Periodic Reporting for period 2 - OPTOGENERAPY (Optogenetic Protein Therapy for Multiple Sclerosis) Periodo di rendicontazione: 2018-08-01 al 2020-01-31 Sintesi del contesto e degli obiettivi generali del progetto Optogenerapy - Optogenetic Protein Therapy for Multiple Sclerosis- aims to develop and demonstrate a new optogenetics implant for controlled beta interferon (IFN-ß) protein delivery for treating Multiple Sclerosis patients, in a 3 years project funded by the European Commission within the Horizon 2020 Programme.Optogenerapy represents an innovative and effective therapeutic delivery with an impact on slowing the disease progression and increasing the Multiple Sclerosis patients’ quality of life. The novelty lies in the continuous delivery of IFN-ß, overcoming current limitations of short drug half-life in vivo, adverse immune reactions, and pain and irritation at the site of local injection.The main objective is to develop and validate a new bio-electronic cell based implant device to be implanted subcutaneously providing controlled drug release during at least 6 months. The cell confinement within a chamber sealed by a porous membrane allows the device to be easily implanted or removed. At the same time, this membrane acts to prevent immune rejection and offers long-term safety in drug release while overcoming the adverse effects of current cellular therapies.Wireless powered optogenetics – light controlling the cellular response of genetically engineered cells – is used to control the production of IFN-ß.It is a low-cost system enabling large scale manufacturing and reduction of time to market up to 30% compared to other cell therapies, combining:• Polymeric biomaterials with strong optical, biocompatibility and barrier requirements, to build the cell chamber and to encapsulate the optoelectronics.• Optoelectronics miniaturization, autonomy and optical performance.• Optimal cellular engineering design, enhanced by computer modelling, for stability and performance of the synthetic optogenetic gene pathway over long-term implantation.• Micro moulding enabling optoelectronics and membrane embedding for safety and minimal invasiveness.Optogenerapy socio-economic impact:Impact for the patients:• Improved drug effectiveness: The novel solution for IFN-β continuous systemic release will improve quality of life of patients with Multiple Sclerosis due to improved drug effectiveness as eliminates the serum levels peaks, the flu-like effects after injection, and liver toxicity in the long term.• Improved compliance with drug taking: The Optogenerapy solution will also improve patients’ treatment adherence as there is no need for daily to weekly self-injections. Patients would only need go to the doctor for follow-up, which helps preventing patients to stop their medications by therapy fatigue and delaying disease progression.Impact for the Healthcare System:• Reduce direct and indirect costs linked to Multiple Sclerosis: Optogenerapy therapy deployment will save the costs of non-adherence to the healthcare system and to the society, mainly related to labour market productivity losses.Impact on Society• Social awareness of efficient therapies improving patient compliance: Optogenerapy outputs will contribute to increase the social awareness about more efficient therapies with improved patient compliance thanks to the project’s highly innovative concept and the real interest and capability to persist during the exploitation strategies once the project ends.• On the other hand, the project will help to generate awareness about Multiple Sclerosis and its prevention measures, treatment options and adherence benefits. Lavoro eseguito dall’inizio del progetto fino alla fine del periodo coperto dalla relazione e principali risultati finora ottenuti Optogenerapy project has developed a new biophotonic cell-based implant as a novel treatment for patients suffering from Multiple Sclerosis. The implant is the result of the combination of cells engineering, optoelectronics, modelling, manufacturing techniques, sterilization techniques and biocompatibility validation, all under a prespective of improving qualiy to live of patients and with a clear regulatory strategy. The therapeutic efficacy of the implant has been validated preclinically in a EAE (Experimental Autoimmune Encephalomyelitis) rodent model showing an improvement of the neurogical score after activation of the implants. The implant development parameters included the selection of materials and components to comply with the mechanical, optoelectronics, wireless, biocompatibility, and minimal invasiveness requirements. The validated design parameters were moved to the manufacturing stage to successfully scale up the manufacturing of a flexible wireless powered optoelectronic circuit and manufacturing the implants using materials commercially available and state of the art manufacturing equipments. In parallel, a human cell line stably expressing the interferon-beta gene under the control of the NIR photoactivable pathway was engineered and the effective production of IFN-β by the cells in the cell chamber of the implant upon stimulation by light through specific time has been validated. Performance data together with RNA expression profiles were analyzed to develop a model of the synthetic optogenetic pathway. Cytocompatibility of materials making up the Optogenerapy implant has been constantly monitored through series of experiments with human fibroblasts that has demonstrated in vitro biocompatibility of the device.As Optogenerapy device falls under the category of ATMPs (Advance Therapy Medicinal Products) a regulatory strategy has been developed for the device along with a preliminary technical file necessary to get the approval for placing the new product on the EU market. Current market for MS treatments has been analysed, along with future competitors (devices currently in clinical trials) in order to foresee the exploitation route for Optogenerapy device.In parallel, a cost-effectiveness analysis (CEA) has been carried out under several scenarios as a decision tool to support decisions about the pricing and reimbursement of an intervention. An approach based on a systematic literature review to understand the treatment decision-making process of MS patients complemented with cross-sectional surveys of MS patients in different EU countries has been followed to deepen into health benefits brought by Optogenerapy implant. Communication, dissemination and training activities have been targeting scientific, industry and clinical audiences as well as other more specialised target groups (e.g. Technical Committees of ISO, CEN and CENELEC) together with diverse actions were performed to address society using various social media supports. The potential to contribute to standardards has been assessed.Optogenerapy represents a step forward in cell-based therapies as it is also potentially applicable to other cell therapies operating as a programmable platform to secrete the needed drug directly into the patient. Progressi oltre lo stato dell’arte e potenziale impatto previsto (incluso l’impatto socioeconomico e le implicazioni sociali più ampie del progetto fino ad ora) The main results include:• Optogenerapy implant prototypes• Flexible optoelectronics prototypes• Therapeutic cell lines• Computer modelling of the optogenetic pathway• Optical design• Micro-injection moulding process• Implant sterilisation protocol• Surgical instruments prototypes• Standardisation studies• Pre-clinical regulatory studies• Disability and Quality of life impact assessment Logo
