Dr. Ana Kostic brings a novel perspective to her role as the Director of Drug Discovery and Development at the Seaver Autism Center for Research and Treatment at Mount Sinai. With significant experience in the pharmaceutical and biotech industry, Dr. Kostic brings expertise from her previous roles in building possible drug candidates for treatment for individuals with autism. While that may sound straightforward, identifying and developing an effective drug for autism presents many challenges, especially due to the heterogeneity of the characteristics and difficulties in modeling the disorder. In this interview, Dr. Kostic unpacks the complexity of drug development and what it takes to translate academic research into treatments that can improve quality of life.
Unique Model at the Seaver Autism Center
The shift from industry to a position in academia was a big one for Dr. Kostic. Instead of focusing on developing products that can reach patients, Dr. Kostic turned to scientific discovery and answering fundamental questions surrounding autism.
“There was a unique set of conditions at the Seaver Autism Center that really attracted me to the role,” Dr. Kostic shared. “We have preclinical teams, including a very large epidemiology group and several research labs that look at autism from the perspective of different model systems.” Epidemiologists at the Center track trends in autism incidence and investigate modifiable risk factors at the population level. “On the other side, we have the clinical center where patients are seen in the context of regular care and clinical studies,” Dr. Kostic added. The Center also provides community outreach via lectures and workshops to families and schools.
Translational Research Across Model Systems
If you are in the autism space, you already know the line, “If you meet one person with autism, you only met one person with autism.” The well-known phrase reflects the immense heterogeneity across the autism spectrum. The behavioral diversity across individuals with autism varies significantly, a complexity attributed to the hundreds of distinct genes that have been implicated in autism.
Much like autism itself, researching autism is multifaceted. Researchers rely on a variety of model systems. Each model answers different questions and sheds light on different aspects of autism. “There is no perfect disease model,” Dr. Kostic mentioned. “There’s no model that will give us absolute confidence in clinical success.” The Seaver Autism Center has recognized this and have tackled their questions from distinct approaches.
For one, the Seaver Center has worked with human iPSC cell lines, also known as induced Pluripotent Stem Cells. These are adult cells that have been artificially reprogrammed back into a stem cell state from which they can be differentiated into almost any cell type. In this case, researchers can use iPSCs to model human brain cells and study gene expression, neuronal development, and network activity. Another approach to modeling autism are animal models built using genetically modified mouse strains.
“We are trying to understand the complexity of autism by using simplified models,” Dr. Kostic added. “We test our hypothesis in one model system and then in another. Maybe you don’t see all the components in each, but collectively, they should give sufficient confidence to bring a candidate drug into patients. This is the ultimate goal.”
Translatable biomarkers are one of the various ways in which the Seaver researchers gain confidence that a drug is working as intended. These are indicators that can be assessed across multiple model systems including animal models, cell cultures, or human patients. These can be observed from EEG (electroencephalogram), which measures electrophysiological activity in the brain. “If we see in mice that the genetic mutation causes a similar deficit as observed in patients with autism, then we can establish it as a biomarker to be measured in both settings and see how they compare,” Dr. Kostic noted. “If we can demonstrate that the drug reverses that deficit, then we get some translational confidence and we can monitor the same marker in the patients receiving the drug once we get to human trials.”
Often the drugs themselves are built to match the exact gene sequence, via a gene therapy approach. Gene therapy aims to correct the underlying genetic cause of a disease and thereby restore the function of the mutated gene.
Of course, as mentioned, no single model system can fully capture the complexity of autism. Rather than relying on one model, the Seaver Autism Center integrates evidence across multiple approaches to provide a more complete picture of autism biology. As autism research has evolved, researchers are increasingly recognizing that improvements in quality of life are of the upmost importance. Researchers ask questions like, “Can this person communicate better?” or “Has their quality life improved?.” Usually, these parameters are more meaningful to individuals with autism and their families.
