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IKC159V: A Next Generation Bicistronic Gene Therapy for the Treatment of Geographic Atrophy

K M Binley(1) E F Warner(1) L Vaux(1) K Boyd(1) P S Widdowson(1) A Osborne(1)


Purpose: Geographic atrophy (GA) is an advanced form of age-related macular degeneration (AMD), that starts with atrophic lesions in the outer retina that expand to cover the macula and fovea, leading to severe vision loss over time. Despite recently approved treatments there remains a need for therapies with a greater efficacy, reduced treatment burden and without an increased risk of ocular neovascularisation. IKC159V is a bicistronic AAV vector that expresses pigment epithelium-derived factor (PEDF) to protect RPE and photoreceptors from atrophy and prevent neovascularisation, and a soluble form of complement cofactor CD46 to reduce pathological activation of the complement cascade. 


Methods: Null, monocistronic (PEDF or sCD46) and bicistronic PEDF/sCD46 (IKC159V) vectors (AAV2 or AAV8) were evaluated in a co-culture angiogenesis assays, complement breakdown assays and murine models of laser-induced CNV and a sodium iodate (SI) induced oxidative stress model following intravitreal or subretinal delivery.


Results: IKC159V and the PEDF-only AAV’s significantly reduced VEGF-induced angiogenesis whilst IKC159V and the sCD46-only AAV’s showed C3b and C4b complement breakdown. In the laser CNV model, IKC159V superiorly reduced both permeability, lesion area and MAC (C5b9) deposition area compared to either monocistronic vectors. IKC159V was also more efficacious than other well-known complement-only gene therapies. In the SI model, PEDF was demonstrated to significantly preserve retinal functional compared to Null vector.


Conclusions:  IKC159V shows greater efficacy in GA disease models than monocistronic vectors. The superior efficacy profile of IKC159V makes it an ideal candidate for clinical development to treat individuals with GA.

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