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<p class="lead">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.</p> | <p class="lead">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.</p> | ||
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Revision as of 11:09, 13 October 2018
Applied Design
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.
Autoimmune Disease Survey
We received 48 responses from members of the public suffering from autoimmune diseases from a range of age groups. The responses gave us a greater understanding of the current treatments, the problems with them and what patients would like from a treatment. We were astounded by the positivity towards GE and for our project. There is a great deal of belief from the public in the potential of GE in medicine.
They survey told us the public wanted a treatment that treats “a condition at its source rather than masking symptoms.” that was also “less invasive and less dangerous”. They also showed support of a device that was able to provide personalised doses according to the patient. From these results we were able to begin the design of our treatment.
Safety
Safety of the product was the main concern raised in the survey. The majority of people are not highly knowledgeable about genetic engineering so we believe it is especially important to make safety a priority due to the apprehension towards the topic. We aimed to promote the safety of GE probiotics and make it clear that the patient's genome will be unaffected.
Concern on what we would engineer lead to greater investigation into species and strains of bacteria we would engineer with a focus on the safety. We also were directed into investigating how our product would alter the natural balance of the microbiome and how we can reduce any possible negative interactions. This is also why we began our initial research into how to test the safety of the product, we realise this is an important issue and aimed to create a plan to ensure the efficacy and safety to the patient and environment.
This led to us modifying our device to include a kill switch for biosafety.
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:
Condition | Linked to the microbiome | Linked to increased intestinal Th17 | Linked to decreased intestinal IL10 | Reference |
---|---|---|---|---|
Crohn's Disease | ✔ | ✔ | ✔ | A |
Ulcerative Colitis | ✔ | ✔ | ✔ | A |
Autoimmune Enteropathy | ✔ | ✔ | ✔ | B |
Coeliac Disease | ✔ | ✔ | ✔ | C, D |
Microscopic Colitis | ✔ | ✔ | E | |
Rheumatoid Arthritis | ✔ | ✔ | ✔ | F, G |
Psoriasis | ✔ | ✔ | ✔ | H, I |
Multiple Sclerosis | ✔ | ✔ | ✔ | J, K |
Lupus | ✔ | ✔ | L, M | |
Graves' Disease | ✔ | ✔ | ✔ | N |
Hashimoto's Thyroiditis | ✔ | ✔ | ✔ | N |
Type 1 Diabetes | ✔ | ✔ | ✔ | O |
Myasthenia Gravis | ✔ | ✔ | ✔ | N, P |
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.
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.
| |
Ciclosporin | Tablet/7 day infusion | Strong immunosuppressant | Short term: tremor, hair growth, swollen gum, feeling/being sick, diarrhoea.
| |
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.