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 – 9:15 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
A new world’s 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 (314-362-6514;
[email protected]) – Dr. Hershey (number on consent; 314-362-5593;
[email protected]) – Dr. Marshall (office 315-454-6051) • 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 Research @ WU Natural history of neurological & other features WFS1 patients
WU Wolfram Syndrome Study Group
iPSCs Neurons, β cells Serum biomarkers
Wfs1 & Wfs2 knock-out mice Funded by NIH, ADA, JDRF, Snow Foundation
Characterization of phenotype
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): 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
Preliminary data on change over time
Cerebellar gray Cerebellar white
Midbrain Pons Medulla 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 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
Biomarker and Treatment
For Wolfram Syndrome
Fumi Urano, MD, PhD Washington University @ Wolfram syndrome Workshop July 20th, 2013
Three Step Formula Treat Clinical Study
Identify Biomarkers Compounds
Understand Registry & Clinic iPSC & Animal Models
Wolfram Syndrome • Insulin dependent diabetes • Optic atrophy
• Neurodegeneration • Sensorineural deafness • Diabetes insipidus • Neuropathic bladder
ER-cytosol shunt
Calcium Leakage
? Cell Death
International Registry
90 patients
26 patients
Wolfram Clinic
Understand Wolfram
Induced Pluripotent Stem Cells (iPS cells)
Beta Cells
Skin fibroblasts
iPS Cells Neurons
Neurons derived from Wolfram-iPSCs
Control subjectl
Wolfram patient
Dysregulated calcium homeostasis in Wolfram iPSC-derived neural progenitor cells
Cytoplasmic calcium levels
0.56 0.55 0.54 0.53 0.52 0.51 0.5 0.49 0.48 0.47 1
2
3
Increased Calpain 2 expression and activation in patients’ neurons Control Wolfram Cleaved-Spectrin CAPN2
Chop expression is increased in Wolfram iPSC-derived neural progenitor cells Neual Progenitor Cell Day 0 CHOP
Relative RNA level
2.5
2
1.5
1
0.5
0 1
2
3
4
ER-cytosol shunt
MOLECULAR PROSTHESIS Calcium Leakage
Calpain Chop
Cell Death
ANTI CELL DEATH
Gel_1 C33 / WS5
1
110 kDa
6
4
5 9
7 8
75 kDa 11
50 kDa
2 3
12
Transferring 10 14
Albumin
13
Molecules increased in patients’ sera 17
15 16
18
40 kDa
19 20
21 23
27 28
25 kDa
24 25 26
22
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
24
Clinical Progress • Center of Excellence – in progress. Call or email 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: http://lighthouse.org/?gclid=CJ29z_nTu7gCFeoWMgodpzkAiA – American Foundation for the Blind: http://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.org
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
Questions?
[email protected] 286-1109
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
