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What's new in LGS research?

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Melanie Huntley, PhD speaks about what's new in LGS research and what the LGS Foundation is doing to accelerate research in LGS

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What's new in LGS research?

  1. 1. #LGSFOUNDATION
  2. 2. What’s new in LGS research? Melanie Huntley, PhD November 11, 2017
  3. 3. How the LGS community can make a difference in finding a cure
  4. 4. How: Genetic and other diagnostic testing Get the right diagnosis, sooner. Discover subtypes of LGS (different response to treatments) How the LGS community can make a difference in finding a cure Find all the causes of LGS
  5. 5. How: Genetic and other diagnostic testing Get the right diagnosis, sooner. Discover subtypes of LGS (different response to treatments) How the LGS community can make a difference in finding a cure Find all the causes of LGS Grow the number of researchers studying LGS How: Raise awareness about LGS Raise funds for our Research Grant Program The causes of LGS help spur ideas for how to cure it
  6. 6. How: Genetic and other diagnostic testing Get the right diagnosis, sooner. Discover subtypes of LGS (different response to treatments) How the LGS community can make a difference in finding a cure Find all the causes of LGS Grow the number of researchers studying LGS How: Raise awareness about LGS Raise funds for our Research Grant Program The causes of LGS help spur ideas for how to cure it Support clinical trial efforts in LGS Trials enable us to have confidence that treatments are effective for our LGS loved ones
  7. 7. How: Genetic and other diagnostic testing Get the right diagnosis, sooner. Discover subtypes of LGS (different response to treatments) How the LGS community can make a difference in finding a cure Find all the causes of LGS Grow the number of researchers studying LGS How: Raise awareness about LGS Raise funds for our Research Grant Program The causes of LGS help spur ideas for how to cure it Support clinical trial efforts in LGS Trials enable us to have confidence that treatments are effective for our LGS loved ones So how does research in LGS work?
  8. 8. There are 3 main types of research
  9. 9. There are 3 main types of research How does it work? Basic Research
  10. 10. There are 3 main types of research Clinical Research How does it work? What are the effects? How well does it work? Basic Research
  11. 11. There are 3 main types of research Clinical Research Translational Research How does it work? Can it be applied to people? What are the effects? How well does it work? Basic Research
  12. 12. There are 3 main types of research Clinical Research Translational Research How does it work? Can it be applied to people? What are the effects? How well does it work? Basic Research
  13. 13. Reverse translation from patient to lab Functional studies Does the model reflect the human disorder? Cause identification Syndrome clinically described Clinical Research Translational Research Basic Research
  14. 14. Patient-centered forward & reverse translation Clinical Research Translational Research What are the effects? How well does it work? Basic Research Can findings be applied to people? Cause identification Syndrome clinically described Functional studies Does the model reflect the human disorder? How does it work? What can we learn?
  15. 15. What’s new in LGS research? (since the LGSF began its research grant program 4 years ago)
  16. 16. LGSF funded research efforts17 Functional studies Gene identification LGS clinically described Clinical Research Translational Research Basic Research How does it cause epilepsy? What can we learn? Can the findings be applied to people? What are the effects? How well does it work?
  17. 17. LGSF funded research efforts17 Functional studies Gene identification LGS clinically described Clinical Research Translational Research Basic Research How does it cause epilepsy? What can we learn? Can the findings be applied to people? What are the effects? How well does it work?
  18. 18. LGSF funded research efforts17 Functional studies Gene identification LGS clinically described Clinical Research Translational Research Basic Research How does it cause epilepsy? What can we learn? Can the findings be applied to people? What are the effects? How well does it work?
  19. 19. Does a low glycemic index diet work in LGS? Elizabeth Thiele Massachusetts General A low glycemic index (LGI) diet is much less restrictive than a ketogenic diet Currently enrolling 10 LGS patients enrolled so far
  20. 20. Can we use patient records to find better treatment combinations for LGS? Nicholas Poolos University of Washington
  21. 21. Can we use patient records to find better treatment combinations for LGS? Nicholas Poolos University of Washington
  22. 22. Can we use patient records to find better treatment combinations for LGS? Are there combinations of therapies that lead to better outcomes in LGS patients? Nicholas Poolos University of Washington
  23. 23. Which LGS patients will benefit from deep brain stimulation? Aaron Warren University of Melbourne
  24. 24. Which LGS patients will benefit from deep brain stimulation? Aaron Warren University of Melbourne Deep brain stimulation (DBS) is an invasive procedure
  25. 25. Which LGS patients will benefit from deep brain stimulation? Aaron Warren University of Melbourne Deep brain stimulation (DBS) is an invasive procedure Can we predict which LGS patients will benefit from DBS, by using less invasive neuroimaging scans?
