CHOP-Penn Autism Experts Share Vision for Accelerated Discovery

Joseph W. St. Geme, MD, chair, Department of Pediatrics at CHOP; Lisa M. Guay-Woodford, MD, senior advisor for Clinical and Translational Research Initiatives at CHOP; and Benjamin Prosser, PhD, director, Center for Epilepsy and Neurodevelopmental Disorders, engage with attendees during the final panel discussion at the CHOP-Penn Autism Research Symposium.

By droseyb [at] chop.edu (Barbara Drosey) and knabk [at] chop.edu (Kate Knab)

Researchers and administrators from Children's Hospital of Philadelphia and the University of Pennsylvania gathered at the Study Hotel in University City to discuss the latest avenues of autism research. Jointly organized by the two institutions on May 9, the CHOP-Penn Autism Research Symposium: Building the Future Together, explored opportunities for collaboration and breakthroughs in the understanding and treatment of autism spectrum disorder (ASD) across the lifespan.

CHOP Research Institute Executive Vice President and Chief Scientific Officer Susan Furth, MD, PhD, and Dean of the Penn Perelman School of Medicine Jonathan Epstein, MD, welcomed attendees and invited each person in the expertise-packed room to join their vision of enhanced collaboration and accelerated discovery.

"Imagine a future where we bring together the remarkable talent gathered here to solve challenges faced by autistic patients and families," Dr. Furth said. "The future is bright for us as a community to make an enormous impact."

With more than 2,000 patients diagnosed with autism spectrum disorder annually at CHOP, the existing connections with these patients and families provide a unique opportunity for the translational research community at CHOP and Penn.

"Making a quantum difference in autism is an audacious goal," Dr. Epstein said. "But who would have thought we would develop a vaccine in one year, be curing blindness in children, and curing cancer? Our scientists have the audacity to make a big difference in a short timeframe."

Daniel J. Rader, MD, Seymour Gray Professor of Molecular Medicine at Penn, elaborated on the extraordinary CHOP and Penn campuses, home to important scientific breakthroughs, leaders in genomics and biomedical informatics, and fueled by more than $1 billion in funding from the National Institutes of Health across CHOP and Penn for fiscal year 2023 alone.

"We have the greatest concentration of expertise in the world to make the quantum differences referenced by Dr. Epstein to understand, diagnose, and treat ASD," Dr. Rader said.

New Approaches to Design Impactful Autism Studies

Researchers consistently identified heterogeneity as an area for improvement in studies for ASD, in close association with a need for larger sample sizes.

"ASD as a single entity does not exist," said Robert T. Schultz, PhD, director of the Center for Autism Research (CAR) at CHOP. "We have kids who grow up to be university professors and others who never learn to speak – it is an incredible spectrum of learning styles, cognitive ability, and physical health conditions."

While the "many autisms" are an enormous challenge to scientists, they are meeting the challenge to find varied mechanisms to observe, measure, and quantify expressions, reaction times, and other physical traits that can reveal clues into the autistic brain.

Speaker and panel moderator, David Mandell, ScD, director of the Penn Center for Mental Health, explained future studies may utilize electronic health records – an already well-integrated system in the CHOP-Penn network that has information for more than 30,000 children – to create "mega-trials" that remotely track many interventions synchronously in one large sample.

Melanie Pellecchia, PhD, from Penn Medicine's Department of Psychiatry, also suggested that studies may be more impactful and invite more diverse participation if we attempt to remove the "clinical" aspects of clinical trials to instead mirror real-life environments — like home and school with interventions delivered by community clinicians, public school teachers, and parents.

Clinical Chair of the Autism Integrated Care Program at CHOP, Amanda Bennett, MD, MPH, emphasized the importance of incorporating research efforts into the primary care setting to include the clinical population more efficiently in research studies.

Digital Phenotyping Advancing Autism Research

Penn and CHOP researchers engage in digital phenotyping, a strategy that captures directly observable information, to collect better quantifiable outcomes data for those with autism.

Heather Nuske, PhD, a research assistant professor of Psychiatry at Penn, analyzes the emotional responses via heart rate of autistic individuals, with the goal of developing novel interventions to help identify and reduce stressors that lead to challenging behaviors.

Julia Parish-Morris, PhD, investigator at CAR at CHOP, uses large language models and machine learning to capture language, articulation, and other linguistic markers as quantifiable social phenotypes to help detect autism and inform treatment.

"Things that you say are the marriage of your cognitive domain, or your brain, and how you use your mouth and your face," Dr. Parish-Morris said. "Each person has a vocal fingerprint with linguistic markers that can potentially be used as a treatment trial outcome."

Scientists can measure movements quite elegantly through audio, speech, and video capabilities, as well as wearable devices that capture data on social communication and gross motor skills. The 180 different measurable signals as a young adult engages in conversation, a child walks across a room, or a toddler interacts with their mother, provide granular data that can be examined for cross correlations.

"As a direct readout of neurocircuitry, behavior provides a biobehavioral marker for ASD," Dr. Schultz said. "The challenge is scaling these capabilities up to reach the most patients."

Aimin Chen, MD, PhD, a senior environmental epidemiologist at Penn, focuses on perinatal and pediatric outcomes. He used the term "exposome" to describe anything not genetic that can affect growth and development such as ecosystems, lifestyle, social determinants, and physical/chemical exposures. The field already has solid evidence that exposures to certain factors impair neurodevelopment; Dr. Chen suggests that integrating these findings with digital phenotyping and genotype enables researchers to view risk for each patient holistically.

