Charcot Marie Tooth Association

• Founded in 1983• Goals are patient

support, public education, promotion of research and treatment for CMT

• 2008, Change in research strategy– Focus on developing Rx

for CMT– CMTA driven projects

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• Physician Scientists– Michael Shy– Steven Scherer

• Lay Board Members– Pat Livney– Dave Hall– Gary Gasper– Elizabeth Ouellette– Herb Beron– Phyllis Sanders– Robert Kleinman– Jason Steinbaum– Vasi Vangelos– Steven O’Donnell

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Experts in PNS Biology

• Ueli Suter : Professor and Chair in Cell Biology, Institute of Cell Biology, ETH Zurich

• Klaus Nave: Director, Max Planck Institute of Experimental Medicine

• Larry Wrabetz: Head, Myelin Biology Unit, San Raffaele Scientific Institute, Milan

• Laura Feltri: Head, NeuroGlia Unit, San Raffaele Scientific Institute, Milan

• Kris Jessen: Professor, University College London• Rhona Mirsky: Professor, University College London• Brian Popko: Professor, University of Chicago• David Colman, Director, Montreal Neurological Institute• Jack Griffin, Professor, Johns Hopkins

Historical Points

• NINDS sponsored Neuropathy Workshop-Oct 2006– Screen for compounds that reduced

PMP22 expression in CMT1A-high priority

• Meetings with Myelin Repair Foundation– Spring 2007– Partnership with Scientists and Industry

NINDS Meeting 2008

• Enthusiastic about projects to reduce PMP22 levels

• Approaches should include milestones • U Grant support potentially available to

help bring together scientists, industry and government if milestones met

Turn the science into therapy

• Present and Future strategies

• Focus on the most likely projects to be successful

• Choose the best people to perform the projects

• Set up the infrastructure to generate high quality clinical trials

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Rational Approaches to Therapy

• FIND TREATMENTS NOW– Begin with CMT1A, the most

common form of CMT– High Throughput Screening– Network of CMT Centers

• FUTURE STRATEGIES– RNA interference (RNAi)– Gene transfer strategies

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Duplication of PMP22 CMT1A (overexpression of the protein)

50 % of all CMT

Deletion of PMP22 HNPP (underexpression of the protein)

CMT1A

• PMP22 functions• Structural protein of

peripheral myelin• Unknown function

What can be screened?

10’s/day

1000’s/day10,000’s/day

100,000’s/day

Throughput

Molecular mechanism

Immediate organismal relevance (??)

“LTS” “MTS” HTS

~1/10 eye drop

Project 1: Make the cells for the HTS

• Professor Ueli Suter• Institute of Cell

Biology, ETH, Zurich

• Discovered PMP22• Proved PMP22

causes CMT1A

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What regulates the mouse Pmp22 gene?

Dr.Ueli Suter

P1 P2

LMSE: late myelination Schwann cell-specific element

NIH Chemical Genomics CenterJim Inglese

• Founded 2004• First center in Molecular Libraries

Screening Center Network• 60 scientists – biologists,

chemists, informaticians, engineers

• Collaborates with >100 investigators worldwide to produce chemical probes of biology– Focus on rare and orphan

disease drug development– Paradigm innovation in early

drug discovery process

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The Production Line

Re-tooled for Drug Discovery

• Typical Screen– Running robot at ~70% max. operational rate– 5 sample wells / sec. – 1.4 s / compound titration (IC50)

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NIH/NHGRI TEAM

• Jim Inglese

• Doug Auld• Sung-Wook Jang

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HTS Assay: Dual bioluminescent reporter cell-based assay for IκBα subunit stabilization

• Design concept used in a PMP22 gene regulation assay for CMTA project

Assay Design (dual bioluminescent reporter)

Assay Output(raw unprocessed data)

Davis, R.E. et al. Assay Drug Devel. Tech. 2007 5 (1) 84-105

Processed Data(ratiometric)►

Signal #2 (R)(nonspecific)

Two-color PMP22 reporter assay

qHTS

Signal #1 (G)(PMP22 specific)

Ratio ( G/R)

Nonspecific ( e.g. cell death)

PMP22 down-regulation

Inactive

luminous clickbeetle (Pyrophorus plagiophthalamus)

