Harnessing the power of milk to treat infections

Antibiotics are key to modern medicine. However, their use is under threat, as bacteria develop resistance faster than scientists can innovate.

While the vast majority of bacterial infections are local, nearly all antibiotics are distributed throughout the whole body when taken as a pill or injections. This exposes the entire body, including the large intestine, allowing trillions of bacteria, most of which are non-harmful, to be killed and evolve. Today, 1 in 6 infections are resistant to standard first-line treatments, and in 2021, resistant infections caused 1.14 million deaths globally.

To address this, the Wellcome Leap Focused Antibiotics programme has awarded $50m across 16 global institutions and businesses to develop innovative solutions. A team from the King’s Institute of Pharmaceutical Science, led by Dr Driton Vllasaliu, Reader in Biotherapeutics Delivery, will utilise its multidisciplinary expertise to generate a solution that provides a more refined approach to treating infection. King’s College London is the only academic institution in the UK selected to be part of this global flagship programme.

A cheap, plentiful and bioavailable drug carrier

Extracellular vesicles (EVs) are biological packages that cells send to each other. A cell can pack an EV with molecules such as proteins, RNA, DNA fragments and lipids, which is protected by a fat membrane. The EV is then taken up by another cell, which receives its package of instructions.

For almost a decade, Dr Vllasaliu’s lab has been researching EVs derived from milk as a way to deliver complex, biological drugs which currently require injections. Milk EVs, which can potentially be delivered orally in pill form, have two special properties that make them prime candidates for this activity. Firstly, they are stable in the gut, and secondly, they can cross the gut wall, entering the bloodstream.  

A thin membrane surrounds the EVs, helping them survive the journey through the stomach and reach the small intestine relatively intact. Biological signals, which researchers believe may have developed as part of mother/baby communication biology, then allows the milk EVs to be absorbed in the small intestine. This is key, because milk EVs may prevent drug contact with trillions of non-harmful bacteria in the large intestine if they were to continue their journey.

Measuring tens to a few hundred nanometres, milk EVs are roughly the same size as a virus. This small size helps them get taken up by the intestinal cells and pass into the bloodstream.

Adding to these special properties is the fact that milk is consumed in vast quantities, is safe, plentiful and cheap, which may make it easier for the technology to be adopted in clinical settings.

Hijacking biological mechanisms to treat infections at their source

Key to progressing the milk EV technology has been a £2.5M UKRI Engineering Biology grant, which is currently led by Vllasaliu, in collaboration with Professor Thanou. In this programme, the focus is engineering milk EVs for oral delivery of nucleic acid-based drugs as “very large, very complex biological molecules”. Important progress made through this research will now be applied to the Focused Antibiotics programme, helping to accelerate the generation of solutions.  

Focusing on currently available, common antibiotic drugs, Dr Vllasaliu and the team will generate new oral formulations for targeted delivery to lung infection.

The project will include co-investigators Professors Maya Thanou (with whom Dr Vllasaliu conceived the idea), Andrew Chan, Mark Sutton and James Mason and Drs Richard Amison and Sally Yunsun Kim. Together, their breadth of expertise - in areas ranging from drug delivery to pharmacology and development of antimicrobial agents - means most of the work can be carried out in-house.

Beyond infections: Can milk EVs help people lose weight?

Dr Vllasaliu and Professor Thanou are currently looking to translate their research on milk EVs by creating a technology for multiple applications. Separately to the Focused Antibiotics programme, the technology could also be used to enable administration of peptide-based drugs (such as insulin) and nucleic acids (gene-based drugs) as a pill. This platform technology is enabled by tailored engineering of milk EVs in a different way for each class of drug molecule, which includes a patent-pending method. Such a powerful platform technology enables a broad clinical focus, from infection to inflammatory bowel disease and metabolic disease. The group are also looking at rare bowel diseases as a proof of concept, before wider deployment to more common diseases.

Another potential application is oral vaccines. So far, mRNA vaccines such as the Covid-19 vaccine, can only be delivered via intramuscular injection, which can cause pain and side effects. The ability to deliver this mRNA vaccine orally with a pill would be a game changer, enabling rapid mass deployment in future pandemics or situations where individuals cannot easily access clinics.  

They are also investigating peptide-based drugs, such as insulin. If their research is successful, people with diabetes may be able to forgo frequent injections and take their insulin via a pill instead. The same principle applies to weight loss drugs, such as GLP-1 agonists. The ability to take these treatments orally could offer a major quality of life boost, as well as cutting down on needle disposal.

However, there are challenges with translating this cutting-edge research for clinical use. There are issues around scalability, cost, and reproducibility. Regulators such as the US Food and Drugs Administration and the European Medicines Agency are currently cautious because EVs are complex biological materials and they want to ensure their safety and quality - particularly reproducibility - before approval for clinical use.  

From lab to clinic

While EVs have yet to be approved for clinical use, Dr Vllasaliu is driven to ensure his research moves beyond the lab where his findings can help improve the lives of patients.

Jointly with Professor Thanou, Dr Vllasaliu is currently in the process of establishing EVora Therapeutics, a spinout company focused on developing the milk EV-based platform technology. In June, the spinout was named one of eight that had been accepted onto the King’s Spinout Accelerator, a 12-month transformative programme that guides early-stage prospective spinouts in shaping robust commercial propositions.