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

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

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

“Sisyphus Stones” New York Atlas Obscura, 2017 Easier to knock them down than to set them up!

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

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

What is Autism Spectrum Disorder? “ Autism is not a disease. ” – Isabelle Rapin It is certainly not a single disease.

Definitional Domains of Difficulty Social Communication Repetitive Behavior (Really multiple spectra itself)

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…

What should go in the center? (Outcome measure of interest?)

Social Function is Fragile! Lots of ways to disrupt social function in mice and men: • Sensory • Motor • Seizures • Cognitive • Language • Circadian • Synaptic • Neurochemical • Neurohormonal

What does it mean when targeting an associated symptom improves social function? • Optimal outcome Methylphenidate – One common pattern is severe ADHD • Improving attention improves social attention Jahromi et al., JADD , 2009

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

How to conceptualize? “Autism Spectrum Disorders”? Inter-individual Pinterest.com

“Autism Spectra Disorder”? Intra-individual Advancedbrainmapping.com

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

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

Model of Autism Risk Rare variants/Syndromes Classic Autism Fragile X (~1-2%) ( FMR1 ) Chr. 16p11 Del (~1%) Autism Tuberous Sclerosis ( TS1/2 ) Spectrum Disorder PTEN hamartoma syndrome Phelan-McDermid (~0.7%) Common variants CHD8 disruption (~ 0.5%) Each overlapping Fetal valproate exposure circle indicates a common risk factor Slide modified from Ed Cook

How is risk realized? Cognitive & Behavioral Domains Information Processing Circuits Regions Synapses Cells Protein Networks Proteins Genes

Risk genes feed a cascade of impact Sensory Repetitive Behavior Social Behavior Cognitive & Behavioral Domains Information Processing Circuits Regions Synapses Cells Protein Networks Proteins Genes

Risk genes feed a cascade of impact Cognitive & Behavioral Domains Information Processing Circuits Regions Synapses Cells Protein Networks Proteins Genes

Risk genes feed a cascade of impact Cognitive & Behavioral Domains Information Processing Circuits Regions Synapses Cells Protein Networks Proteins Genes

Theoretical Convergence at Behavior Cognitive & Behavioral Domains Information Processing Circuits Regions Synapses Cells Protein Networks Proteins Genes

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

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

Prior Model – Behavioral Treatments Cognitive & Behavioral Domains Information Processing Circuits Regions Synapses Cells Protein Networks Proteins Genes

Biomarkers to identify subgroups? Or to gauge target engagement? Or to measure drug response? JAKE, VABS Cognitive & Behavioral Domains Eye Tracking? Information Processing N170? Circuits rs-fMRI?, EEG power? Regions MRS Glx? Synapses Cells Protein Networks Proteins Genes

Biomarkers to identify subgroups? Or to gauge target engagement? Or to measure drug response? JAKE, VABS Cognitive & Behavioral Domains Eye Tracking? Information Processing N170? Circuits rs-fMRI?, EEG power? Regions MRS Glx? Synapses Cells Protein Networks Proteins Genes

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

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

Molecular genetics: FMR1 • Trinucleotide repeat (CGG) expansion • Gene methylation → Silencing • Encodes FMRP, an RNA chaperone Kooy RF, Trends Genetics , 2003

mGlu5 receptor hypothesis Pre-Synaptic Neuron Glutamate mGlu5 AMPA receptor receptor FMRP Dendritic Spine Kim Huber Post-Synaptic Hippocampus Neuron Mark Bear

What if there is no FraX protein? Pre-Synaptic Neuron Glutamate mGlu5 receptor AMPA receptor Dendritic Spine Kim Huber Post-Synaptic Hippocampus Mark Bear Neuron

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

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

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

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

What about humans?

Large Scale Trials in Adults and Adolescents… Complete Methylation Partial Methylation Adults Adolescents Berry-Kravis et al., Sci Transl Med , 2016

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.

Can we better match methods to hypothesis? Black Box Behavioral Domains Information Processing Circuits Regions Synapses Cells Protein Networks Proteins NeuroNEXT FX-LEARN Trial: Genes Berry-Kravis, Abedutto, et al. 2017-2021

Language learning, ET, EEG/ERP in 3-6 year olds Behavioral Domains Information Processing Circuits Regions Synapses Cells Protein Networks Proteins NeuroNEXT FX-LEARN Trial: Genes Berry-Kravis, Abedutto, et al. 2017-2021

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!