Post on 15-Apr-2017
Exciting times! Research and progress in LGS
Melanie Huntley, PhD April 30, 2016
The LGS community can make a difference in finding a cure
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
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
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)
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?
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
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
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?
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?
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?
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?
Cannabidiols: GW & INSYS Open label, safety & efficacy clinical trials (not placebo controlled)
Devinsky et al. 2016. Lancet Neurology
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
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%
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
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)
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
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)
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)
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
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?
Rescue medication
Acorda Therapeutics: Open label, safety & efficacy study
Diazepam nasal spray Diazepam rectal gel
vs.
A wide variety of clinical research!
A wide variety of clinical research!
A wide variety of clinical research!
A wide variety of clinical research!
A wide variety of clinical research!
A wide variety of clinical research!
Accurate seizure detection Is treatment working?
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?
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?
DNA provides instructions to every cell in our bodies
The DNA sequence in our genomes is what makes us human
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
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
If the code in the instructions is misspelled ➡ mutation Sometimes these mutations occur in important pieces of code called “genes”
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
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
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
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
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?
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?
GABRB3 STXBP1 CHD2 ALG13
Model systems for epilepsy
Potential causes of the disease
GABRB3 STXBP1 CHD2 ALG13
Model systems for epilepsy
Potential causes of the disease
GABRB3 STXBP1 CHD2 ALG13
Model systems for epilepsy Does it have seizures?
Potential causes of the disease
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
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
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?
Progress in Zebrafish models of LGS
Model organism for studying human mutations in a vertebrate animal
Scott Baraban & Brian Grone @ UCSF
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
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
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
Progress in Mouse models of LGS
Progress in Mouse models of LGS
Isabela has a mutation
in the CHD2 gene
Progress in Mouse models of LGS
Isabela has a mutation
in the CHD2 gene
CHD2 knockout mouse
Robert Hunt @ UC Irvine
Progress in Mouse models of LGS
Isabela has a mutation
in the CHD2 gene
Robert Hunt @ UC Irvine
CHD2 knockout mouse
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
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
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
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?
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?
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!
Thank-you!
Epilepsy Genetics Initiative (EGI)
Julie Milder, PhD
Associate Research Director
April 30, 2016
Thomas & Berkovic 2014
For ~75% of people with epilepsy, the cause is unknown
Exome Sequencing
• 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?
Principal Sponsors: The John and Barbara Vogelstein Family Foundation
EGI Partners
EGI Partnering Organizations
EGI Partnering Organizations
Current Non-Profit Partners
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
EGI Vision
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