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

开发产前生物疗法以降低母亲 Caspr2 自身抗体导致的 ASD 风险

• 批准号: 9762135
• 负责人: Ronald M Burch
• 金额: $ 67.8万
• 依托单位: SPARK2FLAME, INC.
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-17 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9762135
• 关键词: 1 year old; Address; Adult; Affect; American; Anatomy; Animal Model; Antibodies; Antigen-Antibody Complex; Antigens; Area; Autoantibodies; Autoimmunity; Awareness; Behavioral; Binding; Biological; Biological Assay; Biological Markers; Biological Response Modifier Therapy; Blood; Blood Circulation; Brain; Child; Clinical; Collaborations; Collection; Communication; Consensus; Deposition; Detection; Development; Diagnosis; Diamond; Disease; Dose; Drug Kinetics; Early Intervention; Employment; Environmental Risk Factor; Exhibits; Exposure to; Extracellular Domain; Fc domain; Female; Foundations; Future; Genes; Genetic study; Goals; Half-Life; Human; Human Genetics; Immune system; Immunity; Immunoglobulin G; Impairment; In Vitro; Incidence; Individual; Institutes; Institutionalization; Integral Membrane Protein; Knowledge; Laboratories; Lead; Link; Maternal antibody; Measures; Medical Research; Modeling; Monkeys; Monoclonal Antibodies; Mothers; Mus; Mutation; Neurodevelopmental Disorder; Neurologic; Outcome; Pathogenesis; Pathogenicity; Pathologic; Patients; Persons; Phase; Phenotype; Pregnancy; Prevalence; Preventive; Proteins; Research; Risk; Risk Factors; Safety; Self-Injurious Behavior; Serum; Severities; Sex Bias; Small Business Innovation Research Grant; Social Interaction; Spontaneous abortion; Surface; Symptoms; Testing; Therapeutic; Time; Tissues; Toxic effect; Toxicology; Work; autism spectrum disorder; autistic; autistic children; base; brain morphology; design; disorder risk; efficacy testing; fetal; humanized mouse; immunotoxicity; improved; in utero; in vivo; lead candidate; male; mouse model; neutralizing antibody; offspring; pre-clinical; preclinical development; pregnant; prenatal; prenatal exposure; prevent; prospective; repetitive behavior; stem; therapeutic candidate; trend

PROJECT SUMMARY Autism Spectrum Disorder (ASD) describes a collection of neurodevelopmental abnormalities of varying severity that have been estimated to impact more than 1% 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, > 10% of ASD cases may be explained by fetal exposure to maternal brain-reactive antibodies. Yet this mode of pathogenesis has two salient consequences: 1) maternal Ab represent detectable biomarkers that can indicate ASD risk, and 2) ASD risk could be mitigated by treating mothers with a “decoy antigen” to neutralize deleterious antibodies. Spark2Flame (S2F) seeks to develop clinical products in both of these areas. During Phase I work, S2F showed in mice that prenatal exposure to antibodies that bind the transmembrane protein Caspr2 disrupts brain development and causes behavioral phenotypes in male offspring. This effect, which recapitulates the sex-bias ASD shows in humans, was corroborated in several distinct mouse models. Thus, these results strongly recommend Caspr2-reactive antibodies as targets for a “decoy antigen” therapy. In this Phase II SBIR, S2F will test a panel of therapeutic biologics based on the Caspr2 extracellular domain fused to IgG Fc domain to increase stability. In Aim 1, candidates will be characterized stability and for ability to neutralize Caspr2-reactive antibodies, and the panel will be narrowed to two lead candidates (leads). Aims 2 and 3 conduct preliminary toxicology studies in adult and fetal mice, respectively. In Aim 4, S2F explores the immunotoxicity of leads in mice with humanized immune systems. Aim 5 tests the efficacy of leads for blocking the pathogenic effects of polyclonal maternal Caspr2 immunity by assaying the brain morphology and behavioral phenotypes of offspring. Successful completion of this Phase II project will establish a strong foundation for continued pre-clinical development of leads, which ultimately may result in a first-in-class therapy to mitigate ASD risk caused by a class of pathologic maternal antibodies.

项目摘要 自闭症谱系障碍（ASD）描述了一组不同程度的神经发育异常， 据估计，严重程度影响了超过1%的美国人，主要是男性。ASD可以消极地 影响一个人的沟通和社交能力。在最严重的形式中，ASD也可以 导致自我毁灭，重复的行为，需要受折磨的人被制度化为自己的 安全为代价的近几十年来，ASD的患病率有所增加;对这一趋势的一种解释是， 已认识到的环境因素提高了该疾病的潜在发病率。 子宫早期暴露于循环母体抗体（Ab）已越来越多地被认为是一种主要的 儿童发展ASD的危险因素。该模型假定母体抗体结合到细胞上的蛋白质， 胎儿大脑的表面，并干扰正常发育。它得到了小鼠研究的支持， 研究表明，从患有ASD儿童的母亲那里纯化的血清，当在关键的 在妊娠期，可以引发后代大脑解剖结构和ASD样行为表型的变化。 事实上，> 10%的ASD病例可以解释为胎儿暴露于母体脑反应抗体。然而 这种发病机制有两个显著的结果：1）母体Ab代表可检测的生物标志物， 可以表明ASD的风险，和2）ASD的风险可以减轻治疗母亲与“诱饵抗原”， 中和有害抗体Spark 2Flame（S2 F）寻求在这两个领域开发临床产品。 在第一阶段的工作中，S2 F在小鼠中显示，产前暴露于结合 跨膜蛋白Caspr 2破坏大脑发育并导致男性行为表型 后代这种效应，概括了ASD在人类中表现出的性别偏见，在几个实验中得到了证实。 不同的小鼠模型。因此，这些结果强烈推荐Caspr 2-反应性抗体作为免疫调节剂的靶标。 “诱饵抗原”疗法 在该II期SBIR中，S2 F将测试一组基于Caspr 2细胞外 融合至IgG Fc结构域以增加稳定性。在目标1中，候选人的特点是稳定， 因此，该小组将具有中和Caspr 2反应性抗体的能力，并且该小组将缩小到两个先导候选物（先导物）。 目的2和3分别在成年和胎鼠中进行初步毒理学研究。在目标4中，S2 F 探索了铅对具有人源化免疫系统的小鼠的免疫毒性。目标5测试 通过测定脑来阻断多克隆母体Caspr 2免疫的致病作用的线索 后代的形态学和行为表型。二期工程的顺利完成， 为电极导线的持续临床前开发奠定坚实的基础，最终可能导致 一流的治疗，以减轻由一类病理性母体抗体引起的ASD风险。