  26. 26. Which LGS patients will benefit from deep brain stimulation? Aaron Warren University of Melbourne EEG and functional MRI Deep brain stimulation (DBS) is an invasive procedure Can we predict which LGS patients will benefit from DBS, by using less invasive neuroimaging scans?
  27. 27. Patient-centered forward & reverse translation Clinical Research Translational Research How does it work? What can we learn? What are the effects? How well does it work? Basic Research Can findings be applied to people? Cause identification Syndrome clinically described Functional studies Does the model reflect the human disorder?
  28. 28. DNA provides instructions to every cell in our bodies The DNA sequence in our genomes is what makes us human
  29. 29. DNA provides instructions to every cell in our bodies The DNA sequence in our genomes is what makes us human Differences in our genomes make us unique: - From visible traits - Eye color - Hair color - Medical traits - Blood type
  30. 30. DNA provides instructions to every cell in our bodies The DNA sequence in our genomes is what makes us human Differences in our genomes make us unique: - From visible traits - Eye color - Hair color - Medical traits - Blood type Our genome sequence is a code that is read by each of our cells
  31. 31. If the code in the instructions is misspelled ➡ mutation Sometimes these mutations occur in important pieces of code called “genes”
  32. 32. Progress in finding new LGS genes De novo mutations GCTGCAGCCCCAA GCTGCACCCCCAA Exome DNA sequence analysis of 22 LGS trios Candace Myers @ U of Washington
  33. 33. Progress in finding new LGS genes De novo mutations GCTGCAGCCCCAA GCTGCACCCCCAA Exome DNA sequence analysis of 22 LGS trios Candace Myers @ U of Washington Found 13 candidate genes
  34. 34. Progress in finding new LGS genes De novo mutations GCTGCAGCCCCAA GCTGCACCCCCAA Exome DNA sequence analysis of 22 LGS trios Found 13 candidate genes Test the candidate genes in 600 (LGS + other epilepsy) patients to look for recurrence Candace Myers @ U of Washington
  35. 35. Progress in finding new LGS genes De novo mutations GCTGCAGCCCCAA GCTGCACCCCCAA Exome DNA sequence analysis of 22 LGS trios Found 13 candidate genes Test the candidate genes in 600 (LGS + other epilepsy) patients to look for recurrence Candace Myers @ U of Washington
  36. 36. LGS EGI Exome Project (LEEP) Pilot program: Exome sequencing of 63 individuals (LGS trios and singletons) Progress: 35 processed through EGI genetic counselor 5 have blood samples completely ready for sequencing! who have not had access to genetic testing
  37. 37. Pilot program: Exome sequencing of 63 individuals (LGS trios and singletons) Progress: 35 processed through EGI genetic counselor 5 have blood samples completely ready for sequencing! who have not had access to genetic testing LGS EGI Exome Project (LEEP)
  38. 38. Patient-centered forward & reverse translation Clinical Research Translational Research What are the effects? How well does it work? Basic Research Can findings be applied to people? Cause identification Syndrome clinically described Functional studies Create and evaluate models of LGS in the lab How does it cause epilepsy? What can we learn?
  39. 39. GABRB3 STXBP1 CHD2 ALG13 Model systems for epilepsy Potential causes of the disease
  40. 40. GABRB3 STXBP1 CHD2 ALG13 Model systems for epilepsy Potential causes of the disease
  41. 41. GABRB3 STXBP1 CHD2 ALG13 Model systems for epilepsy Does it have seizures?Potential causes of the disease
  42. 42. GABRB3 STXBP1 CHD2 ALG13 Model systems for epilepsy Does it have seizures? Does the model reflect what we know about the human condition? Potential causes of the disease
  43. 43. GABRB3 STXBP1 CHD2 ALG13 Model systems for epilepsy Does it have seizures? Does the model reflect what we know about the human condition? How does the mutation cause the disease? Potential causes of the disease
  44. 44. GABRB3 STXBP1 CHD2 ALG13 Model systems for epilepsy Does it have seizures? Does the model reflect what we know about the human condition? How does the mutation cause the disease? Potential causes of the disease Can we use this model to screen for effective treatments?