Monogenic Autism as a Drug Development Strategy
In one approach to drug development, Dr. Kostic and her team focus on single-gene causes of autism. In these cases, there is a single gene that is pinned down as the main causative agent. “This is what we call a de novo mutation. This means it is not hereditary but usually happens during conception or at an early stage of development,” Dr. Kostic shared. These de novo mutations can sometimes be deletions and result in large portions of genetic material missing.
Nevertheless, these single genes are critical for development. Usually, the patients with these single-gene causes have other conditions. “Some have epilepsy. Some have heart defects and others have kidney issues, depending on the gene. But what brings them together is the fact that they received an autism diagnosis as well,” Dr. Kostic said. “This helps us to break down the umbrella of autism spectrum disorder into discrete monogenic parts.” By researching more-defined monogenic cases first, the researchers can slowly build up to more complex idiopathic cases of autism, which are due to multiple genes and possibly other factors as well.
Angelman Syndrome is a great example of a monogenic disorder. It’s caused by disruptions in the UBE3A gene, which encodes an enzyme that helps regulate protein degradation. Many individuals with Angelman Syndrome exhibit autistic traits or have an autism diagnosis. Due to the relative simplicity of the genetic background of the syndrome, researchers can develop targeted therapies more easily.
Dr. Kostic has specifically been interested in Phelan-McDermid Syndrome, a monogenic cause of autism. “It is caused by a deletion on chromosome 22 and these deletions tend to be large,” Dr. Kostic shared. “On a karyotype, the affected chromosome appears as a ring structure.” Though the other chromosome appears normal, the mutations severely impact cognitive functioning in individuals with the condition.
Phelan-McDermid Syndrome was one of the earliest to be detected genetic causes of autism because it can be seen on such an old school method, such as karyotypes. “It doesn’t require sequencing nor any fine mapping of genes or anything like that,” Dr. Kostic added. However, Seaver researchers and others have identified a specific gene called SHANK3 on chromosome 22, which is largely responsible for Phelan-McDermid Syndrome. Individuals with single point mutations in these genes are usually affected by a milder form of this disorder. “You can imagine that there’s only a few thousand patients in the U.S. They get referred to us and a couple other centers who see children and young adults with the disorder.”
The Seaver Center is also focused on other monogenic causes, like ADNP (Activity-Dependent Neuroprotective Protein), FOXP1 Syndrome, and DDX3X Syndrome. “There are some themes in terms of how these genes affect development and the faculty became interested in it.” Today, this list has extended to about 150 to 200 genes that fit similar descriptions. Dr. Kostic and her team have developed a platform approach, using similar research pipelines and strategies across many genetic forms of autism, building targeted drugs for each.
Treatment Individualization
Ultimately, everyone with autism is so different and that’s the very nature of a spectrum. The diversity of strengths and challenges means that no single drug and or behavioral outcome is going to work for everyone.
For many complex disorders, including autism, meaningful care often extends beyond medication alone. Behavioral interventions and individualized therapies can all play essential roles alongside medical treatment. As Dr. Kostic emphasized, the goal is not to simply treat a diagnosis but to care for the whole person. In medicine, that means treating the patient, not the disease.
This philosophy is closely related to precision medicine, an approach that Dr. Kostic is a strong proponent of. Rather than assuming that all individuals with the same diagnosis will respond the same, precision medicine advocates for tailoring treatment to each person’s unique clinical presentation and environment.
The decision on whether to prescribe medication or a non-pharmacological intervention will lay in the treating physician, who knows the patient and their circumstance and can make that call. However, the researchers will still make recommendations based on targeting specific symptoms and diagnostic parameters. “Let’s say we develop a drug that helps with epilepsy and motor function, but it does not affect the social component. Then it would be only the patients who actually have seizures and who have moderate deficits that would be the candidates for the drug,” Dr. Kostic explained. Based on those recommendations, the treating physician would determine if a patient is the appropriate candidate for the therapy and decide which intervention or treatment offers the greatest benefit.