MONOCYTE-BASED GENE THERAPY FOR ACUTE NEUTROPHIL-MEDIATED TISSUE INJURY

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This proposal is aimed at developing new treatments for lung diseases caused by excessive activation of cells used by the body to fight infection (neutrophils). In particular, a condition called adult respiratory distress syndrome is fatal in 40% of cases despite modern treatment, and survivors have considerable long-term problems.. The research involves manipulating another defence cell, the monocyte. Monocytes are recruited to inflamed sites alongside neutrophils and are amenable to therapeutic modification. I shall boost monocytes by providing extra copies of a protective gene called elafin. Elafin efficiently neutralises the main toxic product of neutrophils and makes monocytes switch off inflammation. I shall therefore insert elafin into human monocytes in order to reduce the toxic effects of ‘activated‘ neutrophils. I shall extend these findings to mice with the aim of reducing lung injury caused by neutrophils. These pre-clinical studies will lay the grounds for future clinical application in humans. Importantly, the principles of this proposal can be extended not only to other lung diseases associated with neutrophil malfunction (e.g. emphysema, bronchitis, cystic fibrosis) but to all causes of inflammation involving the neutrophil. The work therefore has potential implications for psoriasis, arthritis, peritonitis, and a host of other conditions