Overview

Product design has been at the front of our project since we came up with our initial ideas. We wanted to spend our summer creating a solution to a real world problem that affects a large proportion of the world’s population. In creating a realistic therapeutic product we have looked into current treatments, safety, manufacture, accessibility and the next stage for the product, throughout each stage we have had the patient at the forefront of our minds. After a range of ideas we have settled on a final design for a new therapeutic to treat IBD.

Which Autoimmune Diseases?

Our survey was completed by people suffering from a range of autoimmune conditions. We realised that our initial idea of a general treatment was over ambitious. Many of the responses said that they would feel more comfortable if the treatment was designed with a greater focus on select conditions.

We have specifically designed our treatment with Crohn’s disease and Ulcerative Colitis in mind, however, we also found how closely related other autoimmune diseases are and decided to look into which conditions we have the potential of treating if we were to develop our treatment further. Our treatment has a huge range of applications. For our initial market we would focus on IBD but the range of diseases affected by the intestinal immune system allows our product to be modified for trials on other relevant autoimmune conditions.

Autoimmune enteropathy, Coeliac disease, Rheumatoid Arthritis, Multiple sclerosis, Psoriasis and Type 1 diabetes have all been shown to linked to the balance between intestinal Th17 and Treg populations (or IL10 concentration) in the gut. For Coeliac disease we may also need to combine our system with a mechanism to digest or modify gluten. Other conditions, such as Microscopic colitis, Lupus and Hashimoto’s thyroiditis, also relate to at least one of these populations but more research will be needed to find how they are connected to the gut. As well as this, specific probiotics have been shown to be beneficial in a range of these conditions. Our device may act as an appropriate treatment with some minor modifications for these conditions. An imbalance in the immune cells in the gut has been shown to cause an autoimmune condition in the kidneys due to migration of Th17 cells showing the importance of population control in the gut.

Types of epilepsy have also been found to relate autoimmunity in the gut. The gut-brain axis may connect autoimmunity in the gut to nervous system diseases and promote Th17 cells in the CNS, similar to what has been found with multiple sclerosis. 80% of cases of epilepsy are in the developing world, this is thought to be due to the influence of bacteria, such as segmented filamentous bacteria (SFB), from water sources influencing the gut microbiome and immune cells. The recent and sharp increase in cases shows the necessity of a simple and effective treatment. If the condition is confirmed to be linked to autoimmunity in the gut then our product can offer an easily administered treatment that stops the disease at its source.

We created table to illustrate which autoimmune diseases have been found to be linked to immune cell balance in the gut:

Current Treatments

To ensure the necessity of a novel treatment we looked into what is currently available and the efficacy and side effects of current therapies. We had already learnt a lot about treatments out of our survey for autoimmune patients. The survey told us that the majority of patients use a combination of treatments and highlighted the problems with their treatments.

We have created a table to summarise current treatments and their associated side effects:

Treatment	Delivery	Action	Success	Side Effects
Aminosalicylates (5-ASAS)	Oral/suppository/enema	Reduces Inflammation	Works for 7/10 mild cases. Ineffective for severe IBD and maintaining remission	Rarely Serious
Immunosuppressants	Tablet	Reduces the activity of the immune system	Effective after 2-3 months	Vulnerable to infection, low red blood cell production
Corticosteroids	Oral/suppository/enema/IV	Reduces Inflammation		Short term: acne, weight gain, mood changes, insomnia. Long term: osteoporosis, cataracts
Ciclosporin	Tablet/7 day infusion	Strong immunosuppressant		Short term: tremor, hair growth, swollen gum, feeling/being sick, diarrhoea. Long term: High blood pressure, reduced kidney/liver function
Biologics	Infusion/injection	Block receptors for inflammation stimulating proteins		Increased risk of infection, vertigo, dizziness, allergy-like reaction
Surgery	-	Colectomy/ileostomy	Relieve symptoms but they usually come back	Patient spends a week in hospital and a few months recovering

Current treatments show no effect for 1 out of 5 patients with IBD and those that do often have very serious side effects. From our initial survey we found a number of patients who are currently not on any treatment as nothing has worked or the side effects have been too severe and more stated their current treatments are not working. Others were concerned of long term side effects such as increased risk of developing certain cancers. We believe that a new treatment must be developed that is both more effective and more patient friendly.

Professor Simon Travis

We got in contact with Simon Travis, Professor of Clinical Gastroenterology, who has been the President of the European Crohn’s and Colitis Organisation (ECCO) and an elected Member of the International Organisation of Inflammatory Bowel Disease, to gain more of an insight into the current problems with treatments and what a doctor would like out of a new treatment. He believes probiotics have potential in treating Crohn’s but encouraged us to look for evidence showing it’s success. He also thinks patients won’t mind using genetically modified products, they only care that the treatment will improve symptoms.

In terms of safety he believed, especially compared to current treatments such as anti-TNFa, proteins produced by probiotics are far safer as they will be quickly degraded. His concern came from consideration of the environment. He directed our consideration towards the impact the bacteria would have coming out as waste and possible effects in sewage. This is especially important in developing world.

Finally, he encouraged us to think of the strains we would use in terms of its adhesion properties in the intestinal tract rather than just ease of modification. The localisation of IBD is important to consider when choosing a bacteria as we want our treatment to be as close to the source as possible in order to have the greatest effect as possible.

After our meeting with Simon Travis we gained confidence in the use of probiotics and were directed towards further avenues of research in order to ensure our treatment was as efficient as possible.

Dr Michael Morrison, HeLEX

We met up with Dr Michael Morrison the principal investigator of biomodifying technologies at HeLEX (Centre for Health, Law and Emerging Technologies).

