Star v2 0 e 4-30-10


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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!

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Star v2 0 e 4-30-10

  1. 1. Achieving our vision of a world without CMT…
  2. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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  Stamp/Zazzle/ebay  Holiday donations  Corporate giving and matching programs  Networking and contacts  Who do you know?
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