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Master Slide

Developing Targeted Therapeutics in Autism: Challenges for Clinical Trial Readiness

Alexander Kolevzon, MDClinical Director, Seaver Autism Center

Director, Child and Adolescent Psychiatry

Mount Sinai Health System

Disclosures of Potential Conflicts

Source Research funding

Advisor/consultant

Employee Speakers’ Bureau

Books, Intellectual Property

In-Kind Services

Stock of Equity

Honorarium

SeaverFoundation

X

NIH X

Autism Science

Foundation

X

SimonsFoundation

X

American Psychiatric Publishing

X

New York Community

Trust

X

Vencerx X 

Ovid X

AACAP x

*Mount Sinai and Joseph Buxbaum hold a shared patent for IGF-1 in Phelan-McDermid syndromeThe following presentation contains information concerning a use that has not been approved by the U.S. Food and Drug Administration 

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Symptom Domains and Associated Features of ASD

Restricted,Repetitive Behaviors

Social/Communication

Deficits

Sensory Sensitivity

Obsessive Compulsive

Disorder

AUTISMSPECTRUM DISORDER

Impulsivity/Aggression

Expressive/Receptive Language Disorders

EEG Abnormalities

ADHD Symptoms

Variable Faces of ASD

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Autism

Pathophysiology

Drug Development

Novel Therapeutics

Gene Discovery

Model Systems

Developing Novel Therapeutics

Genomic architecture of ASD

Dolen & Bear, 2009

De Rubeis et al., Nature, 2014

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Autism as a Synaptopathy

Phelan-McDermid syndrome

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Before After

A new view on autism spectrum disorder

Phelan-McDermid Syndrome

global developmental delay

intellectual disability

absent or severely delayed speech

hypotonia

dysmorphic features

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Gene Discovery - SHANK3

SHANK3 is a master scaffolding protein which forms a framework for the connections between nerve cells  

SHANK3 protein induces the formation of nerve cells and promotes growth

SHANK3 and associated proteins represent novel targets for drug intervention 

Model Systems –Synaptic Deficits in PMS

Bozdagi et al, 2010

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Costales & Kolevzon, 2016

Effect of IGF-1 on Synaptic Deficits

Bozdagi et al, 2013

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Reversal of motor deficits in Shank3-deficient mice (Het) after treatment with IGF-1

Bozdagi et al, 2013

Jamie Simon, Salk Institute for Biological Studies

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A Double‐Blind Placebo‐Controlled Crossover Trial of IGF‐1 in Children with Phelan‐McDermid

Syndrome

Placebo Placebo

IGF-1 IGF-1

12 weeks 12 weeks

wash-out

4 weeks

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Change in scores at week 12in social withdrawal and restricted behavior

Change in scores at week 12in hyperactivity

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Change in scores at week 12in sensory reactivity

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IGF-1 in ASD

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Biomarkers for Clinical Trials

Electrophysiological Markers

Identify subtypes of neurodevelopmental disorders based on excitatory/inhibitory (E/I) profiles

Inform personalized treatment approaches

Monitor treatment response and determine optimal responders

Identify associations between neurophysiological responses and clinical outcomes

Paige Siper, PhD Jennifer Foss-Feig, PhD

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Transient VEPs in PMS

Siper, PM

VEP Quiz

Siper, PM

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VEP Quiz

Siper, PM

Effects of IGF‐1 on neural responses

n=6

Band # Hz

1 6‐10

2 12‐28

3 30‐36

4 38‐48

Siper, PM

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Improvement in VEPs after treatment with IGF-1 in PMS

n=6; p=.048

Improvement in VEPs after treatment with OXT in ASD

n=7

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VEP in PMS and ASD

A subset of ~30% of iASD patients fall within 1 SD of the PMS P60-N75 mean and are defined as “PMS-like”

Siper, PMFoss-Feig, J

Clinician‐administered observation and corresponding caregiver interview capturing DSM‐5 sensory reactivity symptoms in children with neurodevelopmental disorders

Sensory Assessment for Neurodevelopmental Disorders (SAND)

Siper, PM et al., 2017

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Sensory Reactivity in PMS – SAND

Siper, PM

Effects of IGF‐1 on Sensory Reactivity

n=6, p = .037

Siper, PM

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Auditory Event Related Potentials

Jennifer Foss-Feig, PhD

Eye Tracking in PMS

Rose et al, 2013

Visual Paired Comparison

Gap-Overlap Task

Elison et al, 2013

Flicker Detection

Farzin et al, 2011

Pilar Trelles

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• 18 subjects with PMS underwent comprehensive evaluations.

• Over 542 hours of audio recording from the home environment was collected using LENA.

• 3 hours of audio was randomly selected for each participant and analyzed by human transcribers

FindingsHow accurately does LENA distinguish the Key Child 

from all others?

k = 0.449 (p <.001), 95% CI (0.443, 0.455).

Rankine et al., 2017

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FindingsHow accurately does LENA distinguish Key Child speech‐related vocalizations from non‐speech 

sounds?

k = 0.455 (p <.001), 95% CI (0.437, 0.473).

Rankine et al., 2017

FindingsWhat factors impact LENA performance?

Rankine et al., 2017

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Gait AnalysisPerformed in real time and captured at 240 Hz 

using 16 electro‐magnetic sensors

All output kinematic features of movement trajectories are analyzed from the head and upper/lower extremities.

Gait is measured during two exercises: 1) walking spontaneously along a six foot marked path; 2) walking along the identical path circumventing a waist‐high obstacle. 

n = 16 PMS; 11 controls

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Summary

Need validated measures specific to syndrome/phenotype

Develop/validate biomarkers

Carefully phenotype and select for target symptom/s of interest

Focus on functional improvements (e.g., motor skills; language; cognition)

Include younger subjects

Increase duration of treatment 

Acknowledgments

• Seaver Foundation• Joseph Buxbaum• Paige Siper• Danielle Halpern• Michelle Gorenstein• Yitzchak Frank• Jennifer Foss‐Feig• Pilar Trelles• Silvia De Rubeis• Hala Harony‐Nicolas• Michael Breen• Lynn Hendrickson• Emily Isenstein• Jordana Norry• Kristin Meyering• Allison Durkin• Elyana Feldman