A diagnostic for maternal autoAb to Caspr to predict increased risk of autism spectrum disorder in children

PROJECT SUMMARY Autism Spectrum Disorder ASD describes a collection of neurodevelopmental abnormalities of varying severity that have been estimated to impact more than of Americans mostly males ASD can negatively impact one s ability to communicate and navigate social interactions In its most severe forms ASD also can lead to self destructive repetitive behaviors that require afflicted persons be institutionalized for their own safety The prevalence of ASD has grown in recent decades one explanation for this trend is that poorly appreciated environmental factors have raised the underlying incidence of the disorder Early in utero exposure to circulating maternal antibodies Ab has been implicated increasingly as a major risk factor for children to develop ASD This model posits that maternal antibodies bind to proteins on the surface of the fetal brain and interfere with normal development It is supported by studies in mice and monkeys that have revealed that sera purified from mothers with ASD children when injected before a critical point in gestation can trigger changes in brain anatomy and ASD like behavioral phenotypes in offspring Indeed andgt of ASD cases may be explained by fetal exposure to maternal brain reactive antibodies Yet this mode of pathogenesis has two salient consequences maternal Ab represent detectable biomarkers that can indicate ASD risk and ASD risk could be mitigated by treating mothers with a decoy antigen to neutralize deleterious antibodies Spark Flame S F seeks to develop clinical products in both of these areas S F s efforts to identify ASD risk biomarkers led to the isolation of a monoclonal antibody C that recognizes the transmembrane protein Caspr which has been associated with ASD through pedigree analysis Injecting pregnant mice with purified C causes defects in brain anatomy and behavioral phenotypes in male offspring recapitulating the sex bias ASD shows in humans Two additional Ab cloned from other mothers also bind Caspr These results argue that Caspr reactive antibodies are predisposing for ASD In this Phase I SBIR S F will examine the feasibility of developing a predictive clinical diagnostic assay for ASD risk based on detecting maternal serum reactivity to Caspr In Aim mice will be immunized with Caspr before pregnancy to test the pathogenicity of pre existing polyclonal Caspr antibodies for disrupting normal brain development In Aim S F will develop a proof of concept ELISA method for rapidly and inexpensively detecting Caspr reactivity in serum Finally to discover predictive biomarkers for ASD risk serum Caspr epitope binding profiles will be compared between mothers of a normally developing child and mothers of an ASD child Aim Successful completion of this Phase I project will identify the most deleterious Caspr reactive maternal antibodies which will focus efforts to develop a predictive clinical diagnostic assay and inform strategies to create a biologic therapeutic to neutralize these antibodies Project Narrative In utero exposure to brain reactive antibodies is a significant risk factor for developing Autism Spectrum Disorder ASD a collection of neurodevelopmental disorders that can have impair an individual s ability to communicate and function independently Spark Flame has developed an innovative strategy to identify pathogenic antibodies Spark Flame is seeking to advance a diagnostic test to gauge ASD risk that incorporates these biomarkers and to develop matched therapeutic biologics to neutralize these antibodies