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Magali Saint-Geniez, Ilakya Senthilkumar, Siwei Cai, Daisy Yao Shu, Erik Butcher, Scott Frank; Anti-angiogenic effects of a novel small molecular activator of PGC-1α. Invest. Ophthalmol. Vis. Sci. 2020;61(7):4341.
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© ARVO (1962-2015); The Authors (2016-present)
Despite the success of anti-VEGF drugs for the treatment of choroidal neovascularization (CNV) in AMD, over 30% of patients are not responding or become resistant to the treatment. Thus, identification of complementary CNV therapies is of high clinical importance. Resistance to anti-VEGF drugs is attributed to aggressive angiogenesis and subretinal fibrosis, both depending on the conversion of endothelial cells (EC) and RPE from oxidative metabolism to glycolysis. We previously identified the small molecule activator of PGC-1α, ZLN005, as a potent inducer of RPE oxidative metabolism and anti-oxidant capacity (Satish et al, 2018) but its direct effect on EC is unknown. This study examined the therapeutic potential of ZLN005 in blocking pathological angiogenesis using in vitro and ex vivo models.
HRECS (primary human retinal endothelial cells) were maintained in EGM2 media and exposed to 0-20µM ZLN005 or DMSO (control). Gene expression changes were analyzed by qPCR. Cell death was quantified by measuring LDH release. Cell migration was investigated in a scratch assay. Cell proliferation was quantified using the Cyquant assay. For the choroid explant assay, choroid/RPE biopsies from 3 weeks old C57bl/6J mice were seeded in growth-factor reduced matrigel and exposed to EGM2 media. The vascular sprouting area was quantified using ImageJ.
ZLN005 robustly blocked HRECs proliferation in a dose-dependent manner (61% inh. at 10µM, p<0.0001) without affecting cell survival. ZLN005 also significantly reduced HRECs migration (20% inh. at 10µM, p<0.0001). These anti-angiogenic effects were associated with the repression of critical glycolytic enzymes, PFKFB3 (51%, p<0.01) and PKM2 (53%, p<0.001), and inhibition of the Notch pathway indicated by reduction in DLL4 (29%, p<0.01), HSP90 (45%, p<0.01), and HES1 (26%, p<0.01). Exposure of choroidal explants to ZLN005 at the start of the assay abrogated vascular sprouting (99% inhibition, p<0.0001). Importantly, ZLN005 also promoted regression of pre-established vascular sprouts (-25% vs +96% growth, p<0.0001). Calcein AM staining confirmed that sprouting inhibition was due to ZLN005 anti-angiogenic effects and not to explant death.
This study identifies ZNL005 as a novel and potent anti-angiogenic drug. ZLN005 anti-angiogenic activity on EC combined with its known anti-oxidant effects on RPE make it a very attractive drug for the treatment of AMD progression.
This is a 2020 ARVO Annual Meeting abstract.
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