Proposed Implementation

Our implementation strategy aims to bring IBD NanoBiotics from bench to bedside. To accomplish this, the human practices team focused on understanding the perspective of the main groups who would be affected by this treatment: IBD patients, medical professionals and regulatory authorities.

It was essential to establish a relationship that allowed us to ask these groups questions to incorporate their views into our strategy. To deliver the fundamental concepts behind our project, we also developed presentations that helped us visualize our project's progress.

The public opinion - an engineered bacteria as a treatment option

To understand if patients would comply with the use of an engineered bacteria as a new therapy, we used our IBDN cohort to gather data about this topic. We were aware that genetic engineering is still a topic with negative connotations. Just last year, the Swiss electorate voted on a popular initiative, "For Switzerland without synthetic pesticides", which triggered a hot discussion among the population. We were interested in understanding if the implementation of genetically engineered organisms for a medical purpose would be evaluated differently. The IBDN cohort data gave us a clear picture as shown in figure 1: Most patients were willing to take a GMO as a treatment option. Good news for IBD Nanobiotics! However, a closer analysis of our data revealed that patients need more information on its efficacy and safety to fully support the therapy. Currently, no data is available on our solution's in-vivo effectiveness and safety. Therefore, to compensate for this lack of information, we designed the informative brochure to introduce patients to our project and provide information on the intended future implementation. Alarmingly, many of the IBDNC participants declared their willingness to use IBDNanoBiotics even if data on its long-term safety was not provided. This finding had different meanings for the future implementation of our project:

• The development of effective treatment is urgently needed, showing us the vast implementation potential of IBD NanoBiotics.
• Future clinical trials participants for the clinical phase development can be certainly recruited.
• We hold the moral responsibility to characterize the safety and efficacy of IBDNanoBiotics to avoid inflicting unnecessary harm on suffering patients.

Collectively, these patient-derived insights will help us shape our priorities in laboratory experiments by focusing on safety and efficacy. Furthermore, future efforts will be directed to simplifying laboratory findings to an accessible language to allow patients to make an informed decision on using this treatment. This strategy is also supported by information we gathered from direct interactions with patients who advocated for a general increase in their participation during the therapy development process. Patients also stated that involving them in research already at early stages would increase their future compliance with a treatment.

Understanding what patients demand from a therapy

Data collected from interactions with patients shed light on important aspects of implementing IBD NanoBiotics as a therapy to be used daily. Patients wished for a less invasive therapy compared to current biologics-based therapies that are administered via intravenous infusions. These therapies require hospitalization, which often limits patients’ daily activities and is perceived as unpleasant. Additionally, patients wished to be independent of any medical staff for daily medication administration. Combined, we have implemented their needs on a therapy by integrating them into our therapeutic design: we will deliver our modified E. coli Nissle 1917 orally to decrease invasiveness and guarantee independence from medical staff. Therefore, our engineered bacteria need to be encapsulated in a pill. A possible solution is to lyophilize our modified Nissle strain. Lyophilization is a method that allows long-term storage of bacteria without losing viability. This method is already widely used in the food industry. We partnered with the ETH spin-off company PharmaBiome to understand and implement this process in our therapy. During our iGEM season, they supported us with their expertise on this topic. Furthermore, they will provide us access to their infrastructure to lyophilize our bacteria once our chassis is ready.

Clinical implementation of IBD NanoBiotics

After a thorough analysis of the project implementation from the patient's side, we needed to turn to medical doctors responsible for patients' clinical management. We contacted various gastroenterologists who are members of IBD Net, a Swiss research and communication network focused on IBD. We were interested in understanding these parameters linked to the use of a therapy in a clinical setting:

• prescription scheme
• perception of IBD patients
• experiences with current treatments

Furthermore, we focused on the requirements of the future clinical implementation of IBD NanoBiotics. For that, we asked for their expectations from a therapeutic approach and their needs to include our approach among first-line therapies. The results and the conclusions we drew are summarized in figure 2.

The road to market approval

To bring IBD NanoBiotics from bench to bedside and allow its future clinical implementation, our idea will have to be further developed and assessed according to the requirements of the local regulatory authorities. To understand what future requirements will be necessary to fulfill, we have contacted the Swiss authority Swissmedic, which is responsible for the authorization and supervision of therapeutic products in Switzerland. In our case, the department responsible for the approval of the conductance of clinical trials using GMOs is the department for advanced therapy medicinal products (ATMPs). In order to apply for a permit, our project idea needs to go through two primary research and development cycles: a preclinical phase and a clinical phase that culminates with possible market approval. This understandably long and challenging path is depicted in figure 3.

The preclinical phase comprises the improvement and development of our chassis before it can be given to future trial participants during the clinical phase. Preclinical development is essential to characterize our proposed chassis. We suggest a stepwise increase in the system's complexity on which our final construct of the engineered E. coli Nissle 1917 strain should be tested. Experiments should start on a monolayer of established cultured cell lines, followed by a 3D recapitulation of the intestine using organoids, murine tissue biopsies and possibly patient-derived cells and organoids as described in fig.3. Through these experiments, we will collect data that will allow our research to continue in vivo through mouse models. Then, we can start dealing with the complexity of an organism in order to assess side and long term effects. This phase is essential to collect the data required by the authorities to apply for clinical trial approval. A short summary of the main data requirements to apply for a clinical trial permit using GMOs is given below in figure 4.

After submission of the application, the data will be additionally evaluated from the Swiss expert Committee for Biosafety (SECB), the Federal Office for the Environment (FOEN) and the Federal Office for Public Health (FOPH). Once the permit has been issued, clinical development of IBD NanoBiotics can start. This phase is divided into three main studies as shown in figure 3. Clinical phase I will address safety in vivo in a few healthy participants, clinical phase II will enroll first patients to determine its effectiveness and clinical phase III serves the comparison to standard treatments already available. We hope to show superiority over standard treatment options for this last step.