Digital phenotyping has a unique advantage when compared to the traditional methods of behavioral research such as questionnaires and lengthy observational visits: It is more accessible, quicker to complete, and more capable of collecting and analyzing data at scale. Ultimately, complete computational behavior analysis and digital phenotyping will be accomplished in three to five minutes, in the office of the patient's primary care provider and even over telecommunications platforms.

Molecular and Genetic Findings Allow for More Personalized Autism Intervention

In understanding ASD, researchers agree that learning how specific genetic variants and environmental stressors impact individual neural circuits is crucial to developing more personalized treatment.

Investigators like Ingo Helbig, MD, pediatric neurologist in the Division of Neurology and a core faculty member of the Epilepsy NeuroGenetics Initiative (ENGIN) Frontier Program, are focused on furthering understanding of genetic factors in ASD. Data integration through the Center for Applied Genomics and Arcus allows researchers to look at variants across information gathered from CHOP and Penn, all linked to clinical data. Dr. Helbig suggests it is through this deep phenotypic complexity that we can begin to understand the co-morbidities of ASD such as asthma, attention-deficit/hyperactivity disorder, allergies, and more.

Session 3 researchers delved into the brain's complex circuitry to investigate various frameworks for successful therapies. This includes the study of animal models and organoids that mimic the developing brain, designed by Guo-li Ming, MD, PhD, from Penn's Department of Neuroscience, as well as the work of CHOP neuroscientist Ethan Goldberg MD, PhD, identifying sodium ion channels related to both autism and epilepsy.

For Marc Fuccillo, MD, PhD, associate professor of Neuroscience at Penn, that means digging deeper into an individual's existing genetics to find ASD-associated circuits based on reward and reinforcement processes that stem from a brain area called the striatum, which is a core circuit center that dysfunctions in those with autism.

"We know a lot about some of these ASD-associated circuits already and the pharmacology that regulates them," Dr. Fuccillo said. "If increased output in a specific pathway is causing a problem for one person, it gives us some ideas as to which pharmacologic options may be more effective."

Speakers in Session 2 zeroed in on biological mechanisms of ASD. Erica Korb, PhD, assistant professor of Genetics at the Penn Epigenetics Institute, explored epigenetic dysregulation as a targetable factor working with animal and primary cell models. With precise manipulations, Dr. Korb investigates epigenetic disruptions in ASD that change synaptic function in the search for novel therapies to rescue behavioral deficits.

Likewise, Thomas Jongens, PhD, associate professor of Genetics at Penn, investigates mitochondrial dysfunction and its potential ramifications in ASD. Working with Drosophila models of Fragile X and 22q, Dr. Jongens aims to determine if targeting deficits that appear in some genetic forms of ASD can restore neuronal function.

"The CHOP-Penn autism model community is building a pipeline of potential cures we can move to clinical trials," Dr. Jongens said.

Session 4 speaker Ted Brodkin, MD, associate professor of Psychiatry at Penn Medicine, explored how nonpharmacologic options, such as cognitive behavioral therapy, can be paired with medication to achieve more effective, personalized outcomes.

Dr. Brodkin recognized CHOP and Penn as a major hub for cognitive behavioral therapy, noting that working with researchers like Dr. Fuccillo and Dr. Goldberg allows them to pair appropriate medication, such as oxytocin which studies suggest facilitates social learning, with strategies for teaching structured learning processes to increase social and daily living skills.

Unique Power of CHOP-Penn Partnership with Autism Community

With their robust network of patients and families and an emphasis on community outreach programs, CHOP and Penn are uniquely poised to involve Philadelphia communities and surrounding areas in an actionable, impactful way.

Co-presenter with Dr. Brodkin, Emily Kuschner, PhD, a clinical psychologist at CHOP, explained that analyzing how effective, affordable, scalable, and efficient intervention is will help determine how well it could be integrated into the community. Similarly, Dr. Pellecchia shared the ways in which community partnerships could improve research and bridge gaps between researchers and the community members they serve.

"To conduct meaningful randomized trials, we have to make sure they stand on pillars that rest on community partnerships," Dr. Pellecchia said. "We need the community's trust to contribute to both internal and external validity of a trial, which will ensure our research has a lifelong impact on outcomes for families and children."

Whitney Guthrie, PhD, a clinical psychologist and scientist at CAR, emphasized the need for scalable screening and treatment solutions for real-world implementation in settings where parents and caregivers go about their daily lives.

Perhaps the event's biggest takeaway is that the strong partnerships between CHOP and Penn are what help bring such valuable discoveries into patient care. Almost every presentation noted an affiliation with researchers from both institutions, citing shared ideas, resources, and goals.

Maja Bućan, PhD, co-director of the Penn Autism Spectrum Program of Excellence, described a path toward accomplishing and maintaining these goals: establishing a combined CHOP-Penn longitudinal autism cohort to harness the wealth of clinical and genetic data.

As CHOP's senior advisor for Clinical and Translational Research Initiatives Lisa Guay-Woodford, MD, remarked at the conclusion of the symposium, only an alley separates CHOP and Penn campuses. Beyond that, they are unified under the same aspirations, consistently striving to listen to their community to better serve their needs with research that has a lasting, collaborative impact.

"It's clear there are already many collaborations between Penn and CHOP campuses," said Joseph St. Geme, MD, Chair of the Department of Pediatrics at CHOP, "and there's … opportunity now more than ever in how we think about the biology of autism, understand diagnoses, and think about approaches to treatment."