Theranostic Molecular Automata for Specific Cell Elimination

描述（由申请人提供）：我们推出第二代治疗设备，该设备将多个靶向部分（例如，基于抗体或适配体的）与两个额外的分子成分结合在一起：(1)分子计算以分析获得的疾病特征；(2)由该计算结果触发的特定药物递送。这些装置将能够基于多种疾病标记物特异性靶向细胞，从而消除狭窄的细胞亚群，并改善恶性肿瘤的治疗。在接下来的两年里，我们将实现两个目标：目标1。抗体或核酸适配体寡核苷酸偶联物靶向淋巴细胞表面分子计算级联的演示和优化。细胞表面的分子计算将基于化学反应的级联，只有当这些级联的所有必需成分都存在于细胞表面（级联与门）或保护因子缺失（级联非门）时，才会发生化学反应。目标2。在分子级联已经完成的细胞表面，药物传递的演示。被分子计算作为消除目标的细胞将在级联末端显示特定的寡核苷酸，而非目标细胞则不会。我们将构建与所展示的寡核苷酸互补的各种毒性制剂，并将研究它们对分子计算级联处理的细胞的影响。大型多学科团队确保在第二年结束时，我们将展示级联的所有组成部分，使我们能够开始第一次动物研究所需的优化过程。

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.