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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

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4th annual washington university wolfram syndrome research clinic research update clinical q a

4th Annual Washington UniversityWolfram Syndrome Research ClinicResearch Update, Clinical Q&A

July 20, 2013

The Jack and J.T. Snow

Scientific Research Foundation

agenda
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
A new world’s record…
  • 21 MRIs
  • 326 individual appointments
  • In 3.5 days!
announcements
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
slide5

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
Wolfram Research @ WU

Funded by NIH, ADA, JDRF, Snow Foundation

human research
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
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 progress1
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
Preliminary data on change over time

Cerebellar gray

Cerebellar white

Midbrain

Pons

Medulla

Lugar et al: 2013 ADA poster

conclusions
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 progress2
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
slide13

Biomarker and Treatment

For Wolfram Syndrome

FumiUrano, MD, PhD

Washington University

@ Wolfram syndrome Workshop

July 20th, 2013

slide14

Three Step Formula

Treat

Clinical Study

Identify

Biomarkers Compounds

Understand

Registry & Clinic

iPSC & Animal Models

wolfram syndrome
Wolfram Syndrome
  • Insulin dependent diabetes
  • Optic atrophy
  • Neurodegeneration
  • Sensorineural deafness
  • Diabetes insipidus
  • Neuropathic bladder
slide16

ER-cytosol shunt

Calcium Leakage

?

Cell Death

slide17

International

Registry

90 patients

26 patients

Wolfram

Clinic

Understand

Wolfram

induced pluripotent stem cells ips cells
Induced Pluripotent Stem Cells (iPS cells)

Beta Cells

Skin fibroblasts

iPS Cells

Neurons

slide19

Neurons derived from Wolfram-iPSCs

Control subjectl

Wolfram patient

slide20

Dysregulated calcium homeostasis

in Wolfram iPSC-derived neural progenitor cells

increased calpain 2 expression and activation in patients neurons

Increased Calpain 2 expression and activation in patients’ neurons

Control

Wolfram

Cleaved-Spectrin

CAPN2

slide23

ER-cytosol shunt

MOLECULAR PROSTHESIS

ANTI CELL DEATH

Calcium Leakage

Calpain

Chop 

Cell Death

slide24

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

clinical progress
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
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
ot services for children and youth

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
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
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
Motor Strategies
  • Stabilization
  • Energy Conservation
  • Cognitive Oriented Approach
    • Develop strategies for success
low vision strategies
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
wu program in ot community practice
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
Questions?

gronskim@wustl.edu

286-1109

endocrinology updates
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