1. 4th Annual Washington University Wolfram Syndrome Research Clinic Research Update, Clinical Q&A July 20, 2013 The Jack and J.T. Snow Scientific Research Foundation

2. Agenda 8:00 Announcements 8:10 – 8:45 WU WFS Study Group Progress » International meeting » Human Research: Dr. Hershey » Cellular Research and Drug screening: Dr. Urano » Clinical: Dr. Marshall 8:45 – 9:15Brief clinical presentations » Dr. Reierson – Child Psychiatry » Dr. Yamada – Sleep » Dr. Gronski – Occupational Therapy » Dr. Marshall – Endocrinology; Treatment of Diabetes Insipidus 9:15 – 10:00 Q&A to physicians, researchers 10:00- 10:30Family/parent open discussion

3. A new worlds record… 21 MRIs 326 individual appointments In 3.5 days!

4. Announcements Pick up handouts on table Fill out Medical Release forms for relevant doctors – Return to Samantha or give to your doctor Fill out reimbursements forms, if necessary – Return to Samantha Return any questionnaires that you still have – Return to Samantha Questions after you get home? – Samantha Ranck (314-362-6514; rancks@npg.wustl.edu)rancks@npg.wustl.edu – Dr. Hershey (number on consent; 314-362-5593; tammy@wustl.edu) tammy@wustl.edu – Dr. Marshall (office 315-454-6051) Skin Biopsy Care

5. Speakers from US, Japan, UK, France, Spain Attendees from these and other countries Topics: – Progress in research – Establishment of new collaborations – Discussion of Basic biology of wolfram protein Development of new biomarkers for monitoring disease progress Development of new treatments for Wolfram syndrome – Harmonization of clinical management Guidelines being written

6. Wolfram Research @ WU WU Wolfram Syndrome Study Group WFS1 patients Natural history of neurological & other features iPSCs Neurons, β cells Serum biomarkers Wfs1 & Wfs2 knock-out mice Characterization of phenotype Funded by NIH, ADA, JDRF, Snow Foundation

7. Human Research Why do longitudinal patient studies? – Clinical trials require: Knowledge of natural history of disease Methods for capturing overall disease severity (rating scale) Reliable and sensitive markers of change in disease status Identification of the most important clinical targets of treatment This information did not exist prior to our study We have made significant progress on addressing these questions, but need more longitudinal data to improve our understanding.

8. Human Research Progress We have: – Defined specific brain structural differences – Determined that balance & gait differences are apparent – Developed, and shown reliability and validity of the Wolfram Unified Rating Scale (WURS) – Described auditory and vestibular findings – Described overall clinical phenotype

9. Human Research Progress Papers from human research: 1. Hershey et al: (2012) Early brain vulnerability in Wolfram syndrome; PLOS ONE; 7(7). 2. Pickett et al: (2012) Balance impairment in Wolfram syndrome. Gait and Posture; Jul, 36(3): 619-624. 3. Nguyen et al: Reliability and validity of the Wolfram Unified Rating Scale (WURS). Orphanet J of Rare Disorders 4. Marshall et al: Clinical phenotype of early Wolfram syndrome. Orphanet J of Rare Disorders 5. Karzon et al: Audiologic and Vestibular Findings in Wolfram Syndrome. Ear and Hearing 6. Pickett et al: Early presentation of gait impairment in Wolfram Syndrome. Orphanet J of Rare Disorders 7. Chisolm et al.: Vision deficits in Wolfram syndrome. In preparation 8. Lugar et al: Longitudinal brain change in early Wolfram Syndrome. In preparation Grants for Human Research: NIH 5 year grant for clinic (in 2 nd year) ADA, JDRF, Snow Fund

10. Preliminary data on change over time Midbrain Pons Medulla Cerebellar gray Cerebellar white Lugar et al: 2013 ADA poster

11. Conclusions Direct, quantified measurement of Wolfram features reveal subtle brain structure and functional differences at an early stage. Understanding the developmental vs. degenerative course of these features will be important. All of this information is crucial for preparing for future clinical trials.

