Developing a prenatal biologic therapy to mitigate ASD risk from maternal autoantibodies to Caspr2

PROJECT SUMMARYAutism Spectrum DisorderASDdescribes a collection of neurodevelopmental abnormalities of varying severity that have been estimated to impact more thanof Americansmostly malesASD can negatively impact one s ability to communicate and navigate social interactionsIn its most severe formsASD also can lead to self destructiverepetitive behaviors that require afflicted persons be institutionalized for their own safetyThe prevalence of ASD has grown in recent decadesone explanation for this trend is that poorly appreciated environmental factors have raised the underlying incidence of the disorderEarly in utero exposure to circulating maternal antibodiesAbhas been implicated increasingly as a major risk factor for children to develop ASDThis model posits that maternal antibodies bind to proteins on the surface of the fetal brain and interfere with normal developmentIt is supported by studies in mice and monkeys that have revealed that sera purified from mothers with ASD childrenwhen injected before a critical point in gestationcan trigger changes in brain anatomy and ASD like behavioral phenotypes in offspringIndeedandgtof ASD cases may be explained by fetal exposure to maternal brain reactive antibodiesYet this mode of pathogenesis has two salient consequencesmaternal Ab represent detectable biomarkers that can indicate ASD riskandASD risk could be mitigated by treating mothers with adecoy antigento neutralize deleterious antibodiesSpark FlameS Fseeks to develop clinical products in both of these areasDuring Phase I workS F showed in mice that prenatal exposure to antibodies that bind the transmembrane protein Casprdisrupts brain development and causes behavioral phenotypes in male offspringThis effectwhich recapitulates the sex bias ASD shows in humanswas corroborated in several distinct mouse modelsThusthese results strongly recommend Casprreactive antibodies as targets for adecoy antigentherapyIn this Phase II SBIRS F will test a panel of therapeutic biologics based on the Casprextracellular domain fused to IgG Fc domain to increase stabilityIn Aimcandidates will be characterized stability and for ability to neutralize Casprreactive antibodiesand the panel will be narrowed to two lead candidatesleadsAimsandconduct preliminary toxicology studies in adult and fetal micerespectivelyIn AimS F explores the immunotoxicity of leads in mice with humanized immune systemsAimtests the efficacy of leads for blocking the pathogenic effects of polyclonal maternal Casprimmunity by assaying the brain morphology and behavioral phenotypes of offspringSuccessful completion of this Phase II project will establish a strong foundation for continued pre clinical development of leadswhich ultimately may result in a first in class therapy to mitigate ASD risk caused by a class of pathologic maternal antibodies Project Narrative In utero exposure to brain reactive antibodies is a significant risk factor for developing Autism Spectrum DisorderASDa collection of neurodevelopmental disorders that can impair an individual s ability to communicate and function independentlySpark Flame has demonstrated a causal link between antibodies that bind Casprand the development of ASD like outcomes in animal modelsSpark Flame has devised a groundbreaking strategy to neutralize these pathogenic antibodies and seeks to develop a first in class therapeutic biologic that can be administered prenatally to mitigate ASD risk in children