Development of a novel anti-inflammatory nanoparticle for the treatment of Acute Lung Injury

Acute lung injury is a life threatening and incapacitating condition that affects 20% of all critically ill patients in intensive care. Around 30-50% of these sufferers will die from the condition and many survivors can have serious reductions in the quality of the life with chronic lung problems. This not only has a major effect on the patients themselves, but is also a serious resource allocation problem for the NHS as an ICU bed costs in excess of £1800 per day. There is no effective treatments for this condition at this time and therefore new medicines are urgently needed that can deal and stabilise the condition. ALI is characterised by a vicious cycle of inflammation in the lung that leads to inappropriate infiltration of immune cells to the lung. We have developed a potential treatment for this condition that may have the ability to be nasally delivered to patients in intensive care that has potent anti-inflammatory effects. This treatment is a nano-sized formulation that binds specifically to immunosuppressive receptors found on the surface of immune cells such as macrophages, resulting in significant reduction of the production of inflammatory signaling molecules called cytokines.

Therefore in this proposal we aim to bring this treatment closer to clinical development by evaluating its effectiveness in a range of preclinical models of ALI. This work will inform us on its effectiveness, side effects and formulation and dosing of the therapeutic required to obtain a significant effect.

Acute Lung Injury (ALI) is a serious condition associated with significant morbidity, mortality and healthcare resource utilisation, for which no effective pharmacologic treatment is available. ALI is caused by the uncontrolled activation of immune cells, resulting in an unregulated cycle of inflammation that leads to damage to the alveolar epithelial-endothelial barrier, leading to acute respiratory failure and the need for mechanical ventilation. This is therefore an area of clear unmet clinical need for effective anti-inflammatory therapies.
We have developed a novel nanoparticle which has potent anti-inflammatory effects. Here we will investigate its application in ALI by examining effects in two clinically relevant murine models of ALI (intratracheal LPS and cecal ligation and puncture), ex vivo patient and volunteer alveolar macrophages and a human ex vivo lung perfusion model. This project will provide data on physiological outcomes and toxicity upon administration with our nanoparticle to determine if further development into preclinical trials is warranted.

The primary goal of this research in terms of impact is that it will significantly help the outcomes to patients in intensive care that present with ALI. This will therefore no only impact them, but carers and also then resource allocation within the health service of the UK (and internationally).

In addition to this condition, the anti-inflammatory effects of the modality make it amenable to the treatment of other conditions underpinned by inappropriate inflammation, both in the lung and in other parts of the body. With this in mind, this research is likely to impact other researchers both academically and industrially in development of follow-on therapeutics and biomaterials that can exploit these effects. Therefore it is tangible that if successful, this project could lead on to the development of other daughter therapeutics that could not only help patients suffering other inflammatory diseases, but also generate new R & D jobs and revenue for the UK.