ISOS-Implantable Ecosystems of Genetically Modified Bacteria for the Personalised Treatment of Patients with Chronic Diseases

在ISOS中，我们建议开发第一种生物医学产品，用于原位制造和自动更新递送治疗化合物，采用集成在生物材料生物反应器中的益生菌基因工程菌（GEB）的复杂生态系统。ISOS旨在治疗需要长期治疗的慢性疾病。包封的GEB群体“按需”产生治疗分子，由患者体内病理环境的信号刺激，即，炎症和/或活性氧。细菌种群之间相互作用，以维持GEB物种的动态平衡，并保证只要疾病持续，产药GEB的生存。GEB生态系统的设计使细菌无法在封装生物材料之外生存，以满足未来的生物安全和监管要求。GEB生态系统的设计和配置将针对每位患者进行个性化，并将使用计算机工具和合成生物学完成。作为概念验证，我们提出设计一种基于GEB的可植入生物反应器，用于治疗湿性年龄相关性黄斑变性（wAMD），这是由血管内皮生长因子（VEGF）的异常产生引起的。该概念验证将证明ISOS能够用单个ISOS生物反应器代替抗VEGF分子的重复眼内注射（当前治疗），这将增强治疗反应并最大限度地减少由于ISOS与病理环境之间的分子串扰引起的副作用。ISOS将建立新一代治疗产品的原则，这些产品将使用重组益生菌菌株库进行个性化治疗，严格控制局部药物生产，并根据病理信号的动态变化进行有效递送。

In ISOS we propose to develop the first biomedical product for the in-situ fabrication and auto-renewed delivery of therapeutic compounds employing complex ecosystems of probiotic genetically engineered bacteria (GEB) integrated in a biomaterial-based bioreactor. ISOS is designed to treat chronic diseases requiring lengthy treatments. The encapsulated GEB populations produce the therapeutic molecules "on demand", stimulated by the signals of the pathological environment within the patient, i.e., inflammation and/or reactive oxygen species. Bacteria populations interact among them to maintain a dynamic equilibrium of the GEB species and to guarantee the survival of the drug-producing GEB as long as the disease persists. The GEB ecosystem is designed in such a way that bacteria cannot survive outside of the encapsulating biomaterial, to meet future biosafety and regulatory requirements. The design and the configuration of the GEB ecosystem will be personalized for each patient, and it will be done using in-silico tools and synthetic biology. As a Proof-of-Concept, we propose to engineer an implantable GEB-based bioreactor for the therapy of the wet form of age-related macular degeneration (wAMD), which is caused by an abnormal production of Vascular Endothelial Growth factor (VEGF). This Proof-of-Concept will demonstrate the ability of ISOS to replace the repeated intraocular injections of Anti-VEGF molecules (current treatment) with a single ISOS bioreactor that will enhance the therapeutic response and minimize side effects due the molecular crosstalk between ISOS and the pathological environment. ISOS will establish the principles of a new generation of therapeutic products that will use recombinant probiotic bacteria strains libraries for personalized treatments with rigorous control of local drug production and efficient delivery based of dynamic variation of pathological signals.