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）描述了一系列不同的神经发育异常 据估计，严重程度会影响超过1％的美国人，主要是男性。 ASD可能会负 影响一个人交流和导航社交互动的能力。以最严重的形式，ASD也可以 导致自我毁灭性的重复行为，需要受苦的人制度化 安全。近几十年以来，ASD的流行率已经增长。这种趋势的一种解释是 欣赏的环境因素增加了疾病的根本事件。 在子宫早期暴露于循环遗传抗体（AB）的早期，已越来越暗示是主要的 儿童发展ASD的风险因素。该模型认为，Mater抗体与蛋白质结合 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， 猴子已经揭示了血清从有ASD子女的母亲那里净化的猴子，当 妊娠点，可以触发后代大脑解剖结构和类似ASD的行为表型的变化。 实际上，> 10％的ASD病例可以通过胎儿暴露于孕产妇脑反应性抗体来解释。然而 这种发病机理有两个显着的后果：1）母体AB代表可检测的生物标志物， 可以表明ASD风险，以及2）可以通过对母亲进行“诱饵抗原”的治疗来减轻ASD风险 中和有害抗体。 Spark2flame（S2F）试图在这两个领域开发临床产品。 在第一阶段的工作中，S2F在小鼠中表明，产前暴露于结合的抗体 跨膜蛋白CASPR2破坏了脑发育并引起男性的行为表型 后代。这种效果概括了人类中的性偏见显示的性偏见，在几种中得到了证实 不同的鼠标模型。这是，这些结果强烈建议CASPR2反应抗体作为A “诱饵抗原”疗法。 在此II阶段SBIR中，S2F将基于CASPR2细胞外测试一组治疗生物制剂 域融合到IgG FC域以提高稳定性。在AIM 1中，候选人将被描述为稳定性和 中和CASPR2反应性抗体的能力，并将面板缩小到两个铅候选者（铅）。 AIM 2和3分别在成年和胎儿小鼠中进行初步毒理学研究。在AIM 4，S2F 探索具有人源化免疫系统小鼠铅的免疫毒性。 AIM 5测试效率 通过测定大脑来阻止多克隆母体CASPR2免疫的致病作用 后代的形态和行为表型。成功完成此第二阶段项目将 为持续的铅前发展建立坚实的基础，最终可能导致 一类疗法来减轻由一类病理材料抗体引起的ASD风险。