One of the things he suggested we look into was the regulatory bodies that our product would have to go through. We found, since our product is not a conventional pharmaceutical or medical device, that it is quite unclear which regulatory category our product would come under. We made a clear plan and flowchart of how our device would go from the lab into a commercially available product. This includes how we can prove the safety and effect of the product pre-clinical trials.

Michael suggested we look into the costs that would be associated with our treatment and how this would compare to current treatments. We would need to consider delivery of our product to patient and regulation to first get an idea of the associated costs. After this we would confidently be able to say how the price differs from current treatments and if our product is a cost-effective alternative. He also directed our attention towards current gene therapies to use as case studies for regulation and costs for the business and patient.

Gene Therapy Case Studies

There are currently very few treatments that are relevant to our project. Gene therapies are on the rise but the cost of these make them unattainable for patients and mean that they can’t be profitable for pharmaceutical companies preventing further research and expansion of the treatment. There are currently 504 gene therapies in clinical trials with 34 of these in the most advanced stage of testing. The sudden surge in this new type of therapy has enlightened many unseen problems shrouded by the confidence in the efficiency of the treatment.

CAR T is the first gene therapy approved by the FDA but has encountered many problems. Patient’s T cells are transformed to recognise and attack cancer cells. Kymriah by Novartis fights against acute lymphoblastic leukemia, 3,100 new patients a year suffer from this and 30% of these people don’t respond to previous treatments. The treatment has a response rate of over 80% and requires only one injection. Although this seems like a miraculous treatment curing a patient is not a sustainable business model especially with the huge $475,000 price tag for the cure. The high cost is from T cell collection, manufacture involving 151 stages with 54 decision points, transport, testing, low number of patients, one administration cure and trained specialists present in only 32 sites in the USA. The requirement of specialists not only increases costs but restricts the locations that it can be administered.

Although the high cost is thought to be cheaper than the lifelong alternative, the one off payment is unaffordable for most customers. This has required Novartis to seek a new business model. If the patient shows no response within a month there is no charge, this increases the customers confidence yet doesn’t lower the cost. The cost has already been reduced by the FDA permitting smaller groups for clinical trials, even though side effects such as cytokine release syndrome were found resulting in deaths during the trials it still passed. This shows how necessary a new treatment is and how closely managed the administration must be. Novartis are currently looking into reducing costs by the use of donor T cells rather than the patients and by automating manufacturing systems reducing the need for skilled operators.

Dr Tony Cutler

Dr Tony Cutler is a researcher in novel immune system treatments. As well as discussing our design and its impact on the immune system, through his knowledge of probiotic treatments for diabetes he was able to advise us on making a successful probiotic.

He emphasised the requirement of safety in our design. The wariness towards genetic engineering means we have to do everything possible to give the patient confidence in using a new form of treatment. It is also necessary to ensure the treatment would be better than anything else available as patients would rather take a standard effective treatment than a gene therapy. In consideration of the bacteria we were advised to look into administration, colony establishment in the intestine and the proximity of the produced proteins to the immune cells.

Genetically Engineered Probiotics

Probiotics are an effective, patient friendly treatment. Genetic engineering of the novel therapy opens up new avenues for treatments. By restricting the genetic engineering to the probiotic rather than the patient dramatically reduces any risks for the patient and allows the treatment to be stopped and the probiotic removed at any point.

GE probiotics are a very new concept, this is demonstrated by how few companies are currently in this market, because of this we have used 4D pharma plc and MaaT pharma as case studies in production and marketing probiotics. 4D pharma plc and MaaT pharma produce natural probiotics, test which strains are effective for which conditions, and research what can be considered a healthy microbiome. Their website contains some basic information about manufacture, clinical trials, finance, patents and more. We used this information with further research to develop our initial model for manufacture of our product and for our business model.

Whilst at New Scientist Live as well as conducting our outreach work we decided to conduct a survey to get a greater understanding of the public’s support of GE probiotics compared to other gene therapies. Our survey was filled in by school and university students with studying sciences and adults with an interest in science with a range of qualifications. We asked if they agreed with germline cell gene therapy, somatic cell genetic gene therapy and genetically modified probiotics.

The general consensus was that all forms of genetic modification have the potential for good and should be encouraged for the treatment of serious diseases. There was a lot of concern over regulation leading to fear of use for in areas other than therapeutics. The survey illustrated that the public has more support for somatic cell gene therapy and GE probiotics compared to germline cell gene therapy.

Strains

When we finish testing our device with E.coli we will use Lactococcus lactis as our probiotic. E.coli is safe and easy to engineer but show poor long term colonization of the gut, we have looked into alternatives that would provide a longer term treatment and so require fewer doses. L.lactis is recognised as a safe species and has been engineered greatly including to act as a probiotic producing IL10 for IBD treatment. L.lactis already has many health benefits so, with our system added, would act as efficient treatment.

L.lactis is able to survive low pH and bile, 98% of the bacteria survive the passage through the stomach and 10-30% survive in the duodenum, which is a relatively high percentage. In the gut the bacteria then adhere to microvilli and form part of the microbiome¹.

We met with Dr Chris Barnes to ask for advice for bacterial population control. He directed us to recent studies using L.lactis and agreed they would be safe to ingest and would successfully colonise the gut. He suggested using quorum sensing with a molecule not normally found in the gut to allow accurate control. He also highlighted the variation in microbiome of different patients would result in large variations in population of our probiotic. We investigated the range in population that our device would be successful at.

Psychological Impact

Manufacture

Design

References