Defining the role of NRP1-ABL1 signalling in adult neovascular eye disease (360G-Wellcome-095623_Z_11_A)

We wish to address if ECM-induced NRP1-ABL1 signalling promotes adult angiogenesis and is a suitable target in anti-angiogenic therapies. In both PDR and wet AMD, VEGF is upregulated and stimulates angiogenesis to counter tissue hypoxia caused by vascular damage. Whereas neovascular lesions in PDR affect intraretinal vessels and resemble those in retinopathy of prematurity, wet AMD is instead caused by abnormal choroidal vessel growth. In addition to causing vascular abnormalities, high ocular VEGF levels are associated with vascular fluid leak, which causes oedema and impairs vision in both conditions. Because anti-VEGF therapies such as Lucentis® and Avastin® efficiently target vascular hyperpermeability, they are the approved treatmentfor oedema in PDR and AMD. They stabilise sight in over 90% of AMD patients, however, only 30% show improved vision (2), demonstrating that these therapiesare not sufficient for all patients. Recent evidence also suggests that anti-VEGF therapy is not curative, because neovascular lesions persist and oedema returns as soon as treatment is discontinued (3). Our prior research predicts that one reason for the persistence of neovascular lesions may be thefailure of anti-VEGF therapy to target ECM-induced angiogenesis via NRP1-ABL1 (Fig. 1). Furthermore, a multicentre cohort clinical study showed that, after seven years of treatment with anti-VEGF therapies, only one third of patients had good visual outcome and another third had poor outcome (4), with loss of protective VEGF functions in the neural retina likely contributing to retinal atrophy (5, 6). Thus, new treatments for neovascular eye disease should not compromise neuroprotection. Our discovery of an angiogenic NRP1/ABL1 pathway that can be targeted with the FDA-approved drug Imatinib independently of VEGFmay therefore provide a timely new therapeutic opportunity for neovascular disease.