Fiscal Year 2015 (FY15) Autism Research Program (ARP) Area(s) of Interest Addressed in the Proposed Research: Our application addresses two of the FY15 ARP Areas of Interest: (1) The role of environmental risk factors in autism spectrum disorder (ASD) pathophysiology and (2) assessment of novel therapeutics using valid preclinical models of ASD.
Innovative Aspect of the Proposed Research: The proposed research is conceptually innovative because it addresses a novel hypothesis that shifts the paradigm in the field of ASD research away from a sole focus on deficits in fetal neurodevelopment and towards examination of alterations in fetal-maternal neuro-immune interactions as a result of maternal infection during pregnancy. Our research will test whether infection as a fetal-maternal insult alters the developmental trajectory by triggering chronic inflammatory cascades. Our overall strategy will be to induce maternal immune activation (MIA) with the viral mimic poly I:C, and then perform follow-up studies of our most promising findings by replicating the MIA models using a live virus (influenza).
Impact of the Proposed Research Project on the Field of ASD Research: There has been little experimental examination of mechanisms underlying fetal-maternal neuro-immune interplay dysregulation, and our gene expression studies, manipulation of MIF and TNF, and neuroanatomical studies represent a congruent short-term approach to defining pathogenic mechanisms. In the long term, successful completion of this proposal will open the door for treatment during the postnatal period for fetuses at risk for ASD due to maternal infection if we are able to move the novel brain-permeant soluble TNF-selective biotherapeutic (XPro1595) to a clinical trial to interrupt the inflammatory cascade that results from MIA.
Relevance to Autism Now: Prenatal infections or abnormal immune responses in children have been implicated in ASD, and immune dysregulation is observed in the brain, periphery, and gastrointestinal tract of individuals with ASD. In the current study, we will focus on a pathway that integrates genetics, prenatal insults, and postnatal immune and neurodevelopmental disturbances in autism-like behaviors. Our translational focus to test the efficacy of a brain-permeant anti-inflammatory biologic (XPro1595) in robust preclinical models of MIA is very timely because XPro1595 is expected to begin clinical trials in ALS to treat the chronic neuroinflammation now believed to play a critical role in disease progression.