Theranostic Molecular Automata for Specific Cell Elimination

描述（由申请人提供）：我们介绍了第二代治疗诊断装置，其整合了多个靶向部分（例如，基于抗体或适体的）与两个额外的分子组分：（1）分子计算，以分析获得的疾病特征;和（2）由该计算的结果触发的特异性药物递送。这些设备将能够基于多种疾病标志物特异性靶向细胞，从而消除狭窄的细胞亚群，并改善恶性肿瘤的治疗。在未来两年中，我们将完成两个目标中描述的目标：目标1。在以抗体或适体-寡核苷酸结合物为靶的淋巴细胞表面上的分子计算级联的演示和优化。细胞表面上的分子计算将基于化学反应的级联，这些级联仅在这些级联的所有必需组分存在于细胞表面（级联与门）或保护因子不存在（级联非门）时发生。目标2.证明药物递送到细胞表面上的分子级联已经完成。用分子计算消除的靶细胞将在级联的末端显示特定的寡核苷酸，而非靶细胞将不显示。我们将构建各种毒性剂与互补的寡核苷酸显示一个集成，我们将研究它们对细胞的影响与分子计算级联处理。大型多学科团队确保在第二年年底，我们将展示级联的所有组件，使我们能够开始第一次动物研究所需的优化过程。 公共卫生相关性：我们提出，复杂的疾病和特征，如许多癌症，自身免疫性疾病或肥胖，可以通过与匹配的多输入分子网络或分子自动机的相互作用来解决。我们项目的成功完成将导致以下个性化治疗的愿景：医生确定他/她希望从患者中消除的细胞类型的独特表面免疫表型。在与健康细胞表型比较的指导下，医生结合了现成的试剂，为患者创建和管理自动机，专门杀死靶细胞类型，同时保护非靶细胞。

DESCRIPTION (provided by applicant): We introduce the second generation theranostic devices that integrate multiple targeting moieties (e.g., antibody- or aptamer-based) with two additional molecular components: (1) molecular computing in order to analyze obtained disease signatures; and (2) specific drug delivery triggered by the outcome of this computing. These devices will be capable of specific targeting of cells based on multiple disease markers, resulting in elimination of narrow subpopulations of cells, and improved treatment of malignancies. Over the next two years we will accomplished goals described in two aims: Aim 1. Demonstration and optimization of molecular computing cascades on the surface of the lymphocytes targeted with antibody- or aptamer-oligonucleotide conjugates. Molecular computing on cell surfaces will be based on cascades of chemical reactions that occur only if all required components of these cascades are present on the cell surface (cascaded AND gates) or protective factors are absent (cascaded NOT gates). Aim 2. Demonstration of drug delivery to the cells on the surface of which molecular cascades have been completed. Cells targeted for elimination with molecular computing will at the end of cascades display specific oligonucleotides, while non-target cells will not. We will construct various toxic agents integrated with an oligonucleotide complementary to the displayed one, and we will study their effects on cells treated with molecular computing cascades. The large multidisciplinary team ensures that at the end of the second year, we will have demonstrated all the components of cascades, putting us in a position to start optimization process needed for the first animal studies. PUBLIC HEALTH RELEVANCE: We propose that complex diseases and traits, such as many cancers, autoimmune diseases, or obesity, can be addressed through interactions with matching multi-input molecular networks or molecular automata. The successful completion of our project will lead to the following vision of personalized therapy: A physician determines the unique surface immunophenotype of a cell type that he/she would like to target for elimination from a patient. Guided by the comparison with the phenotypes of healthy cells, the physician combines off-the- shelf reagents, creating and administering automata to the patient, specifically killing the targeted cell types, while protecting non-target cells.