 18 24 6 5 10 9 8 7 0 Hemoglobin A1c Drug Control 30 0.5
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5 10 Month 15 20 25 Drug Control Insulin use 0 5 10 Month 15 20 25 30
Therapies for Moderate Risk: CTLA 4Ig (Abatacept)
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Moderate risk: >32% 5 year risk 2 antibodies (but not mIAA) Normal OGTT Ages 6-45 1:1 randomization, 206 participants 14 infusions over 1 year (2 in the first month, then 1 monthly) Follow: primary outcome: abnormal GTT secondary outcome: diabetes
CTLA-4Ig (Abatacept) Risks
Infusion and Hypersensitivity Reactions: 2% (47 of 2,514) Infectious Adverse Events: 54% in Abatacept and 48% Control; most upper respiratory infections with no increase in neutropenia or EBV
Therapies for Moderate Risk: Oral Insulin
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Oral Insulin: >32% 5 year risk 2 antibodies, one of which is “insulin autoantibody (mIAA)” Normal Oral Glucose Tolerance Test Ages 4-45 Risk – no adverse events or side effects observed in DPT-1 1 capsule per day (7.5mg) 1:1 randomization
Antigen Based Therapy/Oral Tolerance: Mode of Action
Protective Cytokines Oral Antigen Regulatory (Th2 / Th3) Lymphocytes Producing Protective Cytokines Inhibition of
-Cell Autoimmunity and Prevention of Diabetes Insulin Producing
-cells Autoimmune Lymphocytes
Therapy for Low to Moderate Risk Helminths: Trichuris suis ova
(Porcine whipworm ova) •
Proof of principle established in inflammatory bowel disease and MS
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Oral bi-weekly administration
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Well tolerated
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Use of therapeutic helminth therapy based on the “Hygiene Hypothesis”
Hygiene Hypothesis
1910 = 65% helminthic infections; current = < 2%
1901 Paul Ehrlich dictum: “autotoxicus”: body’s immune system would never attack host tissue to cause disease
20 th Century
brought an end to this theory with the identification of
> 80 autoimmune diseases.
Coronado Biosciences Enhance expression Of Protective T Regulatory Cells
Patients and Methods
This was a randomized, double blind, placebo controlled trial conducted at the University of Iowa and select private practices. Trichuris suis ova were obtained from the US Department of Agriculture. The trial included 54 patients with active colitis, defined by an Ulcerative Colitis Disease Activity Index of > or =4. Patients were recruited from physician participants and were randomly assigned to receive placebo or ova treatment. Patients received 2500 Trichuris suis ova or placebo orally at 2-week intervals for 12 weeks.
Results Conclusion
ASP 1002 significantly improved UCDAI versus placebo (stool frequency, presence of blood in the stool, mucosal appearance) Ova therapy seems safe and effective in patients with active colitis.
Coronado Biosciences
Summers, et.al., Gastroenterology 2005
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Does not multiply in human host
Colonization is self-limited in humans
No systemic phase
No direct transmission
Ova stable Side Effects limited to GI symptoms: nausea, upper abdominal cramping, Diarrhea, flatulence occurring during the first few weeks of treatment and then subsiding Coronado Biosciences
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Coronado Biosciences
Cooke, et.al., Parasite Immunology 1999 42
Coronado Biosciences
Saunders, et.al, Infect. Immunol 2007 43
Can Type 1 Diabetes be Prevented?
GENETIC PREDISPOSITION INSULITIS BETA CELL INJURY
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Combination Therapies may need to be employed primary prevention anti-inflammatory agents beta cell expansion therapies antigen-specific therapies immunosuppressive agents ORAL INSULIN CTLA-4IG Helminths “PRE” DIABETES ANTI CD3 CLINICAL ONSET DIABETES TIME
New Onset Studies Underway:
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UCSF, Phase 1 Study: Infusion of T regulatory cells; 14 participants, ages 18-45
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Albert Einstein College of Medicine, Bronx NY, Phase 4: Exenatide; 20 patients, ages 12-18
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University Sao Paulo General Hospital, Phase 1: High Dose Immunosuppression and Autologous Hematopoeitic Stem Cells; 30 participants, ages 16-35
Why is Prevention Important?
Without prevention there is no Cure!!!!
Evidence of reactivated autoimmunity after whole organ and islet cell transplantation Get Involved – participate in Research www.clinicaltrials.gov
www.diabetestrialnet.org
www.immunetolerance.org