This is a slide show, with notes, about the CMTA's STAR initiative, created by Dana Schwertfeger and myself. It is to enhance your understanding of the CMTA's research STAR project and bring you up to date on recent news. Enjoy!

1. Achieving our vision of a world without CMT…

2. The Goals of STAR
 Within 5 years, introduce effective therapies for the
three most common types of CMT
 Within 10 years, stabilize or even reverse symptoms of
the disorder in some instances
“The Strategy to Accelerate Research is the most
important initiative ever undertaken by the Charcot-
Marie-Tooth Association. In addition to developing
specific therapies for CMT patients, the
translational science employed in the research
could have major implications for the treatment of a
host of related genetic disorders.”
—Michael E. Shy, MD
Chairman, CMTA Medical Advisory Board

3. Changing the Face of Research
In January, 2007, the CMTA Board convened to
discuss the status of the current research strategy
and identified the following roadblocks:
 Research was not being conducted in a way that
would lead directly to treatments and cures for CMT.
 Researchers worked on isolated projects, often with
no or little communication between investigators.
 The CMTA could only financially commit to funding,
at most, 1-2 $100,000 research grants/year.
 The CMTA funded research grants considered most
likely to produce promising results.

4. The New Strategy
The CMTA established an External Medical
Advisory Board with a common vision:
developing a plan to focus research on
delivering treatments and cures for CMT
through collaborative efforts between
scientists, clinicians and entrepreneurs.
This strategy would be funded and directed
exclusively by the CMTA.
The Goal: A World Without CMT

5. External Medical Advisory Board
Dr. Michael Shy
Dr. Steven Scherer
Wayne State
Dr. John Griffin Dr. Laura Feltri University of
University
John Hopkins University Milan, Italy Pennsylvania
Dr. Vincent Timmerman
Dr Larry Wrabetz, University of Antwerp
Milan, Italy Belgium
Dr. Brian Popko Dr. Kristjan Jessen
University of Chicago UCL - London Dr. Rhona Mirsky
UCL - London

6. Why was CMT Type 1A
the first STAR project?
 CMT 1A is the most common type of CMT, so finding a
treatment would benefit the greatest number of people.
 We understood the underlying mechanisms of CMT1A.
 We had the ability to use cutting-edge technology,
methodology and equipment (High-Throughput Screening) to
quickly identify candidate compounds that could be used to
potentially treat CMT1A.
 If we identified compounds that were already FDA-approved,
we could greatly accelerate the drug development process and
start Phase III clinical trials in 3-5 years.

7. The Science:
Myelin and CMT1A
 Myelin (produced by Schwann cells) is
a protective layer of insulation that
envelops peripheral nerves, enabling
them to conduct impulses from the
brain and spinal cord to different parts
of the body.
 Myelin is composed of proteins and
lipids.
 One of these proteins is called
Peripheral Myelin Protein 22 or
PMP22.

8. PMP22 and the
Breakdown of Myelin
 A gene duplication on chromosome
17 causes one parent to pass an
extra or third copy of the PMP22
gene to the child.*
 Although PMP22 comprises only
5% of all peripheral myelin protein,
this extra copy is enough to disrupt
the production of myelin and slow
the conduction of nerve impulses.
*This duplication can also occur in a child for the first
time as a spontaneous mutation.

9. The Plan of Attack
The success of the CMTA’s Strategy to Accelerate
Research involves two key principles:
The first is directly engaging some of the
world’s foremost peripheral nerve and myelin
experts and having them work together in a
well-defined research initiative.
The second is having them undertake their
independent assignments simultaneously in
order to speed up the overall process.

10. The Four Phases of STAR
1. Grow a CMT1A cell line that expresses PMP22.
2. Work in conjunction with the NationaI Institutes of
Health’s (NIH) National Chemical Genomics Center
(NCGC) to screen more than 300,000 compounds
against the CMT1A cell line.
3. Further evaluate the most promising candidate
compounds in animal models.
4. Conduct human clinical trials.