12. Human Research Progress Research clinic funded until 2016 Next years dates: 7/15/14 – 7/19/14 Possible additional research clinics during the year or overlapping clinics – e.g. 7/14-7/16 and 7/16-7/19 Add siblings? Possibly move some assessments to the clinical side only Collaboration with Dr. Barrett in UK – Blending registries – Harmonizing data collection, disseminate WURS

13. Biomarker and Treatment For Wolfram Syndrome Fumi Urano, MD, PhD Washington University @ Wolfram syndrome Workshop July 20 th, 2013

14. Understand Registry & Clinic iPSC & Animal Models Identify Biomarkers Compounds Treat Clinical Study Three Step Formula

15. Wolfram Syndrome Insulin dependent diabetes Optic atrophy Neurodegeneration Sensorineural deafness Diabetes insipidus Neuropathic bladder

16. ER-cytosol shunt ? Calcium Leakage Cell Death

17. Understand Wolfram International Registry Wolfram Clinic 90 patients 26 patients

18. Induced Pluripotent Stem Cells (iPS cells) Skin fibroblastsiPS Cells Beta Cells Neurons

19. Control subjectlWolfram patient Neurons derived from Wolfram-iPSCs

20. Dysregulated calcium homeostasis in Wolfram iPSC-derived neural progenitor cells

21. Increased Calpain 2 expression and activation in patients neurons Control Cleaved-Spectrin CAPN2 Wolfram

22. Chop expression is increased in Wolfram iPSC-derived neural progenitor cells

23. ER-cytosol shunt Calpain Chop Calcium Leakage Cell Death MOLECULAR PROSTHESIS ANTI CELL DEATH

24. 24 Gel_1 C33 / WS5 1 2 3 4 5 6 7 8 9 10 12 11 14 13 16 15 17 19 18 20 21 22 23 24 25 26 27 28 29 30 110 kDa 75 kDa 50 kDa 40 kDa 25 kDa 20 kDa 14 kDa pH 4.0 5.0 5.5 6.0 6.5 7.0 8.0 9.0 Albumin Transferring Molecules increased in patients sera Three candidates 1. Caspase-12 2. MANF 3. Genomic DNA from beta cells

25. Clinical Progress Center of Excellence – in progress. Call or email if interested. Clinically valid genetic testing now available at WUSM

26. Clinical Presentations 5 min each Angela Reierson, MD – Child and adolescent psychiatrist Kel Yamada, MD – Pediatric neurology; Sleep and epilepsy specialist Meredith Gronski, OTD – Pediatric occupational therapist; school specialist Bess Marshall, MD – Pediatric endocrinologist; Medical director of Wolfram Research Clinic

27. OT Services for Children and Youth Meredith Gronski, OTD, OTR/L Occupational Therapist Washington University Program in Occupational Therapy Community Practice Program: Children, Youth & Families

28. Occupational therapy… Enables people with illness, injuries and chronic conditions to live life to its fullest Designing strategies for everyday life and customizing environments to develop and maximize performance. How many of you utilize OT services?

29. Areas of Concern Fine motor Gross motor/Balance Attention Behavior Multisensory Processing Visual Perception Social Interaction Executive Function/Cognition Play Skills Self-Care/Adaptive Skills Feeding & Eating Environmental barriers

30. Motor Strategies Stabilization Energy Conservation Cognitive Oriented Approach – Develop strategies for success

31. Low Vision Strategies Low vision rehab – Lighthouse for the Blind: http://lighthouse.org/?gclid=CJ29z_nTu7gCFeoWMgodpzkAiA http://lighthouse.org/?gclid=CJ29z_nTu7gCFeoWMgodpzkAiA – American Foundation for the Blind: http://www.afb.org/default.aspxttp://www.afb.org/default.aspx – Find local resources… St. Louis- StL Soc for Blind and Visually Impaired; Delta Gamma Occupational therapy strategies: – Magnification – Increase Contrast – Lighting – Visual scanning techniques/ Eccentric viewing Hearing Loss – Alexander Graham Bell Association: www.agbell.orgwww.agbell.org

32. WU Program in OT: Community Practice Community practice vs clinical practice – Home-school-neighborhood connections Objective, comprehensive evaluation for children & youth receiving public special education services Social skills and other therapeutic group programming Early Intervention providers Consultation to private/parochial schools – Advocacy and navigating school-based services 314-362-5079

33. Questions? gronskim@wustl.edu 286-1109

34. Endocrinology updates Diabetes insipidus in Wolfram – Very difficult to manage due to confusion of cause of excessive urine output. – Working on obtaining home sodium monitors – Contact me if you would like a letter to send to your insurance regarding getting a home sodium meter Letters – insurance appeals, disability, school, etc. – please feel free to request