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In Molecular therapy : the journal of the American Society of Gene Therapy

Glaucoma is the leading cause of irreversible vision loss, affecting more than 70 million individuals worldwide. Circulatory disturbances of aqueous humor (AH) have long been central pathological contributors to glaucomatous lesions. Thus, targeting the AH outflow is a promising approach to treat glaucoma. However, the epigenetic mechanisms initiating AH outflow disorders and the targeted treatments remain to be developed. Studying glaucoma patients, we identified GDF7 (Growth Differentiation Factor 7) hypomethylation as a crucial event in the onset of AH outflow disorders. Regarding the underlying mechanism, the hypomethylated GDF7 promoter was responsible for the increased GDF7 production and secretion in POAG. Excessive GDF7 protein promoted trabecular meshwork (TM) fibrosis through BMPR2/Smad signaling and up-regulated pro-fibrotic genes, α-smooth muscle actin (α-SMA) and fibronectin (FN). GDF7 protein expression formed a positive feedback loop in GTM. This positive feedback loop was dependent on activated TET (ten-eleven translocation) enzyme, which kept GDF7 promoter region hypomethylated. The phenotypic transition in TM fortified the AH outflow resistance, thus elevating the intraocular pressure (IOP) and attenuating the nerve fiber layer. This methylation dependent mechanism is also confirmed by a machine-learning model in silico with a specificity of 84.38% and a sensitivity of 89.38%. In rhesus monkeys, we developed GDF7 neutralization therapy to inhibit TM fibrosis and consequent AH outflow resistance that contributes to glaucoma. The neutralization therapy achieved high-efficiency control of the IOP (from 21.3±0.3 to 17.6±0.2 mmHg), a three-fold improvement in the outflow facility (from 0.1 to 0.3 μl/min·mmHg), and protection of nerve fibers. This study provides new insights into the epigenetic mechanism of glaucoma and proposes an innovative GDF7 neutralization therapy as a promising intervention.

Wan Peixing, Long Erping, Li Zhidong, Zhu Yingting, Su Wenru, Zhuo Yehong

2020-Dec-31

Computational modeling, DNA methylation, Fibrosis, Glaucoma, Neutralizing antibody, Trabecular meshwork