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PreClinOmics , Inc.

The ZDSD Rat as a Translational Model for the Development of Drugs for Obesity, Metabolic Syndrome and Diabetes that Demonstrates Many of the Serious Complications of Diabetes. PreClinOmics , Inc. 1. ZDSD as a Preclinical Model of Metabolic Syndrome.

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PreClinOmics , Inc.

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  1. The ZDSD Rat as a Translational Model for the Development of Drugs for Obesity, Metabolic Syndrome and Diabetes that Demonstrates Many of the Serious Complications of Diabetes. PreClinOmics, Inc. 1

  2. ZDSD as a Preclinical Model of Metabolic Syndrome Metabolic Syndrome affects a large proportion of the population and is becoming increasingly important in adolescents. The syndrome has many components including central obesity, insulin resistance, dyslipidemia and hypertension. In addition, the syndrome features a chronic low grade inflammatory state, vascular endothelial dysfunction, and a prothrombotic environment. Long standing metabolic syndrome can thus pre-dispose to atherosclerosis, microvasculature disease (retina), stroke, renal injury and diabetes. Due to the complicated mechanisms involved in the syndrome and its sequelae, current standard of care reflects poly-pharmacy and is aimed at controlling atherogenic dyslipidemia, hyperglycemia and hypertension as well as intervening in secondary diseases such as renal dysfunction, stroke, and micro-vascular disease related to retinopathy. Development of new chemical entities with the potential to control more than one risk factor is hampered by currently available animal models. To that end, the ZDSD rat was designed to spontaneously develop a phenotype that mimics many aspects of the human metabolic syndrome, including hypertension and the progression to frank diabetes with long-standing disease. 2

  3. Development Scheme: Zucker Diabetic-Sprague Dawley Rat (ZDSD) Produced by crossing diet induced obese (DIO) rats derived from the Crl:CD (SD) strain (exhibiting polygenetic obesity and insulin resistance) with homozygous lean ZDF/Crl rats (which expresses beta cell failure with the Leprfa/Leprfa genotype). Selectively bred for obesity and diabetes. Selected for genetically matched breeders to develop phenotypic homogeneity. Studied male rats at different ages. 3

  4. Characteristics of Metabolic Syndrome seen in the ZDSD Rat • Increased body weight with increased abdominal fat • Increased fed and fasting glucose and HbA1c levels • Insulin resistance / Glucose intolerance • Hyperlipidemia • Increased blood pressure --> Hypertension • Increased Serum Biomarkers of Coagulation, Inflammation and Vascular Disease 4

  5. Comparative Growth Curvesin SD and ZDSD Rat Fed 5008 chow ZDSD rats were significantly (15%) heavier than their SD counterparts at 8 weeks of age. In addition, the rate of body weight gain was increased in ZDSD rats as evidenced by an 82% vs 62% weight gain when compared to SD rats over 24 weeks of observation. All time points statistically different 5 Study # 09-550-170

  6. Spontaneous Development of Obesity in ZDSD Rats Fed 5008 Chow Body composition was assessed using QNMR . The percentage of body weight identified as fat was 50 % higher in ZDSD rats compared to SD controls as early as 8 weeks of age. Body fat percentage continued to increase throughout the study and remained significantly higher than control rats at each time-point. All time points statistically different 6 Study # 09-550-170

  7. Spontaneous Development of Hyperglycemia in ZDSD Rats Fed 5008 Chow All time points statistically different 7 Study # 09-550-170

  8. Spontaneous Development of Glucose Intolerance Shown by OGTT in ZDSD Rats Fed 5008 Chow 8

  9. Progressive Development of Insulin Resistance (HOMA-IR) in ZDSD Rats ZDSD rats become increasingly more insulin resistant with age as evidenced by the calculated HOMA-IR. The insulin resistance is evident compared to SD rats as early as 8 weeks of age (fed Purina 5008 chow). All time points statistically different 9

  10. Representative Islets from 28 wk old ZDSDRats • Pre-diabetic Diabetic 10

  11. 160 ZDSD CD 140 Systolic BP (mmHg) 120 100 80 60 70 80 90 100 Age in Days Blood Pressure in ZDSDvs CD Rats 8-16 weeks of age Blood pressure data produced in collaboration with Dr. Subah Packer’s Laboratory, IU School of Medicine 11

  12. Time Course of Urinary Biomarkers Urinary albumin beta-2 microglobulin g/day) 150 2000 SD m SD ZDSD 125 ZDSD 1500 100 -2 microglobulin ( Urinary albumin (mg/day) 75 1000 50 500 b 25 Urinary 0 0 10 20 22 24 26 30 10 20 22 24 26 30 Age (weeks) Age (weeks) Cystatin C KIM-1 30 15.0 SD SD g/day) ZDSD ZDSD 12.5 m 20 10.0 Urinary KIM-1 (ng/day) 7.5 Urinary cystatin C ( 10 5.0 2.5 0 0.0 10 20 22 24 26 30 10 20 22 24 26 30 Age (weeks) Age (weeks) 12

  13. Glomerular Basement Membrane Thickness 500 400 300 • Thickness (mm) 200 100 0 CD Control 12 Weeks 16.5 Weeks Time of Diabetes in the ZDSD Rat 13

  14. Kidney Histopathology of theZDSD Rat 4.0 * compared to Non-diabetic animals (t-testp<0.05) Non-diabetic Diabetic 3.5 * 3.0 * * * 2.5 Histopathology Score (0-5) 2.0 1.5 1.0 0.5 0.0 Glomerulopathy Tubular dilation Protein casts Inflammation /degeneration 14

  15. Wound Healing in the ZDSD Rat Separated Diabetic and Non-Diabetic ZDSD Combined ZDSD Data 0 0 SD * * SD * Diabetic ZDSD ZDSD -20 * -20 Non-Diabetic ZDSD * * * * -40 -40 * % Change From Iniital Wound % Change From Iniital Wound * * -60 -60 * -80 -80 *compared to SD (Dunnett's) *compared to SD (t-test) -100 -100 4 7 9 11 14 4 7 9 11 14 Time(days) post-wounding Time(days) post-wounding This figure demonstrates the wound healing in the three groups of animals. There were no differences between diabetic and non-diabetic ZDSD animals. There were several statistically significant differences between the SD group and the ZDSD groups (* p<0.05). Since the data were not different in the ZDSD groups there were also analyzed as a combined group. 15

  16. Structural Properties L4 vertebrae P-values for differences in diabetic rats vs. respective controls ZDF ZDSD Biomechanical Test – axial compression Yield Force (N) p<0.050 p<0.001 Stiffness (N/mm) p<0.001 p<0.005 Ultimate Load (N) p<0.001 p<0.001 Energy to Ultimate Load ( mJ) p<0.050 p<0.001 90 90 80 80 70 70 60 60 50 50 Energy to Ultimate Load (mJ) Energy to Ultimate Load (mJ) * * 40 40 30 30 20 20 10 10 0 0 Mean ±SEM ZDSD Controls ZDF (fa/fa) ZDF (+/fa) n=12-17/group 16

  17. TheZDSDRat: One Rat – Many Models 17

  18. ZDSD Summary- One Rat, Many Models • Polygenic phenotype that can be modulated by diet • Functional Leptin Pathway • Early onset of hyperglycemia with slower progression to frank diabetes when compared to the ZDF rat • Mirrors human development of type II diabetes • Manifests diabetic complications: • Diabetic nephropathy • Hypertension • Inflammation • Osteoporosis • Delayed wound healing 18 18

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