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

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.