Category: Research

Month: 06 Jul 2016

Issue: not yet available

Researchers demonstrate potential benefit from targeting phospholipase A2 in model of diabetic macular edema (DME)

Research, led by the Centre for Experimental Medicine, Queen’s University Belfast, has shown that inhibition of lipoprotein-associated phospholipase A2 (Lp-PLA2) with darapladib, an experimental GSK atherosclerosis drug, may be capable of preventing diabetes-mediated blood-retinal barrier dysfunction. The pre-clinical research study also demonstrated that lysophosphatidylcholine (LPC), the substrate for Lp-PLA2, appears to impact on the retinal vascular endothelium to induce vaso-permeability via VEGFR2. As such, the authors of the study suggest that Lp-PLA2 may be a viable therapeutic target to treat patients with diabetic macular edema (DME), potentially in combination with other anti-VEGF agents currently approved in the market.

 

The Belfast-based research group undertook their studies due to significant reports that repeated intravitreal injections of anti-VEGF therapies do not work in up to 50% of patients. The absence of a clinical response with such medication suggested that another mechanism may underlie vascular permeability in DME. Plasma from patients with DME had previously been shown to contain high levels of LPC, which has demonstrated permeability-enhancing activity. One of the enzymes responsible for the production of LPC is Lp-PLA2, a calcium dependent phospholipase which has been independently proposed as a predictive biomarker in stroke, atherosclerosis and coronary heart disease. GSK had previously investigated the potential for darapladib, an inhibitor of Lp-PLA2, to treat atherosclerosis and, although the drug failed to reach its primary endpoint in an acute coronary syndrome trial, a 3-month daily treatment of 160mg darapladib reduced DME and increased patients’ visual acuity. Such observations warranted further investigation leading to the current studies on the inhibition of Lp-PLA2 in diabetic animal models regarding blood-retinal barrier function and investigations into the effect of LPC on neural microvascular endothelial cells.

 

Results from the study showed that systemic administration of the Lp-PLA2 inhibitor at 10 mg/kg (i.p.) suppressed blood-retinal barrier breakdown in diabetic animal models and indicated that the inhibitory effect was similar to VEGF neutralization. Moreover, the protection against blood-retinal barrier dysfunction appeared to be additive when both Lp-PLA2 and VEGF were inhibited simultaneously. On the basis of the results the authors commented that, “Lp-PLA2 activity and its plasma-borne reaction products may constitute another pathway to retinal vaso-permeability. Data from the present study has identified Lp-PLA2 as a valid VEGF independent therapeutic target in DME, but also indicated that Lp-PLA2 inhibition could be combined with that of VEGF. This finding opens the possibility of combination therapy with the benefits of use of lower drug dosages and lower potential toxicity.”

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