1. STOP progression PROTECT & REGROW remaining tissues REPLACE damaged tissues A Cure For Wolfram Three Steps 2.0 Fumi Urano, MD, PhD

2. 1. Stop the progression FDA-approved drugs Novel drugs

3. Common Molecular Pathway ER Calcium leakage

4. Identify FDA-approved DRUGS that can prevent ER calcium depletion-mediated Cell Death

5. Urano F. Diabetes (2014) Induced Pluripotent Stem Cells from Wolfram patients

6. Drug A prevents apoptosis in Wolfram iPSC-derived neuronal cells Lu et al. unpublished TREATMENT

7. High in Patients Low in Non-Patients

8. Drug A in a mouse model of Wolfram 1 2 3

9. 2. Protect and Regrow remaining tissues

10. What is MANF? Purified from Brain Promotes Cell Growth Prevents Cell Death Retinitis Pigmentosa Parkison’s disease

11. MANF-based treatment Eye cells derived from Wolfram iPS cells MANF peptide From Amarantus

12. 3. Replace the damaged tissues REGENERATIVE MEDICINE

13. Brain Cells and Eye cells from skin cells Skin fibroblasts BRAIN EYE iPS Cells

15. Replace disease-causing DNA with the healthy one L 1 2 3 4 5 6 7 8 Expected size 877bp Expected size 1268bp 5’3’

16. STOP progression PROTECT & REGROW remaining tissues REPLACE damaged tissues A Cure For Wolfram Three Steps 2.0