- Novel Probiotic Therapies for Autism
- Intranasal Oxytocin for the Treatment of Children and Adolescents with Autism Spectrum Disorders (ASD)
Interplay between the immune system and autism spectrum disorders (ASD) has been shown by a variety of studies, including epidemiological surveys and analyses of postmortem brains of individuals with ASD. This connection was successfully reproduced in an animal model of an ASD risk factor, maternal infection. In mice, maternal immune activation (MIA) during pregnancy leads to offspring with ASD features. Dr. Paul Patterson at the California Institute of Technology recently published a paper in PNAS, on a project led by graduate student Ms. Elaine Hsiao, reporting that offspring in the MIA model not only have ASD features (such as repetitive or stereotyped behaviors, decreased social interactions, and impaired communication) but also have indicators of inflammation that persist through adulthood. When these mice are given bone marrow transplants from typical mice (a process that should restore immune functioning), a reduction is seen in the behavioral impairments. These observations support the idea that the immune system may be a novel therapeutic target for individuals with ASD.
The Autism Research Program awarded Dr. Patterson and collaborator Dr. Sarkis Mazmanian an Idea Development Award in Fiscal Year 2010 to evaluate gastrointestinal (GI) changes in mice in the MIA model and to explore the potential for manipulation of the GI system with probiotics ("healthy" bacteria, here Bacteroides fragilis) to reduce inflammation and ameliorate ASD-like behaviors. In fact, the offspring of immune-activated mothers appear to display a striking GI pathology believed to be also found in many ASD children, "leaky gut syndrome." In this condition, the barrier of the gut lining allows molecules to leak from the gut into the bloodstream. In a paper currently under review, Ms. Hsiao, Drs. Patterson and Mazmanian, and their collaborators report that probiotic treatment (through food) of newly weaned MIA offspring restores GI function and results in significantly fewer ASD-like behaviors. Current work involves identifying the molecules that leak from the gut into the blood in MIA offspring, and testing whether any of these might be responsible for inducing the abnormal behaviors. Altering gut bacteria as a potential therapy to mediate ASD severity is an exciting possibility, one that has been anecdotally tried by individual families. Performing this study in a controlled environment is one of the first steps in better understanding if and how this type of treatment affects individuals with ASD behaviors.
Intranasal Oxytocin for the Treatment of Children and Adolescents with Autism Spectrum Disorders (ASD)
Posted April 5, 2012
Evdokia Anagnostou, MD, Holland Bloorview Kids Rehabilitation Hospital, Toronto, CA
Significant deficits in social cognitive skills, language and repetitive behaviors are prominent characteristics of children with Autism Spectrum Disorders (ASD). Furthermore, in comparison with other neurodevelopmental disorders, individuals with autism are much less likely to attend or orient their attention to social stimuli in their environment such as having eye-to-eye gaze, facial expression, and pointing gestures, that lack of which are considered early signs of autism.
There has not been any pharmacological treatment for mitigating the deficits in social cognition and related social functioning in children with ASD. The hormone oxytocin, originally known to help stimulate childbirth and breast-feeding, is a neurotransmitter and neuromodulator; it has a spectrum of central and peripheral effects. Animal studies and preliminary human studies have indicated oxytocin may play a role in social bonding, emotion regulation, repetitive and affiliated behaviors, and anxiety modulation. Furthermore, blood oxytocin levels are reported to be lower in children with ASD compared to those of typically developing children. The blood oxytocin levels in children with ASD remain unchanged, while those in typically developing children increase. In addition, recent research indicates an association between a single nucleotide polymorphism (SNP) in the oxytocin receptor gene (OXTR) and autism.
Dr. Evdokia Anagnostou, whose preliminary data suggested therapeutic potential of intranasal oxytocin (IN-OXT) for social cognition/functioning and repetitive behaviors in adults with autism, received a Fiscal Year 2009 Autism Research Program (ARP) Clinical Trial Award to determine the effects of IN-OXT on social cognition and related functions in older children and adolescent (ages 12-17) with ASD in a two-phase study.
Phase I is a 12-week prospective open label, randomized, dose finding study to examine safety and tolerability of 15 to 24 high functioning ASD individuals. Phase II is a randomized, double-blinded, placebo-controlled trial to evaluate the safety and efficacy of IN-OXT in 60 participants with ASD on social cognition and function. It is being conducted at two sites: Holland Bloorview Kids Rehabilitation and University of Illinois, Chicago, and is currently in progress with all regulatory documents being completed, and recruitment is ongoing (ClinicalTrial.gov Identifier of NCT01256060).
Dr. Anagnostou and her coinvestigator Dr Jacob hypothesize that the oxytocin treatment may be effective in children and adolescents in improving social cognition deficits. They will also test the hypothesis that those who have lower blood oxytocin levels before treatment but show an increase in oxytocin levels and dose-related tolerability during treatment, would be most likely to respond. Since there are no medications yet available to treat and improve the core symptoms of autism (social cognition and social functioning), the trial may have tremendous therapeutic impact for social deficits of ASD.