Rao Pushpa, Mishra Manish, Cashman Siobhan M, Walton David S, Kumar-Singh Rajendra
Department of Developmental, Molecular and Chemical Biology, Tufts University School of Medicine, MA, Boston, United States.
Department of Ophthalmology, