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

1. Stop the progression FDA-approved drugs Novel drugs

Common Molecular Pathway ER Calcium leakage

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

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

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 unpublished TREATMENT

High in Patients Low in Non-Patients

Drug A in a mouse model of Wolfram 1 2 3

2. Protect and Regrow remaining tissues

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

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

3. Replace the damaged tissues REGENERATIVE MEDICINE

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

Replace disease-causing DNA with the healthy one L Expected size 877bp Expected size 1268bp 5’3’

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