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, MDChairman, CMTA Medical Advisory Board 3. Changing the Face of ResearchIn January, 2007, the CMTA Board convened to discuss the status of the current research strategyand 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 MedicalAdvisory Board with a common vision:developing a plan to focus research ondelivering treatments and cures for CMTthrough collaborative efforts betweenscientists, clinicians and entrepreneurs. This strategy would be funded and directedexclusively by the CMTA. The Goal: A World Without CMT 5. External Medical Advisory BoardDr. Michael ShyDr. Steven SchererWayne State Dr. John GriffinDr. Laura FeltriUniversity ofUniversity John Hopkins University Milan, ItalyPennsylvania Dr. Vincent Timmerman Dr Larry Wrabetz,University of AntwerpMilan, Italy Belgium Dr. Brian Popko Dr. Kristjan Jessen University of Chicago UCL - LondonDr. Rhona MirskyUCL - London 6. Why was CMT Type 1Athe 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 firsttime as a spontaneous mutation. 9. The Plan of Attack The success of the CMTAs Strategy to AccelerateResearch involves two key principles:The first is directly engaging some of theworlds foremost peripheral nerve and myelinexperts and having them work together in awell-defined research initiative. The second is having them undertake theirindependent assignments simultaneously inorder 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 ofHealths (NIH) National Chemical Genomics Center(NCGC) to screen more than 300,000 compoundsagainst the CMT1A cell line. 3. Further evaluate the most promising candidatecompounds in animal models. 4. Conduct human clinical trials. 11. The CMT1A Cell LinePrinciple Investigator: Professor Ueli Suter Dr. Suter is Professor for Cell Biology at the ETH, Zrich. 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 obtainedSchwann cells from tissue cultures. To promote growth, these cells wereimmortalized or made to grow and divideindefinitely in culture dishes. Dr. Suters cells also contain a florescent markercalled luciferase to indicate luminescence everytime the PMP22 protein is present. 13. The NIH National ChemicalGenomics 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 Healths National Chemical Genomics Center under the direction of Dr. Jim Inglese.Dr. Jim Inglese Director of BiomolecularScreening and Profiling Division 14. The Investigators at the NCGC Dr. Sung-Wook JangDr. Doug Auld In July, 2009, Dr. Sung-Wook Jang Dr. Doug Auld, is supervising was appointed to a three-year Sung Wooks thesis work. Doug term as a CMTA post-doctoralAuld 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 ModelsPrincipal Investigator: Dr. Klaus-Armin Nave Dr. Klaus-Armin Nave is the Director, Department of Neurogenetics, Max Planck Institute for Experimental Medicine, Gttingen, 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 PMP22Dr. John Svaren - Department ofComparative 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 beencompleted and a number of candidatecompounds have been identified. These initial results are highly encouraging, butadditional screening and testing must be doneto 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?