Trichuris Suis Ova (TSO) as an Immune-inflammatory Treatment for Repetitive Behaviors in ASD
Background: Inflammatory mechanisms have been implicated in Autism Spectrum Disorders (ASD) and immunomodulatory interventions, such as Trichuris Suis Ova (TSO) may be an experimental therapeutic option for some individuals with ASD.
In particular, ASD patients are observed to have dampened Th2 anti-inflammatory cytokine response, and an increased Th1 proinflammatory cytokine response.
Furthermore, the observation that some ASD patients manifest clinical improvement in response to fever suggests that ASD symptoms may be modulated by immune-inflammatory factors. The study of helminth worms, specifically TSO, for the treatment of autoimmune disorders emerged in part from the hygiene hypothesis, which suggests that simulation of the immune system by microbes is protective against the development of inflammatory diseases, and that arise in hygiene in urban settings has been associated with less protective microbes in humans and an increase in autoimmune inflammatory disorders such as multiple sclerosis, inflammatory bowel disease, asthma, allergic rhinitis and possibly ASD.
The porcine whipworm TSO is proposed to work through multiple mechanisms, including interference with antigen presentation, cell proliferation, activation and antibody production. The interaction of the developing immune system with microorganisms, including helminthes, may be an important component of normal immune system maturation. Helminthes, including TSO, are well known to induce tolerance in their hosts via differential modulation of anti-inflammatory Th2 cytokine (IL-4, IL-5, IL-10, IL-13) and proinflammatory Th1 and Th17 cytokine (IL-1, IL-12, IFN-γ, TNF-α, IL-6) response. Th2 cell induction leads to strong IgE, mast cell and eosinophil response, while cytokines IL-4 and IL-13 trigger intestinal mucous secretion, enhance smooth muscle contractibility, and stimulate fluid secretion in the intestinal lumen.
Additional studies have shown that a similar exposure to TSO results in the augmentation of the anti-inflammatory Th2 response, and a dampening of the toll-like receptor (TLR)-induced proinflammatory Th1 and Th17 responses, and an increased presence of myeloid and plasmacytoid dendritic cells, which are antigen producing cells that stimulate T-cells. Currently, TSO is being studied in multiple clinical trials of other immune-inflammatory disorders, with much success; however, we are the first to study this treatment in the ASD population.
Methods: A 28 week double-blinded, randomized crossover study of TSO vs placebo in 10 adults, aged 17.5–35, with Autism Spectrum Disorder was completed. ASD diagnosis was confirmed by DSM-IV criteria supported by the Autism Diagnostic and Observation Schedule (ADOS). Subjects had a personal or family history of allergies, a baseline YBOCS score of 6 and an IQ greater than 70. Subjects eligible after the screening visit, returned to the Autism and Obsessive Compulsive Spectrum Program every two weeks to complete subject (DANVA-2, Affective Speech Recognition Task, Reading the Mind in the Eyes Test), parent (ABC, SRS, RBS-R) and clinician (YBOCS, Vineland-II) assessments in addition to safety monitoring. Subjects also completed clinical labs, including stools samples every 6 weeks. After the first 12 week phase of TSO or placebo subjects entered a 4 week washout before beginning the second 12 week phase; assessments and safety measures were continued throughout.
Results: This exploratory safety and efficacy study included young adults with high functioning ASD, normal intelligence and good verbal skills.
The irritability scores on the ABC-I were low at baseline.
Of interest, measures of rigidity, restricted interests, flexibility, and ability to transition were noted to improve in patients on TSO.
Patients also demonstrated reduced discomfort and protest associated with interruption of restricted interests or deviation from expectations.
These changes of rigidity and compulsivity were observed on the clinician rated YBOCS (YBOCS compulsions and rigidity subscale) and parent rated RBS-R (restricted interests subscale). As in previous studies of TSO in other populations, the side effect profile is low. Throughout the study only minimal gastrointestinal distress was observed in some patients.
Conclusions: This is the first placebo controlled trial of TSO in an ASD population. The preliminary analyses from our exploratory pilot study demonstrate feasibility of completing a 28 week study of TSO in an ASD population, safety of TSO in this population, and potential efficacy for repetitive behaviors/restricted interests in some patients.
Limitations of the trial included a small sample size, lack of irritability at baseline, and use of parent outcomes measures in this population that potentially impact our understanding of the results. Future studies are needed in a younger population stratified for higher baseline irritability, and further exploration of target engagement with the immune system and relationship to clinical improvement in ASD. Funding provided by the Simons Foundation. Drug/Placebo provided by Coronado Biosciences.
Keywords: treatment, autism, immune, inflammation, repetitive behaviors.
Disclosures: E. Hollander, Part 1: Consultant to Coronado Biosciences Inc., Part 4: Funded by The Simons Foundation. Drug/Placebo provided by Coronado Biosciences Inc.; C. Ferretti, Nothing to Disclose; B. Taylor, Nothing to Disclose; R. Noone, Nothing to Disclose; J. Kirsch, Nothing to Disclose; E. Racine, Nothing to Disclose.
Further Readings of Interest