Challenges and Promises in Translational Therapeutics for Childhood Autism

Challenges and Promises in Translational Therapeutics for Childhood Autism

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Dr. Evdokia Anagnostou
Senior Clinician-Scientist, Bloorview Research Institute, Holland Bloorview Kids Rehabilitation Hospital
Associate Professor, Department of Pediatrics, University of Toronto


By: Mikaeel Valli

Autism spectrum disorder (ASD), commonly referred to as autism, is a complex neurodevelopmental condition characterized by repetitive behaviours and challenges with social communication. ‘Autism’ is not defined by a single set of behaviours, but rather by a range of conditions that reflect many differences in symptoms, skills, and degrees of disability. The signs associated with ASD emerge in childhood, and may appear as early as 18 months of age. I had the pleasure of meeting Dr. Evdokia Anagnostou, a paediatric neurologist and clinician-scientist at Holland Bloorview Kids Rehabilitation Hospital, who is one of the few who work tirelessly to find effective treatments to improve the quality of life for individuals with ASD.

On a sunny evening in Toronto, Dr. Anagnostou recounted a challenge from her neurology residency training in the early 2000’s. She was taught to use signs and symptoms to localize the brain lesion in paediatric patients; “However, this was almost an impossible task in autism,” she explained. “It was difficult to localize in these children because of the pervasiveness of the lesion.”  Clinical challenges in localizing brain lesions in ASD, the elusive neural mechanisms of this condition, and the deficiency of recent improvements in its care have motivated Dr. Anagnostou to study ASD as a clinician-scientist. She established her lab in 2008 at the Bloorview Research Institute, where she studies neuropsychopharmacology and neuroimaging of children with ASD to elucidate the underlying lesions characteristic of this condition. Furthermore, her lab investigates novel treatments as part of clinical trials. Putting her research interests together, Dr. Anagnostou aims to unravel the biological mechanisms of ASD, which would facilitate discoveries of effective treatments to improve outcomes for children with ASD.

A glaring void exists in the field of ASD symptom treatment—not a single approved drug is available except for anti-psychotics, which are often used for aggression and agitation management, not for core ASD symptoms. In addition, anti-psychotic medications have severe side effects that include metabolic disturbances and obesity. “We need medications that are effective for core symptom domains such as social challenges seen in ASD,” Dr. Anagnostou emphasized. “We need to cross this threshold.” She further explained that she does not seek a ‘cure drug,’ as such is unlikely to be found and likely not desired by many in the autism community, but rather a drug that can manipulate the condition’s neural mechanisms to enhance learning, especially during behaviour therapy. One reason for the lack of treatments that manage core ASD symptoms is inconsistencies in the biology of autism and other neurodevelopmental disorders. While these disorders are diagnosed based on the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria, the classification system does not accurately reflect the contribution of genetics to the underlying dysfunction. In autism, genetic sequencing shows hundreds of mutations that may be implicated in the presentation of this condition. Furthering the complexity of understanding the genetics of ASD is the fact that these mutations are not exclusive to autism but are also seen in other neurodevelopmental disorders, including intellectual disability, attention deficit hyperactivity disorder, and obsessive-compulsive disorder. This lack of specificity in autism diagnosis, as well as the heterogeneity within ASD, is among the factors that hamper the success of clinical trials on the condition, as they may alter the response to treatment in these studies. The need for better diagnosis prompted Dr. Anagnostou and her colleagues to tackle this puzzle in a top-down approach by examining various neurodevelopmental disorders and ASD as one group. She is currently exploring biologically homogenous groups that may exist within the neurodevelopmental spectrum based on neuroscience, genetics, cognition, and behaviour, as opposed to traditionally consulting the DSM-5 as a sole diagnostic resource. This paradigm shift is part of an effort called the Province of Ontario Neurodevelopmental Disorders (POND) Network.

While the POND Network initiative is still in its development, Dr. Anagnostou is investigating the implications of certain mutations in ASD and whether these may reveal new molecular targets for medications. Along with her colleagues, she is carrying out clinical trials of drugs simultaneously in humans and mice. “We are trying to understand whether the information we get from the mice—where we have genetic clarity—and downstream effects on the brain are translatable to humans, and whether this will help us stratify children based on biological makers that may predict treatment response,” she explains. In addition to testing drugs aimed at molecular targets, Dr. Anagnostou also studies drugs in clinical trials that are attuned to neuropathological targets. For example, Pioglitazone, a drug that is used to treat diabetes, has promising secondary properties that act to reduce microglial activation. Microglial cells are the main immune defense system in the brain and spinal cord which have been shown, through post-mortem studies, to be activated in ASD patients, and thereby play a role in neuroinflammation. Hence, Dr. Anagnostou is testing this drug as part of an ongoing clinical trial to evaluate its safety and efficacy in children with ASD. “This drug is showing promising preliminary findings in potentially improving challenging behaviours of ASD children,” she commented optimistically.

Another clinical trial that is underway focuses on oxytocin, a hormone intimately involved with social behaviour. Dr. Anagnostou explained that oxytocin may enhance the neural circuity involved in social cognition and reward processing. She recently began administering oxytocin to adolescents with ASD and encouragingly stated, “We are seeing nice effects on aspects of social perception such as face recognition.” Dr. Anagnostou hopes that these drugs will provide a meaningful improvement to the quality of life of individuals with ASD.

Discovering new medications, Dr. Anagnostou explained, is not the end of the translational work. The next challenge is to translate evidence into practice and ensure access to treatment. This is a whole different arena, involving collaboration between researchers and experts in economics, knowledge translation, and public health.

Dr. Anagnostou stresses that the knowledge gaps in the ASD field needs to be addressed in the next five to ten years. One knowledge gap in particular pertains to our understanding of aging in those with ASD. “It is unclear what happens when they age and whether they are at an increased risk for dementia or other neurological disorders,” she says.

Despite the challenges, frustrations, and long hours of being a clinician-scientist, Dr. Anagnostou continues forward with fortitude, attributing her driving force to her passion for individuals with ASD and related conditions. She advises students who seek to become clinician-scientists to pursue an area where they “feel they are contributing meaningfully, and doing what they enjoy,” reasoning that work-life balance is less of a problem when you do something you love.