The document discusses progress in research for Landau-Kleffner syndrome (LGS), including benefits of genetic testing, clinical trials underway to test treatments like cannabidiol, efforts to develop animal models of LGS, and the LGS Foundation's funding of research into gene identification, functional studies, and applying findings to help people with LGS.

2. Exciting times!
Research and progress in LGS
Melanie Huntley, PhD
April 30, 2016

3. The LGS community can make a difference
in finding a cure

4. Benefits of genetic testing:
Get the right diagnosis, sooner
Discover subtypes of LGS
(different response to treatments)
The LGS community can make a difference
in finding a cure
Find the cause(s) of LGS

5. Benefits of genetic testing:
Get the right diagnosis, sooner
Discover subtypes of LGS
(different response to treatments)
The LGS community can make a difference
in finding a cure
Find the cause(s) of LGS Grow the number of researchers
studying LGS
Raise awareness about LGS
Raise funds for our Research Grant Program
More causes of LGS to follow up in the lab

6. Benefits of genetic testing:
Get the right diagnosis, sooner
Discover subtypes of LGS
(different response to treatments)
The LGS community can make a difference
in finding a cure
Find the cause(s) of LGS Grow the number of researchers
studying LGS
Raise awareness about LGS
Raise funds for our Research Grant Program
More causes of LGS to follow up in the lab
Support clinical research
efforts in LGS
Advocacy and laws (CBD)
Participation
Seizure diaries (data mining)
(data driven treatment decisions)

7. Benefits of genetic testing:
Get the right diagnosis, sooner
Discover subtypes of LGS
(different response to treatments)
The LGS community can make a difference
in finding a cure
Find the cause(s) of LGS Grow the number of researchers
studying LGS
Raise awareness about LGS
Raise funds for our Research Grant Program
More causes of LGS to follow up in the lab
Support clinical research
efforts in LGS
Advocacy and laws (CBD)
Participation
Seizure diaries (data mining)
(data driven treatment decisions)
So how does research in LGS work?

8. Basic, Translational & Clinical Research
Model
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

9. Back 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

10. Patient-centered forward & reverse
translation
Clinical
Research
Translational
Research
How does it work?
What can we learn?
Basic
Research
Cause identification Syndrome clinically
described
Functional studies
Does the model reflect the
human disorder?

11. Patient-centered forward & reverse
translation
Clinical
Research
Translational
Research
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?

12. 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?

13. 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?
What progress are we making with clinical trials in LGS?

15. Cannabidiols: GW & INSYS
Open label, safety & efficacy clinical trials (not placebo controlled)
Devinsky et al. 2016. Lancet Neurology

16. Cannabidiols: GW & INSYS
Open label, safety & efficacy clinical trials (not placebo controlled)
Devinsky et al. 2016. Lancet Neurology
30 patients with LGS in the efficacy study

17. Cannabidiols: GW & INSYS
Open label, safety & efficacy clinical trials (not placebo controlled)
Devinsky et al. 2016. Lancet Neurology
30 patients with LGS in the efficacy study Median reduction in total monthly seizures: 35.5%

18. Cannabidiols: GW & INSYS
Open label, safety & efficacy clinical trials (not placebo controlled)
Devinsky et al. 2016. Lancet Neurology
30 patients with LGS in the efficacy study Median reduction in total monthly seizures: 35.5%
Zero were seizure free after 3 months of treatment

19. Cannabidiols: GW & INSYS
Open label, safety & efficacy clinical trials (not placebo controlled)
30 patients with LGS in the efficacy study
Devinsky et al. 2016. Lancet Neurology
Median reduction in total monthly seizures: 35.5%
Zero were seizure free after 3 months of treatment
No reduction in tonic-clonic seizures (n=16)

20. Cannabidiols: GW & INSYS
Open label, safety & efficacy clinical trials (not placebo controlled)
30 patients with LGS in the efficacy study
Devinsky et al. 2016. Lancet Neurology
Median reduction in total monthly seizures: 35.5%
Zero were seizure free after 3 months of treatment
No reduction in tonic-clonic seizures in LGS patients
(n=16)
Median reduction in motor seizures: 36.8%
- 11 had > 50% reduction

