Heterogeneity of autism makes clinical trials difficult, says CHLA expert

Each year in the U.S. the incidence of autism spectrum disorder increases, yet the number of medications to treat the core features of autism remains stuck at zero. Therapies and medications that address related symptoms like sleep, focus and behavioral issues are the current "gold standard" for autism treatment. But what's next?

Why is there no medication to treat autism?

Although at any given time there are hundreds of ongoing clinical trials testing drugs to treat autism, there are many reasons why none have been proven effective. Autism is a heterogeneous disorder. It isn't caused by a single factor like a bacteria or even a single gene. It's a complex condition that has been linked to myriad genetic changes, as well as a variety of environmental factors. In addition, symptoms and the degree of their impact vary widely, giving rise to the now-famous quote, "If you've met one person with autism, you've met one person with autism."

Given all this variability, how can a study definitively show that a medication is working?

Even with a viable therapeutic, the heterogeneity of autism makes clinical trials difficult. Maybe you didn't measure the right thing or wait long enough to see a change."

Shafali Spurling Jeste, MD, Chief of Neurology, Co-Director of the Neurological Institute and Las Madrinas Chair at Children's Hospital Los Angeles

According to Dr. Jeste, a validated biomarker for autism is necessary to make real progress. She explains that biomarkers are measurable, biological features that provide information about a clinical condition-;like insulin levels for diabetes or temperature for infection.

Dr. Jeste is site principal investigator for the Autism Biomarkers Consortium for Clinical Trials (ABC-CT)-;one of the largest initiatives ever undertaken by the National Institutes of Health focused on autism research. She is six years into the search to identify, quantify and validate biomarkers and clinical endpoints relevant for autism.

For this study, children come to the clinic for a comprehensive set of assessments. The biomarker testing includes electroencephalography (EEG) to measure brain function, eye tracking to determine visual attention, and recordings for studying behavior and speech. The same assessments are done again at six weeks and six months later. The objective is to determine if the potential biomarkers are stable over time in a growing child. The measurements will also be compared with those of typically developing children.

"Biomarkers would give us a way to meaningfully group children with common characteristics with the goal of eventually testing a medication in less heterogenous groups," says Dr. Jeste. "Changes in a stable biomarker also would provide an objective way to determine if a medication was affecting the brain and, as a result, could improve a core feature of autism."

Two years ago, Dr. Jeste moved her Kids with Neurogenetic Developmental Disabilities (KiNDD) lab to Children's Hospital Los Angeles, in part because of CHLA's patient population. She explains that most participants in autism studies are high-income white families. This creates bias in the studies.

"Families of other ethnicities and socioeconomic status typically don't typically participate in research-;including many of our families at CHLA," she says. "As a field, we have done a poor job of introducing these studies to families from underrepresented minority groups and those with low incomes, and as a result there is a lack of knowledge about the benefits of research. There are also some very real barriers to participation in studies, especially cost and time."

Dr. Jeste's team has tried to remove some of those barriers by paying for transportation to the clinic for assessments, providing child care for siblings and having evening and weekend appointments.

"We want all children to benefit from research, and as the nation's largest safety net children's hospital, CHLA should be the leader in increasing diversity in this area," says Dr. Jeste.

Why does diversity matter?

Recent research indicates that 40% to 80% of autism risk is genetic, with more than 200 specific genes linked to the disorder. Increasingly, clinicians are using advanced genetic testing to identify the cause of a person's autism. Interpretation of this genetic data relies upon large databases that, unfortunately, lack diversity.

Bridget Fernandez, MD, MS, a medical geneticist at CHLA, explains that most of what we know about genomic changes underlying particular medical conditions, including autism, comes from looking at individuals from families of European ancestry. Databases for people of other ancestral origins are needed to effectively interpret their genetic data.

"At CHLA, we are working to establish a basis for evaluating Hispanic children in the way that children of European ancestry have been studied," says Dr. Fernandez, who is also Associate Director of Clinical Research at The Saban Research Institute of Children's Hospital Los Angeles.

Is personalized medicine the answer?

Dr. Fernandez is leading a study with the goal of conducting whole genome sequencing of 1,000 Hispanic children to build an ethnically appropriate database. She is also using "deep phenotyping" to better inform genetic studies of these kids. This involves gathering a lot of clinical information to pair with the genomic sequencing data to develop a more complete picture of the child's condition.

"Our hope is that we will eventually be able to provide families with therapeutic options-;like medications-;that are targeted to the specific genetic profile of their child," she explains.

These treatments can have significant benefits. "A child, who even with intense behavioral therapy remains nonverbal, may benefit from a medication that takes into account their specific genetic makeup," says Dr. Fernandez. "What if these future therapies helped this child develop expressive language? It would be life-changing."

She is concerned that if clinical trials are only enrolling children of European ancestry because those are the ones volunteering, other children may be left behind in the development of biologically based therapies. Dr. Fernandez, Dr. Jeste and other investigators at CHLA are working to address this imbalance and are actively recruiting children from underserved populations.

"While this particular study is not focused on producing a therapy, unless we do this kind of work, treatments informed by genomics may only be available to children of European ancestry," says Dr. Fernandez. "In the future when there are biological therapies, we want all children to be able to benefit."

Shafali Spurling Jeste, MD, Chief of Neurology, Co-Director of the Neurological Institute and Las Madrinas Chair at Children's Hospital Los Angeles