4th Annual Washington University Wolfram Syndrome Research Clinic Research Update, Clinical Q&A

1. 4th Annual Washington UniversityWolfram Syndrome Research ClinicResearch 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 – 9:15 Brief 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- 10:30 Family/parent open discussion

3. A new world’s 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) • Dr. Hershey (number on consent; 314-362-5593; 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 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 2nd year) • ADA, JDRF, Snow Fund

10. Preliminary data on change over time Cerebellar gray Cerebellar white Midbrain Pons Medulla 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 year’s 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 FumiUrano, MD, PhD Washington University @ Wolfram syndrome Workshop July 20th, 2013

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

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

16. ER-cytosol shunt Calcium Leakage ? Cell Death

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

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

19. Neurons derived from Wolfram-iPSCs Control subjectl Wolfram patient

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

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

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

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

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

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

26. Clinical Presentations5 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 • American Foundation for the Blind: http://www.afb.org/default.aspx • Find local resources… • St. Louis- StLSoc 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.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