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Mehreen Adhi, Siobhan M. Cashman, Rajendra Kumar-Singh; Adeno-associated Virus Mediated Delivery of Complement and Kallikrein-kinin System Inhibitors Reduce Vascular and Neuronal Complications in a Model of Diabetic Retinopathy. Invest. Ophthalmol. Vis. Sci. 2012;53(14):1888.
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Retinal vascular permeability and neuronal cell death have been postulated as plausible mechanisms of visual dysfunction associated with proliferative diabetic retinopathy (PDR) and diabetic macular edema (DME). We aimed to investigate the effect of complement and kallikrein-kinin system (KKS) inhibitors in diabetic retinopathy (DR), using a streptozotocin (STZ) induced diabetic mouse model.
Using adeno-associated virus serotype 8 as an expression system, we tested efficacy of three molecules: (i) human C1-esterase inhibitor (hC1INH), an inhibitor of the classical complement pathway and KKS; (ii) soluble human CD59 (sCD59), an inhibitor of the terminal product of complement activation, the membrane attack complex (MAC); and (iii) a novel molecule consisting of a modified human tissue-factor pathway inhibitor (mhTFPI), an inhibitor of KKS. Each of these viruses was injected into the vitreous of C57BL/6J mice. After 2 weeks of transgene expression, mice were rendered diabetic using STZ. After 4 days of STZ treatment, mice were injected intraperitoneally with 2.5% sodium fluorescein and vitreous samples were collected to quantify leakage. Retinal sections were stained for ganglion cell apoptosis (GCA) and MAC deposition.
Fluorescein Angiography revealed a reduction in capillary dropout and a 3.4-fold, 1.6-fold and 1.2-fold reduction in leakage in hC1INH, sCD59 and mhTFPI injected eyes respectively, when compared to control eyes. GCA was significantly reduced in hC1INH, sCD59 and mhTFPI injected eyes compared to controls. In addition, reduction in MAC deposition in the ganglion cell layer was observed in hC1INH and sCD59 injected eyes compared to controls.
We have demonstrated reduction in both vascular and neuronal complications in a model of DR using AAV-mediated delivery of natural inhibitors of the complement system and KKS, and a novel inhibitor of KKS. To our knowledge, this is the first study showing efficacy of MAC inhibition as a potential treatment for DR. These approaches warrant further exploration as potential therapies for visual dysfunction associated with PDR and DME, leading causes of visual impairment in DR patients.
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