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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要自闭症谱系障碍 (ASD) 描述了一系列不同程度的神经发育异常据估计，自闭症谱系障碍的严重程度会对超过 1% 的美国人（主要是男性）产生负面影响。在最严重的情况下，自闭症谱系障碍也会影响一个人的沟通和社交能力。导致自我毁灭、重复行为，需要将受折磨的人送入收容机构近几十年来，自闭症谱系障碍（ASD）的患病率有所增加；对这一趋势的一个解释是，安全性较差。认识到的环境因素增加了该疾病的潜在发病率。子宫早期暴露于循环母体抗体 (Ab) 已日益成为一个主要的因素。该模型假设母源抗体与蛋白质结合。老鼠的研究证实了这一点。猴子们发现，在危急关头之前注射时，可以从患有自闭症谱系障碍儿童的母亲身上纯化出血清妊娠期，可以引发大脑解剖结构的变化和后代类似 ASD 的行为表型。事实上，超过 10% 的自闭症谱系障碍病例可能是由于胎儿接触母体脑反应性抗体所致。这种发病机制有两个显着的后果：1) 母体抗体代表可检测的生物标志物，可以表明自闭症谱系障碍 (ASD) 风险，并且 2) 通过使用“诱饵抗原”治疗母亲可以减轻自闭症谱系障碍 (ASD) 风险 Spark2Flame (S2F) 致力于开发这两个领域的临床产品。在第一阶段的工作中，S2F 在小鼠中表明，产前暴露于结合跨膜蛋白 Caspr2 破坏大脑发育并导致男性行为表型这种效应概括了自闭症谱系障碍在人类身上表现出的性别偏见，并在几个例子中得到了证实。因此，这些结果强烈推荐 Caspr2 反应抗体作为 “诱饵抗原”疗法。在此 II 期 SBIR 中，S2F 将测试一组基于 Caspr2 细胞外的治疗生物制剂与 IgG Fc 结构域融合以提高稳定性在目标 1 中，将对候选物进行稳定性和稳定性表征。中和 Caspr2 反应性抗体的能力，并且该小组将缩小到两个主要候选者（先导）。目标 2 和目标 3 分别在成年小鼠和胎儿小鼠中进行初步毒理学研究。目标 4，S2F。探索了铅对具有人源化免疫系统的小鼠的免疫毒性，目的 5 测试了其功效。通过检测大脑来阻断多克隆母体 Caspr2 免疫的致病作用后代的形态学和行为表型的成功完成该第二阶段项目将。为先导化合物的持续临床前开发奠定坚实的基础，最终可能导致降低由一类病理性母体抗体引起的 ASD 风险的一流疗法。