Everything about this work is hard, but we push on.

4th Annual Washington UniversityWolfram Syndrome Research Clinic

Research Update, Clinical Q&AJuly 20, 2013

The Jack and J.T. Snow Scientific Research Foundation

Agenda8:00 Announcements

8:10 8:45 WU WFS Study Group Progress International meetingHuman Research: Dr. Hershey Cellular Research and Drug screening: Dr. UranoClinical: Dr. Marshall

8:45 9:15Brief clinical presentations Dr. Reierson Child PsychiatryDr. Yamada Sleep Dr. Gronski Occupational TherapyDr. Marshall Endocrinology; Treatment of Diabetes Insipidus

9:15 10:00 Q&A to physicians, researchers

10:00- 10:30Family/parent open discussionA new worlds record21 MRIs326 individual appointments

In 3.5 days!AnnouncementsPick up handouts on tableFill out Medical Release forms for relevant doctorsReturn to Samantha or give to your doctorFill out reimbursements forms, if necessary Return to SamanthaReturn 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

Speakers from US, Japan, UK, France, SpainAttendees from these and other countriesTopics: Progress in researchEstablishment of new collaborationsDiscussion ofBasic biology of wolfram proteinDevelopment of new biomarkers for monitoring disease progressDevelopment of new treatments for Wolfram syndromeHarmonization of clinical managementGuidelines being written

Wolfram Research @ WUFunded by NIH, ADA, JDRF, Snow Foundation6Human ResearchWhy do longitudinal patient studies?Clinical trials require:Knowledge of natural history of diseaseMethods for capturing overall disease severity (rating scale)Reliable and sensitive markers of change in disease statusIdentification of the most important clinical targets of treatment

This information did not exist prior to our studyWe have made significant progress on addressing these questions, but need more longitudinal data to improve our understanding.

Human Research ProgressWe have:Defined specific brain structural differencesDetermined that balance & gait differences are apparentDeveloped, and shown reliability and validity of the Wolfram Unified Rating Scale (WURS)Described auditory and vestibular findingsDescribed overall clinical phenotype

Human Research ProgressPapers 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 Disorders5. Karzon et al: Audiologic and Vestibular Findings in Wolfram Syndrome. Ear and Hearing6. 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 preparation8. 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

Preliminary data on change over time

MidbrainPonsMedullaCerebellar grayCerebellar whiteLugar et al: 2013 ADA poster

ConclusionsDirect, 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 ProgressResearch clinic funded until 2016Next years dates: 7/15/14 7/19/14Possible additional research clinics during the year or overlapping clinics e.g. 7/14-7/16 and 7/16-7/19Add siblings?Possibly move some assessments to the clinical side onlyCollaboration with Dr. Barrett in UKBlending registriesHarmonizing data collection, disseminate WURS

Biomarker and TreatmentFor Wolfram Syndrome Fumi Urano, MD, PhDWashington University@ Wolfram syndrome Workshop July 20th, 201313

UnderstandRegistry & CliniciPSC & Animal ModelsIdentifyBiomarkers Compounds TreatClinical StudyThree Step FormulaWolfram SyndromeInsulin dependent diabetesOptic atrophyNeurodegenerationSensorineural deafnessDiabetes insipidusNeuropathic bladder15

ER-cytosol shunt?Calcium LeakageCell Death

UnderstandWolframInternationalRegistryWolframClinic90 patients26 patients17Induced Pluripotent Stem Cells (iPS cells)

Skin fibroblastsiPS CellsBeta CellsNeurons

Control subjectlWolfram patientNeurons derived from Wolfram-iPSCs Dysregulated calcium homeostasisin Wolfram iPSC-derived neural progenitor cellsIncreased Calpain 2 expression and activation in patients neurons

ControlCleaved-SpectrinCAPN2WolframChop expression is increased in Wolfram iPSC-derived neural progenitor cells

ER-cytosol shuntCalpain Chop

Calcium LeakageCell DeathMOLECULAR PROSTHESISANTI CELL DEATH24Gel_1C33 / WS5

123456789101211141316151719182021222324252627282930110 kDa75 kDa50 kDa40 kDa25 kDa20 kDa14 kDapH 4.0 5.0 5.5 6.0 6.5 7.0 8.0 9.0 AlbuminTransferringMolecules increased in patients seraThree candidates1. Caspase-122. MANF3. Genomic DNA from beta cells

24Clinical ProgressCenter of Excellence in progress. Call or email if interested.Clinically valid genetic testing now available at WUSM

Clinical Presentations5 min eachAngela Reierson, MDChild and adolescent psychiatristKel Yamada, MDPediatric neurology; Sleep and epilepsy specialistMeredith Gronski, OTDPediatric occupational therapist; school specialistBess Marshall, MDPediatric endocrinologist; Medical director of Wolfram Research Clinic

OT Services for Children and YouthMeredith Gronski, OTD, OTR/LOccupational TherapistWashington University Program in Occupational TherapyCommunity Practice Program: Children, Youth & FamiliesOccupational 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 ConcernFine motorGross motor/BalanceAttentionBehaviorMultisensory ProcessingVisual PerceptionSocial InteractionExecutive Function/CognitionPlay SkillsSelf-Care/Adaptive SkillsFeeding & EatingEnvironmental barriers

Do you or have you had patients with these?29Motor StrategiesStabilizationEnergy ConservationCognitive Oriented ApproachDevelop strategies for success

Low Vision StrategiesLow vision rehabLighthouse for the Blind: http://lighthouse.org/?gclid=CJ29z_nTu7gCFeoWMgodpzkAiAAmerican Foundation for the Blind: http://www.afb.org/default.aspxFind local resourcesSt. Louis- StL Soc for Blind and Visually Impaired; Delta Gamma

Occupational therapy strategies:MagnificationIncrease ContrastLightingVisual scanning techniques/ Eccentric viewing

Hearing LossAlexander Graham Bell Association: www.agbell.orgWU Program in OT: Community PracticeCommunity practice vs clinical practiceHome-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 services314-362-5079Questions?gronskim@wustl.edu286-1109Endocrinology updatesDiabetes insipidus in WolframVery difficult to manage due to confusion of cause of excessive urine output.Working on obtaining home sodium monitorsContact me if you would like a letter to send to your insurance regarding getting a home sodium meterLetters insurance appeals, disability, school, etc. please feel free to request