11. The CMT1A Cell Line
Principle Investigator: Professor Ueli Suter
 Dr. Suter is Professor for Cell Biology at the ETH, Zürich.
 Dr. Suter, who also demonstrated that over-expression
of PMP22 causes CMT1A, was asked to create the
CMT1A cell line for use in high-throughput screening at
the NCGC.
 Dr. Suter has completed this project, and the CMT1A
cell line was sent to the NCGC in April of 2009.

12. What is a Cell Line?
To create the cell line, Dr. Suter first obtained
Schwann cells from tissue cultures.
To promote growth, these cells were
“immortalized” or made to grow and divide
indefinitely in culture dishes.
Dr. Suter’s cells also contain a florescent marker
called luciferase to indicate luminescence every
time the PMP22 protein is present.

13. The NIH National Chemical
Genomics Center (NCGC)
 When the CMT1A cell line was generated, it was sent to
the High-Throughput Screening (HTS) facility housed at
the National Institutes of Health’s National Chemical
Genomics Center under the direction of Dr. Jim Inglese.
Dr. Jim Inglese
Director of Biomolecular
Screening and Profiling Division

14. The Investigators at the NCGC
Dr. Sung-Wook Jang Dr. Doug Auld
 In July, 2009, Dr. Sung-Wook Jang  Dr. Doug Auld, is supervising
was appointed to a three-year Sung Wook’s thesis work. Doug
term as a CMTA post-doctoral Auld is now Group Leader for
fellow at the NCGC. He is working Genomic Assay Technologies at
closely with scientists at the NCGC the NCGC.
on the development and
performance of screening efforts
using the NIH compound library to
find therapies for Charcot-Marie-
Tooth disorders.

15. High-Throughput Screening (HTS)
 Using robots like the one pictured below holding a plate with
1,536 individual wells, Dr. Inglese and his colleagues at the
NCGC would screen the CMT1A cell line against more than
300,000 compounds in its library.
Each plate contains 1536 wells

16. HTS – How it works.
 The cells express luciferase when PMP22 is present.
 The more PMP22 in cells, the brighter they glow.
 Compounds (medications) that make cells dim indicate a
reduction of the amount of PMP22.
 “Hits” are considered as candidate medications to treat CMT1A.

17. The Laboratory Models
Principal Investigator: Dr. Klaus-Armin Nave
 Dr. Klaus-Armin Nave is the Director, Department of
Neurogenetics, Max Planck Institute for Experimental
Medicine, Göttingen, Germany.
 He is responsible for creating the CMT1A mouse
model, a project done in parallel with the cell line
preparation and screening.
 When we have finalized the selection of the
compound(s) identified through HTS, the mouse model
will be used to test the safety and efficacy of the
compound(s).

18. Understanding PMP22
Dr. John Svaren - Department of
Comparative Biosciences, Waisman Center,
University of Wisconsin, Madison
 Dr. Svaren is working on understanding how the
human PMP22 gene is regulated and how
overproduction of PMP22 causes the onset of CMT.
 He is developing additional assays (tests performed to
measure the effect of a substance on living matter,
e.g., the CMT1A cells) to determine the best candidate
medications to be used in future human trials.
 His work will help determine whether the same
constructs will be observed in humans.

19. The Screening
The High-Throughput Screening has been
completed and a number of candidate
compounds have been identified.
These initial results are highly encouraging, but
additional screening and testing must be done
to identify the most promising compound(s)
before we proceed to testing in animal models.

20. How can you help?
 STAR is privately funded by our members, supporters, friends
and families.
 To complete the STAR Initiative, we need to raise more
than $9 million over the next 3 years!!!
 How can YOU help????
 IDEAS for Fundraising
 The CMTA Board Challenge
 The CMTA Circle of Friends
 Igive.com/CMT Stamp/Zazzle/ebay
 Holiday donations
 Corporate giving and matching programs
 Networking and contacts
 Who do you know?