In pursuit of a preventive therapeutic for maternal autoantibody-related (MAR) autism, we assessed the toxicity, biodistribution, and clearance of a MAR specific peptide-functionalized dextran iron oxide nanoparticle system in pregnant murine dams. We previously synthesized ~15 nm citrate-coated dextran iron oxide nanoparticles (DIONPs), surface-modified with polyethylene glycol and MAR peptides to produce systems for nanoparticle-based autoantibody reception and entrapments (SNAREs). First, we investigated their immunogenicity and MAR lactate dehydrogenase B antibody uptake in murine serum in vitro. To assess biodistribution and toxicity, as well as systemic effects, we performed in vivo clinical and post mortem pathological evaluations. We observed minimal production of inflammatory cytokines-interleukin 10 (IL-10) and IL-12 following in vitro exposure of macrophages to SNAREs. We established the maximum tolerated dose of SNAREs to be 150 mg/kg at which deposition of iron was evident in the liver and lungs by histology and magnetic resonance imaging but no concurrent evidence of liver toxicity or lung infarction was detected. Further, SNAREs exhibited slower clearance from the maternal blood in pregnant dams compared to DIONPs based on serum total iron concentration. These findings demonstrated that the SNAREs have a prolonged presence in the blood and are safe for use in pregnant mice as evidenced by no associated organ damage, failure, inflammation, and fetal mortality. Determination of the MTD dose sets the basis for future studies investigating the efficacy of our nanoparticle formulation in a MAR autism mouse model.

Introduction: Autism Spectrum Disorder (ASD) comprises a range of developmental disorders diagnosed in early childhood, where their ability to communicate and interact are impaired. In the U.S., an estimated 1 in 59 children1 is born with ASD and the economic burden is a staggering $268 billion per year2. Current therapies are post-symptomatic and include behavioral interventions or symptom-derived pharmacological treatments. Recently, the Van De Water group discovered that about a quarter of ASD cases are caused by maternal autoantibodies (autoAbs) that can hinder normal neurodevelopment in the fetus. Moreover, they elucidated the seven proteins targeted by these autoAbs in the fetal brain, including lactate dehydrogenase A and B (LDHA, LDHB)3. Herein, we aim to develop a System for Nanoparticle-based Autoantibody Retention and Entrapment (SNARE) prophylactic as a biomagnetic trap-for sequestration of disease-propagating Maternal Autoantibody-Related (MAR) autoAbs. Our central hypothesis is that upon intravenous injection, the iron oxide NPs surface-conjugated with autoantigens will circulate throughout the maternal vasculature, and specifically ligate MAR autoAbs, thereby limiting antibody (Ab) transport across the placenta and preventing MAR autism. Currently, investigative aims are to synthesize SNAREs, assess Ab binding capacity, cytotoxicity and immunogenicity in vitro, as well as determine in vivo distribution and maximum tolerated dose.