Proposed Implementation

“Pioneering a new method for treatment of disease”

NeuroTone does not need to be for just neurodegenerative disease
Adaptable technology for future projects, future teams, future treatments
Novel, unique, new, creative, imaginative

Introduction to NeuroTone

The final vision for NeuroTone is a capsule containing spores of our novel biotherapeutic strain of Clostridium sporogenes, which may be prescribed to delay or prevent the onset of neurodegeneration in patients.
The gastro resistant capsule will deliver spores capable of germinating in the anaerobic environment of the lower gut. These germinated cells will establish a colony capable of producing and secreting therapeutic concentrations of neuroprotective DBHB. Using mathematical modelling, we simulated initial doses of 0.05, 0.1 and 0.4 mmol and found no difference in the behaviour of the colony. After discussion we decided that the best approach would be to start with an initial small dose of spores and build up to a larger dose to allow the colony to establish gradually and minimise disruption to the gut microbiome.

Who and why?

The patients for NeuroTone will be individuals identified as at risk of neurodegeneration, through family history or early diagnosis with genetic screening or other diagnostic methods which may become available in the near future [1]. Individuals in this at risk group may be prescribed NeuroTone in a prophylactic manner to delay the onset or progression of neurodegeneration at the critical time before irreversible damage to neurons has occurred and the symptoms of these diseases can manifest. Ideally we would look to start treatment as soon as possible to have the most impact.

Neurodegenerative diseases cause damage before symptoms start to appear [2]. Therefore, it is vital to identify or start treatment on this as early as possible. With NeuroTone, we are hoping to delay significant symptoms so that quality of life can be extended. Through talking to real people working in the care sector (more details can be found on our Human Practices page), we recognised that symptoms such as memory loss, loss of coordination, cognitive change can have massive effects on daily life.

They start with small lifestyle changes before progression of the disease means that patients can be moved to care homes - becoming bed-bound and a struggling to carry out basic tasks such as eating and washing. The loss of independence is tragic to see, both for the carers and the family.

If we could extend the quality of life by even five years, through early, long-term management, this would have an incredible impact on everyone involved with the end user.

Safety

As C. sporogenes is non-pathogenic and has been known to colonise the human gut, the bacteria itself is not considered a safety risk, however if the patient appears to exhibit any adverse reactions or side effects to NeuroTone, we have designed failsafe safety measures in to our strain. The bacteria have been engineered to be unable to sporulate and so without repeated dosing, it is hypothesised that over a period of weeks, without repeated dosage, the NeuroTone colony will gradually diminish to sub clinical levels. We will also implemented a molecular kill switch mechanism, where the administration or subsequent withdrawal of a growth essential metabolite allows us to safely control the growth and colonisation status of the NeuroTone bacteria.
The mechanism of conditional sporulation also ensures strong biocontrol. The NeuroTone strain of C. sporogenes is a strictly anaerobic bacteria, and without the survival mechanism of sporulation, will be unable to survive outside of the intended host. This approach ensures that our modified strain can not escape and replicate in the environment.

Potential challenges

Before NeuroTone can be brought to market, as with any therapeutic, it will need to be subjected to robust clinical trials. These trials will make certain the safety of our strain and bring to light any potential unforeseen consequences which may arise due to the addition of a synthetic microbe of this nature to the human gut. The process of bringing a drug to market is a long and expensive one. We would need to work in collaboration with a pharmaceutical company to get our biotherapeutic to market. This presents many challenges of its own including securing funding, ensuring that the biotherapeutic is followed through by the pharmaceutical company (not shelved) and ensuring that the end price of a course of treatment is not too extortionate so as to exclude the majority of patients. These would be difficult challenges to face over a decade or more. An alternative to this would be to administer our biotherapeutic through a food supplement. This would avoid the need to involve big pharma and would make the process of getting our biotherapeutic to market and patients quicker We would still need to prove that the biotherapeutic was safe for consumption but the regulatory process for food standards is shorter and less expensive than for drugs. We considered both approaches carefully and decided that if we were to implement our project in the real world, we would take the drug approval path. This is because we can ensure that patients take the biotherapeutic in the most effective way. Additionally, our research suggests that increasing DBHB concentration in the blood may be a problem for patients with diabetes or kidney problems. We would want to ensure that the biotherapeutic did not cause harm to anyone, so drug trials would be the most robust and responsible approach to tackling this problem.

An additional challenge that NeuroTone may face could be due to drug interactions, specifically antibiotics, which may have an effect upon its efficacy in the gut. The levels of colonisation of NeuroTone may be monitored using patient fecal samples and so upon the event that a patient has to be administered antibiotics, the NeuroTone dosage can be altered to minimise these effects and restore the therapeutic NeuroTone colony post antibiotic treatment.

How would we envision others using our project?

We see value in NeuroTone not only as a treatment for neurodegenerative disease, but as an adaptable method of drug delivery.

By allowing targeting the microbiome of lower gastrointestinal tract, we have unlocked access to almost any part of the body. Molecule absorbing cells, enterocytes, line the outer layer of the colon where our NeuroTone colonies will grow. These cells are our gateway to the circulatory system and this means that drugs or molecules can reach any part of the body that is supplied blood. We see this highway as a way to deliver our molecule, DBHB – but this same route can be utilised by other scientists or companies around the world to use their own drug treatment.

NeuroTone is an innovative, novel idea and its use can set a precedent for the future of drug delivery. The flexibility of Clostridium sporogenes allows it to be controlled safely within the gut and we want others to take advantage of the adaptability of our project and mould it to fit their own design.

References:

1. Turner, R.S., Stubbs, T., Davies, D.A., & Albensi, B.C. (2020). Potential new approaches for diagnosis of Alzheimer's disease and related dementias. Frontiers in Neurology 11, 496. doi: 10.3389/fneur.2020.00496

2. Cheng, H. C., Ulane, C. M., & Burke, R. E. (2010). Clinical progression in Parkinson disease and the neurobiology of axons. Annals of Neurology 67(6), 715–725. doi: 10.1002/ana.21995

Team:Nottingham/Implementation