lgs foundation 2016 conference - saturday morning

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)


Find the cause(s) of LGS





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)







Support clinical research efforts in LGS


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


Basic Research

Patient-centered forward & reverse translation

Clinical Research


How does it work? What can we learn?

Basic Research



human disorder?


Clinical Research


Basic Research

Can findings be applied to people?



human disorder?



Clinical Research


What are the effects? How well does it work?

Basic Research




human disorder?



Clinical Research



Basic Research




human disorder?


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



30 patients with LGS in the efficacy study



30 patients with LGS in the efficacy study Median reduction in total monthly seizures: 35.5%



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




Median reduction in total monthly seizures: 35.5%


No reduction in tonic-clonic seizures (n=16)






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)









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!


Accurate seizure detection Is treatment working?


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?


Clinical Research




Basic Research



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


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


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



Exome DNA sequence


(10/22 complete)

Found 8 candidate

genes (10 trios)

Candace Myers @ U of Washington



Exome DNA sequence


(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


Pilot program: Exome sequencing of 100 individuals (LGS trios and singletons) who have not had access to genetic testing


Clinical Research



Basic Research



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


Model systems for epilepsy Does it have seizures?



Model systems for epilepsy Does it have seizures? Does the model reflect what we know about the human condition?



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?



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?


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


Baraban et al. 2013. Nature Comm.


Dravet Syndrome

Control SCN1A

mutation





Dravet Syndrome

Control SCN1A

mutation


Clemizole as a potential new treatment for Dravet Syndrome

Progress in Zebrafish models of LGS LGS Models

Grone et al. 2016. Plos ONE.



Dravet Syndrome

Control SCN1A

mutation

STXBP1 mutant zebrafish

GABRB3 mutant zebrafish


Clemizole as a potential new treatment for Dravet Syndrome

Progress in Mouse models of LGS


Isabela has a mutation

in the CHD2 gene



in the CHD2 gene

CHD2 knockout mouse

Robert Hunt @ UC Irvine



in the CHD2 gene


CHD2 knockout mouse



in the CHD2 gene


CHD2 knockout mouse

Brain structure looks mostly

normal



in the CHD2 gene


CHD2 knockout mouse


normal

EEG, learning and memory

testing planned this spring



in the CHD2 gene


CHD2 knockout mouse


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


Basic Research


Can the findings be applied to people?

LGSF funded research efforts 2016-17

Functional studies Gene identification LGS clinically described

Clinical Research


Basic Research


Can the findings be applied to people?


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


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

lgs foundation 2016 conference - saturday morning

Healthcare