| Summary: | Exudative age-related macular degeneration, characterised by choroidal neovascularisation (CNV), is the leading cause of severe visual impairment in developed societies. Until recently, established treatments were of limited efficacy, and associated with other disadvantages including being inherently destructive therapies. Although novel anti-VEGF pharmacotherapy has since revolutionised the management and prognosis of many patients, current treatment regimens have distinct limitations, particularly in terms of the probable requirement for life-long, frequent invasive dosing, and associated cumulative medical, financial and logistical consequences. Furthermore, many patients respond suboptimally despite frequent administration. Continued development of superior therapies, therefore remains essential. Targeted angiostatic gene delivery may achieve many of the characteristics required of an ideal treatment modality. Work is presented which further expands the possibility of safe and efficacious retinal gene therapy by viral methods, for the ultimate intention of controlling human CNV. Proof of principle is demonstrated for in vivo intraocular expression from equine infectious anaemia virus-based vectors and non-integrating HIV-1-based vectors, which both represent significant advances in biosafety. The angiostatic efficacies of sFlt-1, endostatin, angiostatin and Pedf are then evaluated in an established murine laser model of CNV. This model is further optimised to quantify CNV-associated hyperpermeability in addition to CNV area. Lentiviral transfer of sFlt-1, endostatin or angiostatin, and Pedf upregulation by bespoke zinc finger transcription factors delivered by adeno-associated viral vectors potently inhibited angiogenesis, with sFlt-1, endostatin and angiostatin additionally inhibiting CNV-associated hyperpermeability. Finally, a novel angiogenic role of sonic hedgehog signalling in experimental CNV is identified, and its pharmacological inhibition demonstrated to be angiostatic. These results complement the current body of experimental evidence, which coupled with the demonstration of efficacious molecular targeting of angiogenic pathways in humans, support the further development of this technology to provide novel treatments which may be used as adjuncts or as superior alternatives to existing therapies.
|
|---|