  45. 45. Progress in Zebrafish models of LGS Model organism for studying human mutations in a vertebrate animal Scott Baraban & Brian Grone @ UCSF
  46. 46. Progress in Zebrafish models of LGS Baraban et al. 2013. Nature Comm. Model organism for studying human mutations in a vertebrate animal Dravet Syndrome Control SCN1A mutation Scott Baraban & Brian Grone @ UCSF
  47. 47. Progress in Zebrafish models of LGS Baraban et al. 2013. Nature Comm. Model organism for studying human mutations in a vertebrate animal Dravet Syndrome Control SCN1A mutation Scott Baraban & Brian Grone @ UCSF Clemizole as a potential new treatment for Dravet Syndrome
  48. 48. Progress in Zebrafish models of LGS LGS Models Grone et al. 2016. Plos ONE. Baraban et al. 2013. Nature Comm. Model organism for studying human mutations in a vertebrate animal Dravet Syndrome Control SCN1A mutation STXBP1 mutant zebrafish Scott Baraban & Brian Grone @ UCSF Clemizole as a potential new treatment for Dravet Syndrome
  49. 49. May be hyperactive both day and night Progress in Zebrafish models of LGS LGS Models Grone et al. 2016. Plos ONE. Baraban et al. 2013. Nature Comm. Model organism for studying human mutations in a vertebrate animal Dravet Syndrome Control SCN1A mutation STXBP1 mutant zebrafish GABRB3 mutant zebrafish Scott Baraban & Brian Grone @ UCSF Clemizole as a potential new treatment for Dravet Syndrome
  50. 50. Progress in models of LGS
  51. 51. Progress in Mouse models of LGS Isabela has a mutation in the CHD2 gene
  52. 52. Progress in Mouse models of LGS Isabela has a mutation in the CHD2 gene Robert Hunt @ UC Irvine CHD2 knockout mouse
  53. 53. Progress in Mouse models of LGS Isabela has a mutation in the CHD2 gene Robert Hunt @ UC Irvine CHD2 knockout mouse
  54. 54. Progress in Mouse models of LGS Isabela has a mutation in the CHD2 gene Robert Hunt @ UC Irvine CHD2 knockout mouse Missing certain types of inhibitory neurons
  55. 55. Progress in Mouse models of LGS Isabela has a mutation in the CHD2 gene Robert Hunt @ UC Irvine CHD2 knockout mouse Missing certain types of inhibitory neurons EEG, learning and memory testing in progress
  56. 56. Progress in Mouse models of LGS Isabela has a mutation in the CHD2 gene Robert Hunt @ UC Irvine CHD2 knockout mouse Missing certain types of inhibitory neurons Saad Abbasi Jan Frankowski Sunyoung Lee Kimberly Gonzalez Received 2 much larger NIH grants based on the data from his LGSF grant! EEG, learning and memory testing in progress
  57. 57. Progress in models of LGS
  58. 58. Progress in models of LGS
  59. 59. An LGS brain organoid model Vanesa Nieto-Estévez UT Southwestern
  60. 60. An LGS brain organoid model Vanesa Nieto-Estévez UT Southwestern
  61. 61. An LGS brain organoid model How does a CHD2 mutation alter human brain development? Why do CHD2 mutant mini-brain organoids have seizures? How can we stop them? Vanesa Nieto-Estévez UT Southwestern
  62. 62. LGSF funded research efforts Generating model systems for studying LGS Identifying the cause of LGS LGS clinically described Clinical Research Translational Research Basic Research How does it cause epilepsy? What can we learn? Can the findings be applied to people? What are the effects? How well does it work?
  63. 63. LGSF funded research efforts Generating model systems for studying LGS Identifying the cause of LGS LGS clinically described Clinical Research Translational Research Basic Research How does it cause epilepsy? What can we learn? Can the findings be applied to people? What are the effects? How well does it work?
  64. 64. LGSF funded research efforts Generating model systems for studying LGS Identifying the cause of LGS LGS clinically described Clinical Research Translational Research Basic Research How does it cause epilepsy? What can we learn? Can the findings be applied to people? What are the effects? How well does it work?
  65. 65. LGSF funded research efforts Generating model systems for studying LGS Identifying the cause of LGS LGS clinically described Clinical Research Translational Research Basic Research How does it cause epilepsy? What can we learn? Can the findings be applied to people? What are the effects? How well does it work?
  66. 66. How: Genetic and other diagnostic testing Get the right diagnosis, sooner. Discover subtypes of LGS (different response to treatments) Find all the causes of LGS Grow the number of researchers studying LGS How: Raise awareness about LGS Raise funds for our Research Grant Program The causes of LGS help spur ideas for how to cure it Support clinical trial efforts in LGS Trials enable us to have confidence that treatments are effective for our LGS loved ones The LGS community is making a difference in LGS research & progress!
  67. 67. How: Genetic and other diagnostic testing Get the right diagnosis, sooner. Discover subtypes of LGS (different response to treatments) Find all the causes of LGS Grow the number of researchers studying LGS How: Raise awareness about LGS Raise funds for our Research Grant Program The causes of LGS help spur ideas for how to cure it Support clinical trial efforts in LGS Trials enable us to have confidence that treatments are effective for our LGS loved ones The LGS community is making a difference in LGS research & progress! Help us continue the work to find a cure for LGS!
  68. 68. Thank-you!

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