“Luciferase” = enzyme that makes fireflies glow

Dual Approach

• FDA approved compound screen– Several thousand compounds– Preliminary hits in validation screen

• Non-FDA approved screen– Several hundred thousand compounds– Potential chemical modifications needed

• IMPORTANCE OF SECONDARY SCREENS & ANIMAL STUDIES

Project 3: Generate an improved laboratory model of CMT1A

• Klaus-Armin Nave• Director, Max Planck

Institute of Experimental Medicine, Gottingen, Germany

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Making a Reporter Rat

Dr. Klaus-Armin Nave

Project 4: How is human PMP22 regulated

• John Svaren, Department of Comparative Biosciences, U. of Wisconsin, Waisman Center

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What regulates the mouse Pmp22 gene?

Dr.Ueli Suter

P1 P2

LMSE: late myelination Schwann cell-specific element

What regulates the mouse Pmp22 gene?

Dr. John Svaren

Krox20

Sox10

P1 P2

What regulates the human PMP22 gene?

Dr. John Svaren

Krox20

Sox10

P1 P2

CMTA Workshop: DEFINING THERAPEUTIC APPROACHES TO CMT2 November 10-12, 2010 San Diego, CA

* Draft program *

Wednesday, Nov 10, 2010 09.00 - 10.30 Overview of the workshop 09.00 – 09.15 Welcome, David Hall 09.15 - 09.30 STAR and CMTA, Pat Livney 09.30 – 12.30 Axonal degeneration, axonal transport, and trophic factors Rhona Mirsky & Zhigang He - moderators 09.30 – 10.00 Axons and axonal degeneration – Jack Griffin 10.00 – 10.30 Mechanisms of axonal degeneration – Marc Freeman 10.30 – 11.00 Coffee break 11:00 – 11.30 Axonal transport and disease - Erika Holzbaur 11.30 – 12.00 Trophic factors in neurons - David Ginty 12.00 – 12.30 Trophic factors as potential therapies - Ahmet Hoke 12.30 – 14.00 Lunch 14.00 – 16.00 How do faulty mitochondria cause CMT? Elena Rugarli & Bob Baloh - moderators 14.00 – 14.30 Overview of CMT2 – Stephan Zuchner 14.30 – 15.00 Mitochondria, mitofusin, and CMT - David Chan 14.00 – 15.30 GDAP1 and CMT - Ueli Suter 15.30 – 16.00 Panel discussion/Qs&As/Therapeutic strategies - Bob

Baloh, David Chan, Elena Rugarli, Ueli Suter, Stephan Zuchner

16.00-16.30 Coffee/Tea/snacks

16.30 - 18.30 Neurofilaments, axonal cytoskeleton, and CMT2E Michael Garcia & Yanmin Yang - moderators 16.30 -17.00 The biology of neurofilaments; Mouse models - Jean-Pierre Julien 17.00 - 17.30 Cellular models of CMT2E - Ron Liem 17.30-18.0 HSP and CMT - Vincent Timmerman

Valley of Death in Biomedical Research

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CMT CENTERS OF EXCELLENCE

• Wayne State University, M Shy• University of Pennsylvania, R Finkel (CHOP)

and S Scherer (adults)• Johns Hopkins (A Hoke or C Sumner)• U. Washington (Seattle), T Bird• U of Rochester (MSG), D Herrman• U Tx (Southwestern) S Ianaconne (children)

Rare Disease Clinical Research Center

• NINDS/NORD

• Wayne State University, M Shy, C. Siskind, G. Acsadi• University of Pennsylvania, R Finkel (CHOP) and S Scherer

(adults)• National Hospital for Neurology & Neurosurgery, London, M.

Reilly, F. Muntoni• U. of Miami, S. Zuchner• U of Rochester (MSG), D Herrman, M. McDermott

TREAT-NMD and Datasets

• International patient registries for trials– Patient protected– Investigator Protected

• Advantages– Trials for rare forms of CMT– Concomitant trials for common forms like

CMT1A

TREAT-NMD and Datasets

• International patient registries for trials– Patient protected– Investigator Protected

• Advantages– Trials for rare forms of CMT– Concomitant trials for common forms like

CMT1A

THIS IS AN ONGOING COLLABORATION

THANKS !!!!