Flightless I

Flightless I (Flii) is a novel drug target that regulates important cellular behaviours including mobility, contraction, adhesion, proliferation and cytokine production. The activity of Flii is mediated through interaction with components of the cell’s cytoskeleton, modulation of intracellular signalling pathways and regulation of cellular transcription events.

The flightless I gene was originally identified in Drosophila melanogaster, where mutations in the flightless I locus were found to cause flightlessness due to disordered indirect flight muscles (Campbell et al., (1993) PNAS 90 11386-11390).

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A significant body of research has shown that Flii is a negative regulator of the migratory and proliferative events of tissue repair [see publications]. For example, using transgenic models, it has been demonstrated that Flii ‘over-expressing’ mice exhibit larger, less contracted, wounds, reduced cellular proliferation and delayed reepithelialisation. Conversely, Flii-deficient mice show improved epidermal migration and re-epithelialisation, and enhanced wound vascularisation.

Importantly, neutralising antibodies to Flightless I have been shown to improve wound repair in murine and porcine models of normal and compromised would healing11, 17, and a murine model of epidermolysis bullosa15.

In addition, administration of anti-Flightless I antibodies reduces the incidence and growth of skin tumours in a mouse model of cutaneous squamous cell carcinoma (Kopecki et al., (2014) J Invest Dermatol 134:S28).

Repeated application of neutralising antibodies to Flightless I reduces the severity of blister formation in a mouse model of epidermolysis bullosa

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Anti-flightless antibodies or IgG dose-matched control antibodies formulated in a cream vehicle were applied onto the skin of EB mice on alternate days during blister development (Days 0-10). EB mice treated with anti-Flightless I antibodies had significantly fewer blister lesions, decreased extent of blistering (Days 8-12) and lower histological blister scores compared with EB mice treated with control IgG antibody (Kopecki et al., 2012 J Invest Dermatol 133:1008-16).

Neutralising antibodies to Flightless I decrease skin tumour growth and severity.

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Anti-flightless antibodies or IgG dose-matched control antibodies were administered every two weeks (weeks, 0, 2, 4, 8) to primary squamous cell carcinomas induced on the back of Balb/c mice. Mice treated with anti-Flightless I had significantly decreased tumour volume from week 4.