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

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

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

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 ( ; – Dr. Hershey (number on consent; ; – Dr. Marshall (office ) Skin Biopsy Care

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

Wolfram 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

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.

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

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): 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

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

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.

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

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

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

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

ER-cytosol shunt ? Calcium Leakage Cell Death

Understand Wolfram International Registry Wolfram Clinic 90 patients 26 patients

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

Control subjectlWolfram patient Neurons derived from Wolfram-iPSCs

Dysregulated calcium homeostasis in Wolfram iPSC-derived neural progenitor cells

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

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

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

24 Gel_1 C33 / WS kDa 75 kDa 50 kDa 40 kDa 25 kDa 20 kDa 14 kDa pH Albumin Transferring Molecules increased in patients sera Three candidates 1. Caspase MANF 3. Genomic DNA from beta cells

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

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

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

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?

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

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

Low Vision Strategies Low vision rehab – Lighthouse for the Blind: – American Foundation for the Blind: – 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:

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

Questions?

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