Fusogenic liposomes: the innovative delivery of compounds into human platelets to reduce animal use in platelet research

Platelets are small cells in the blood which, when activated, play a critical role in the prevention of excessive bleeding at sites of injury. Conversely, inappropriate platelet activation can block the blood supply to the heart and brain resulting in life threatening heart attacks or strokes. The impact of platelets in heart attack and stroke contributes to an estimated 40% of cardiovascular deaths. Current therapy in the prevention of heart attacks and strokes is based on drugs which suppress normal platelet function. While effective in approximately two thirds of patients, the remainder succumb to a second heart attack or stroke. As anti-platelet drugs suppress normal platelet function they can also have the undesirable side effect of nuisance bleeding which for approximately 5% of patients can lead to a severe bleed which can be fatal. Therefore an understanding of the molecular mechanisms governing platelet activation and function is fundamental to understanding how platelets impact health and disease and to the identification of new and improved drug targets. To facilitate this, platelet research is currently heavily reliant on the use of genetically altered mouse models.

As platelets lack a cell nucleus standard molecular biology methods, used to study biological processes in nucleated cells, cannot be used. This limitation has resulted in the greater use of animals, particularly mouse models, in platelet research. Mice are routinely genetically altered to disrupt genes of interest or to engineer the expression of fluorescent protein markers to enable biological process to be studied in platelets. However mouse models are not always a suitable alternative to investigate human platelet function. Platelet size and the total number of receptors and intracellular signalling molecules per platelet vary widely between human and mice. The functional consequence of these differences and the implications for drug development targeting platelets are poorly understood. With no robust methods to modify human platelets humanized mouse models are emerging to tackle problems with poor translation of findings from mouse to human platelets.

This project seeks to develop a robust, versatile and low cost experimental platform to deliver antibodies and imaging probes into human platelets using fusogenic liposomes. The aim of this strategy is to replace the need to use platelets from genetically modified animals by enabling antibody mediated knockdown and the labelling of proteins in human platelets. This will enable human tissue to be used directly which will reduce the number of animals used in platelet research.

This Studentship was co-awarded with the British Heart Foundation (BHF).

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