Autism Spectra Disorder(s)? Jeremy Veenstra-VanderWeele, MD Ruane - - PowerPoint PPT Presentation

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Autism Spectra Disorder(s)? Jeremy Veenstra-VanderWeele, MD Ruane - - PowerPoint PPT Presentation

Feb 04, 2023 396 likes •846 views

The Way(s) Forward in Drug Development for Autism Spectra Disorder(s)? Jeremy Veenstra-VanderWeele, MD Ruane Professor and Director, Division of Child Psychiatry Columbia University and New York State Psychiatric Institute Interim Director,

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The Way(s) Forward in Drug Development for Autism Spectra Disorder(s)?

Jeremy Veenstra-VanderWeele, MD Ruane Professor and Director, Division of Child Psychiatry Columbia University and New York State Psychiatric Institute Interim Director, Center for Autism and the Developing Brain

ISCTM-ECNP Joint Autumn Conference ▪ 6 September 2019 ▪ Copenhagen, Denmark

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Disclosures

Source Consultant Grant Support Honorarium for this meeting Research / Editorial Support American Academy of Child & Adolescent Psychiatry X X Springer / Wiley X Autism Speaks X X Forest Laboratories, Inc. X Health Resources and Services Administration X Hoffmann-La Roche Inc. X X National Institute of Child Health and Human Development X National Institute of Mental Health X Novartis Pharmaceutical Corporation X X Seaside Therapeutics X SynapDx X

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“Sisyphus Stones” New York

Easier to knock them down than to set them up! Atlas Obscura, 2017

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Core Challenges

  • Definitional
  • Conceptual
  • Hierarchical
  • Key: Match methods to clearest articulation of hypothesis!
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Core Challenges

  • Definitional
  • Conceptual
  • Hierarchical
  • Key: Match methods to clearest articulation of hypothesis!
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What is Autism Spectrum Disorder?

“Autism is not a disease.” – Isabelle Rapin It is certainly not a single disease.

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Definitional Domains of Difficulty

Social Communication Repetitive Behavior (Really multiple spectra itself)

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May also see…

  • Intellectual disability
  • Language impairment
  • Coordination problems

– Fine motor and large motor skills

  • Savant skills

– Preserved area of function

  • Seizure disorder
  • Gastrointestinal symptoms

– Most commonly constipation

  • Hyperactivity
  • Anxiety, depression…
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What should go in the center? (Outcome measure of interest?)

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Social Function is Fragile!

Lots of ways to disrupt social function in mice and men:

  • Sensory
  • Motor
  • Seizures
  • Cognitive
  • Language
  • Circadian
  • Synaptic
  • Neurochemical
  • Neurohormonal
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What does it mean when targeting an associated symptom improves social function?

  • Optimal outcome

– One common pattern is severe ADHD

  • Improving attention

improves social attention

Jahromi et al., JADD, 2009 Methylphenidate

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Core Challenges

  • Definitional
  • Conceptual
  • Hierarchical
  • Key: Match methods to clearest articulation of hypothesis!
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How to conceptualize? “Autism Spectrum Disorders”?

Pinterest.com Inter-individual

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“Autism Spectra Disorder”?

Advancedbrainmapping.com Intra-individual

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Conceptualization

  • Autism spectrum disorders

– Defined by etiology (genetics) – Precision medicine for syndromal autism – Etiological certainty but behavioral variation

  • Autism spectra disorder

– Defined by symptoms or biomarkers – Treatments within ASD – Etiological uncertainty but defined by behavior

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Core Challenges

  • Definitional
  • Conceptual
  • Hierarchical
  • Key: Match methods to clearest articulation of hypothesis!
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Classic Autism Autism Spectrum Disorder Each overlapping circle indicates a common risk factor

Model of Autism Risk

Tuberous Sclerosis (TS1/2) Fragile X (~1-2%) (FMR1) PTEN hamartoma syndrome Phelan-McDermid (~0.7%) CHD8 disruption (~ 0.5%)

  • Chr. 16p11 Del (~1%)

Rare variants/Syndromes Common variants

Fetal valproate exposure

Slide modified from Ed Cook

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How is risk realized?