21. Cannabidiols: GW & INSYS
Open label, safety & efficacy clinical trials (not placebo controlled)
30 patients with LGS in the efficacy study
Devinsky et al. 2016. Lancet Neurology
Median reduction in total monthly seizures: 35.5%
Zero were seizure free after 3 months of treatment
No reduction in tonic-clonic seizures in LGS patients
(n=16)
Median reduction in motor seizures: 36.8%
- 11 had > 50% reduction
Median reduction in tonic seizures: 40% (n = 21)

22. Cannabidiols: GW & INSYS
Open label, safety & efficacy clinical trials (not placebo controlled)
30 patients with LGS in the efficacy study
Devinsky et al. 2016. Lancet Neurology
Median reduction in total monthly seizures: 35.5%
Zero were seizure free after 3 months of treatment
No reduction in tonic-clonic seizures in LGS patients
(n=16)
Median reduction in motor seizures: 36.8%
- 11 had > 50% reduction
Median reduction in tonic seizures: 40% (n = 21)
Median reduction in atonic seizures: 68.8% (n = 14)

23. Cannabidiols: GW & INSYS
Open label, safety & efficacy clinical trials (not placebo controlled)
30 patients with LGS in the efficacy study
Devinsky et al. 2016. Lancet Neurology
Median reduction in total monthly seizures: 35.5%
Zero were seizure free after 3 months of treatment
No reduction in tonic-clonic seizures in LGS patients
(n=16)
Median reduction in motor seizures: 36.8%
- 11 had > 50% reduction
Median reduction in tonic seizures: 40% (n = 21)
Median reduction in atonic seizures: 68.8% (n = 14)
Not a placebo controlled trial, but promising results

24. Cannabidiols
Phase 3 (placebo controlled trials)
Number of LGS patients Expected to have results
GW 171 April 2016
GW 210 June 2016
INSYS 86 Dec 2016
Answer the lingering question: is the efficacy signal real?

25. Rescue medication
Acorda Therapeutics: Open label, safety & efficacy study
Diazepam nasal spray Diazepam rectal gel
vs.

26. A wide variety of clinical research!

27. A wide variety of clinical research!

28. A wide variety of clinical research!

29. A wide variety of clinical research!

30. A wide variety of clinical research!

31. A wide variety of clinical research!
Accurate seizure detection
Is treatment working?

32. A wide variety of clinical research!
Accurate seizure detection
Is treatment working?
What is the LGS Foundation doing to
further LGS research in the 2 years since
we began our Research Grant Program?

33. 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?

34. DNA provides instructions to every cell in
our bodies
The DNA sequence in our genomes is what
makes us human

35. 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

36. 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

37. If the code in the instructions is
misspelled ➡ mutation
Sometimes these mutations occur
in important pieces of code called
“genes”

38. Progress in finding new LGS genes
De novo mutations
GCTGCAGCCCCAA
GCTGCACCCCCAA
Exome DNA sequence
analysis of 22 LGS trios
(10/22 complete)
Candace Myers @ U of Washington

39. Progress in finding new LGS genes
De novo mutations
GCTGCAGCCCCAA
GCTGCACCCCCAA
Exome DNA sequence
analysis of 22 LGS trios
(10/22 complete)
Found 8 candidate
genes (10 trios)
Candace Myers @ U of Washington

40. Progress in finding new LGS genes
De novo mutations
GCTGCAGCCCCAA
GCTGCACCCCCAA
Exome DNA sequence
analysis of 22 LGS trios
(10/22 complete)
Found 8 candidate
genes (10 trios)
Test the candidate genes in 600
(LGS + other epilepsy) patients to
look for recurrence
Candace Myers @ U of Washington

41. Progress in finding new LGS genes
Pilot program: Exome sequencing of 100 individuals (LGS trios and singletons)
who have not had access to genetic testing

42. 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?

43. 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?

44. GABRB3
STXBP1
CHD2
ALG13
Model systems for epilepsy
Potential causes of
the disease

45. GABRB3
STXBP1
CHD2
ALG13
Model systems for epilepsy
Potential causes of
the disease

46. GABRB3
STXBP1
CHD2
ALG13
Model systems for epilepsy
Does it have seizures?Potential causes of
the disease

47. 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

48. 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

49. 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?

