MSCs in the DRI BioHUB Strategy OPTIMIZATION OF THE TRANSPLANT SITE TOLERANCE INDUCTION REVERSAL OF AUTOIMMUNITY IMMUNOISOLATION SOURCE OF INSULIN PRODUCING CELLS BIOLOGIC CURE

TOLEROGENIC IMMUNOMODULATION T regs Regulatory T Cells MSCs DIPIT Vitamin D Low Dose IL-2 Omega 3

for Infusion of MSCs in Subjects with Type 1 Diabetes Interventional Radiology for Selective Targeting of Pancreatic Arteries for Infusion of MSCs in Subjects with Type 1 Diabetes

MSCs in T1DM (DRI-Stanford/CIRM) Study Design Enrollment Month 6 Post T1D Diagnosis MSC 2.5 x 106 cells/kg Month 18 Crossover Month 30 GROUP 1 (N=20) MSC Assessment CONTROL Assessment GROUP 2 (N=20) CONTROL Assessment MSC Assessment Placebo

Chronic Complications: Chronic Kidney Disease End stage renal disease (ESRD) remains the major cause of excess morbidity and premature mortality in patients with T1D. Despite almost universal implementation of renoprotective therapies and attempts to improve glycemic control, the risk of ESDR in T1D is not decreasing but increasing, suggesting that more effective therapies are needed. U.S. Renal Data System (http://www.usrds.org/) Rosolowsky ET et al., J Am Soc Nephrol 2011; Krolewski AS et al., Diabetes Care 2015

U.S. Renal Data System (http://www.usrds.org/) The number of new cases of ESRD almost doubled in patients aged 40-49 yrs, suggesting that improved care has not reduced but postponed the onset of ESRD. U.S. Renal Data System (http://www.usrds.org/) Rosolowsky ET et al., J Am Soc Nephrol 2011; Krolewski AS et al., Diabetes Care 2015

Interventional Radiology for Selective Targeting of Renal Arteries for Infusion of MSCs in Subjects with Chronic Renal Disease Overall ↑ in eGFR 2 months after injection. Deterioration between 12 – 18 months for advanced patients. Patients with eGFR >35 at start (all in stage 3A and most in 3B), experienced long-term improvement. Baseline 18 months STAGE 3A STAGE 3B STAGE 4 STAGE 5 Vascular structural changes within the kidneys 2 months after the injection, reflected by a sustained reduction in the Renal Resistive Index (RRI) at both renal artery (hilar) and interlobar arteries. Hilar artery Interlobar artery PRE-PROCEDURE 2 MONTHS POST-INJECTION

Encapsulated Islets-MSC Transplants in a Biologic Resorbable Scaffold on the Omentum

Osp. Niguarda Ca’Granda Allotransplantation of Microencapsulated Human Islets in T1D without Immunosuppression Azienda Ospedaliera Osp. Niguarda Ca’Granda Milano

DRI Federation Protocol: Allotransplantation in brittle type 1 diabetes mellitus (Niguarda Hospital, Milan, Italy) Microencapsulation of human islets (University of Perugia, Italy) Transplant in omentum (DRI, University of Miami BioHUB Protocol) Peritransplant treatment with Omega-3 and Vit D (DRI, University of Miami Poseidon Protocol) Oxygen (DRI, University of Miami Protocol) Liraglutide treatment of recipients No immunosuppression

15%

THE AUTOIMMUNE EPIDEMIC What role chemicals, heavy metals, viruses, diet, stress, lifestyle and genes play in developing autoimmune disease How our modern lifestyles and environmental contamination have created a “perfect storm” — the ripest possible conditions for today’s autoimmune epidemic to take hold The connection between autoimmune disease and allergies, the rates of which are likewise skyrocketing (https://donnajacksonnakazawa.com/autoimmune-epidemic/) https://www.focusforhealth.org/autoimmune-disease/?gclid=Cj0KCQiA5NPjBRDDARIsAM9X1GLqorlluWtzASWRT7EqbPYk4wGgHFxMI867yewX-3jKX-Sp-BUduBIaAhDQEALw_wcB

Healthy Lifespan Potential Telomere Shortening: Age 0 - 40 INFLAMMATORY DIET 1% 50% 100% Healthy Lifespan Potential ANTI-INFLAMMATORY DIET

Healthy Lifespan Potential Telomere Shortening: Age 40 - 70 INFLAMMATORY DIET 1% 50% 100% Healthy Lifespan Potential ANTI-INFLAMMATORY DIET

AA/EPA Ratio as Healthspan Predictor

The Perfect Nutritional Storm Increased Omega-6 Increased Refined Carbohydrates Decreased Omega-3 Decreased Polyphenols

Shared Tolerogenic Immunomodulation Pathways MSC and T1DM MSCs, Vitamin D, Omega 3 Shared Tolerogenic Immunomodulation Pathways October 2014 MSCs Vitamin D Omega 3 Carlsson P-O , Schwarcz E, Korsgren O and Le Blanc K. Diabetes 2014 doi: 10.2337/db14-0656, PMID: 25204974

TOLEROGENIC IMMUNOMODULATION T regs Regulatory T Cells MSCs DIPIT Vitamin D Low Dose IL-2 Omega 3