Cognitive & Behavioral Domains Information Processing Circuits Regions Synapses Cells Protein Networks Proteins Genes

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Risk genes feed a cascade of impact

Cognitive & Behavioral Domains Information Processing Circuits Regions Synapses Cells Protein Networks Proteins Genes Repetitive Behavior Social Behavior Sensory

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Risk genes feed a cascade of impact

Cognitive & Behavioral Domains Information Processing Circuits Regions Synapses Cells Protein Networks Proteins Genes

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Risk genes feed a cascade of impact

Cognitive & Behavioral Domains Information Processing Circuits Regions Synapses Cells Protein Networks Proteins Genes

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Theoretical Convergence at Behavior

Cognitive & Behavioral Domains Information Processing Circuits Regions Synapses Cells Protein Networks Proteins Genes

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Data Convergence

Cognitive & Behavioral Domains Information Processing Circuits Regions Synapses Cells Protein Networks Proteins Genes

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Data Convergence

Cognitive & Behavioral Domains Information Processing Circuits Regions Synapses Cells Protein Networks Proteins Genes

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Prior Model – Behavioral Treatments

Cognitive & Behavioral Domains Information Processing Circuits Regions Synapses Cells Protein Networks Proteins Genes

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Biomarkers to identify subgroups? Or to gauge target engagement? Or to measure drug response?

Cognitive & Behavioral Domains Information Processing Circuits Regions Synapses Cells Protein Networks Proteins Genes

N170? Eye Tracking? rs-fMRI?, EEG power? MRS Glx? JAKE, VABS

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Biomarkers to identify subgroups? Or to gauge target engagement? Or to measure drug response?

Cognitive & Behavioral Domains Information Processing Circuits Regions Synapses Cells Protein Networks Proteins Genes

N170? Eye Tracking? rs-fMRI?, EEG power? MRS Glx? JAKE, VABS

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Core Challenges

  • Definitional
  • Conceptual
  • Hierarchical
  • Key: Match methods to clearest articulation of hypothesis!
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Fragile X Syndrome (FXS)

  • X-linked
  • Mild to moderate intellectual disability
  • Autism in ~20-30%

– Autism Spectrum Disorder in 30-60% – Most patients have social difficulties

  • Hyperactivity, impulsivity
  • Sensory sensitivity
  • Seizures
  • Long face with prominent ears
  • Enlarged testes (after puberty)

Specialchild.org

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Molecular genetics: FMR1

  • Trinucleotide repeat (CGG) expansion
  • Gene methylation → Silencing
  • Encodes FMRP, an RNA chaperone

Kooy RF, Trends Genetics, 2003

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Post-Synaptic Neuron Dendritic Spine

mGlu5 receptor hypothesis

Pre-Synaptic Neuron

mGlu5 receptor FMRP AMPA receptor Glutamate

Kim Huber Mark Bear

Hippocampus

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Post-Synaptic Neuron Dendritic Spine

What if there is no FraX protein?

Pre-Synaptic Neuron

mGlu5 receptor AMPA receptor Glutamate

Kim Huber Mark Bear

Hippocampus

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How does this affect a mouse?

  • Altered dendritic spine density and shape
  • Hyperactivity (mild)
  • Social deficits (subtle and inconsistent)
  • Impaired learning (subtle and inconsistent)
  • Inducible seizures

Comery TA, PNAS, 1997

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Pharmacological Rescue

  • Novel mGluR5 negative allosteric

modulator = CTEP

– Roche compound

  • Rescues brain and behavior

– Decreased dendritic spines – Improved hyperactivity – Improved learning (subtle) – Improved auditory sensitivity – Decreased seizures – No obvious negative effects on health

Michalon et al., Neuron, 2012

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Cascade

Behavioral Domains Circuits Regions Brain Regions Synapses Cells Protein Networks Proteins Genes Social Repetitive Behavior Cognitive

Black Box

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Cascade

Behavioral Domains Circuits Regions Brain Regions Synapses Cells Protein Networks Proteins Genes Social Repetitive Behavior Cognitive

Black Box

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What about humans?

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Large Scale Trials in Adults and Adolescents…

Berry-Kravis et al., Sci Transl Med, 2016

Complete Methylation Partial Methylation Adults Adolescents

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Why did these trials fail?

  • Novartis and Roche FXS programs closed

– Placebo effect? – Wrong target? – Wrong Drugs? – Wrong Doses? – Wrong Ages? – Wrong Outcome Measures? – {Wrong Species?}

  • Child study now funded

– NINDS NeuroNext: Berry-Kravis, Abedutto et al.

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Can we better match methods to hypothesis?

Behavioral Domains Information Processing Circuits Regions Synapses Cells Protein Networks Proteins Genes

Black Box NeuroNEXT FX-LEARN Trial: Berry-Kravis, Abedutto, et al. 2017-2021

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Language learning, ET, EEG/ERP in 3-6 year olds

Behavioral Domains Information Processing Circuits Regions Synapses Cells Protein Networks Proteins Genes

NeuroNEXT FX-LEARN Trial: Berry-Kravis, Abedutto, et al. 2017-2021

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This isn’t easy!

  • Develop clear hypotheses
  • Match methods to hypotheses

– Acknowledge their limits

  • Differentiate failed trials from flawed hypotheses
  • Maximize knowledge gained from success

– Harness knowledge from behavioral treatments

But it is worth doing!