50. Progress in Zebrafish models of LGS
Model organism for studying human
mutations in a vertebrate animal
Scott Baraban & Brian Grone @ UCSF

51. 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

52. 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

53. 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

54. Progress in Mouse models of LGS

55. Progress in Mouse models of LGS
Isabela has a mutation
in the CHD2 gene

56. Progress in Mouse models of LGS
Isabela has a mutation
in the CHD2 gene
CHD2 knockout mouse
Robert Hunt @ UC Irvine

57. Progress in Mouse models of LGS
Isabela has a mutation
in the CHD2 gene
Robert Hunt @ UC Irvine
CHD2 knockout mouse

58. Progress in Mouse models of LGS
Isabela has a mutation
in the CHD2 gene
Robert Hunt @ UC Irvine
CHD2 knockout mouse
Brain structure looks mostly
normal

59. Progress in Mouse models of LGS
Isabela has a mutation
in the CHD2 gene
Robert Hunt @ UC Irvine
CHD2 knockout mouse
Brain structure looks mostly
normal
EEG, learning and memory
testing planned this spring

60. Progress in Mouse models of LGS
Isabela has a mutation
in the CHD2 gene
Robert Hunt @ UC Irvine
CHD2 knockout mouse
Brain structure looks mostly
normal
EEG, learning and memory
testing planned this spring
Saad Abbasi
Jan Frankowski
Sunyoung Lee
Kimberly Gonzalez

61. LGSF funded research efforts 2014-15
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?

62. LGSF funded research efforts 2016-17
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?

63. Genetic testing
Get the right diagnosis, sooner
Discover subtypes of LGS
The LGS community is making a difference
in LGS research & progress!
Find the cause of LGS Grow the number of researchers
studying LGS
Raise awareness and funds for LGS research
Provide genomes to analyze
Find candidate genes to follow up in the lab
Support clinical research
in LGS
Advocacy and laws (CBD)
Participation
Seizure diaries
The time is right for us to build on this momentum!

64. Thank-you!

65. Epilepsy Genetics Initiative (EGI)
Julie Milder, PhD
Associate Research Director
April 30, 2016

66. Thomas & Berkovic 2014
For ~75% of people with
epilepsy, the cause is unknown

67. Exome Sequencing

68. • The EGI will create a data
repository of clinical exome and
genome sequences
• Data will be reanalyzed every 6
months for novel genetic changes
• New results will be communicated
back to patients via their doctor
• Data will also be made available to
advance epilepsy research
What is EGI?

70. Principal Sponsors: The John and Barbara Vogelstein
Family Foundation
EGI Partners

71. EGI Partnering
Organizations

72. EGI Partnering
Organizations
Current Non-Profit Partners

73. Status as of
April 7, 2016
• 89 families enrolled (233 individuals)
• New enrollment sites:
Colorado Children’s Hospital
University of Iowa
• 28 families analyzed November 2015
• 4 cases with confirmed positive results
• 4 cases of likely pathogenic results
• 1 solved – new diagnosis

74. EGI Vision

75. Acknowledgements
EGI Steering Committee: Sam Berkovic, Tracy Dixon-Salazar, Brandy Fureman, David
Goldstein, Katrina Gwinn, Erin Heinzen, Dan Lowenstein, Julie Milder, Randy Stewart, Steve
White, Vicky Whittemore
EGI Enrollment Sites:
Boston Children’s Hospital: Annapurna Poduri, Beth Sheidley, Lacey Smith
CHOP: Dennis Dlugos, Ingo Helbig, Eric Marsh, Holly Dubbs
Columbia University: David Goldstein, Erin Heinzen, Carl Bazil, Jim Riviello, Cigdem Akman,
Danielle McBrian, Tiffani McDonough, Louise Bier, Natalie Lippa, Maureen Mulhern, Sitharthan
Kamalakaran, Joshua Bridgers, Nick Ren
Duke University: William Gallentine, Mohamad Makati
Lurie Children’s Hospital of Chicago: John Millichap, Diana Miazga
NYU: Orrin Devinsky, Judith Bluvstein, Patricia Dugan, Patricia Tolete
UCSF: Dan Lowenstein, Roberta Cilio, Susannah Cornes, Joseph Sullivan, Nilika Singhal,
Kaleas Johnson
University of Melbourne: Sam Berkovic, Ingrid Scheffer, Amy Schneider
CURE EGI: Tracy Dixon-Salazar, Brandon Laughlin
Contributing Labs: Ambry, Baylor, CHOP, Columbia PGM, Emory, GeneDx, MedGenome,
UCLA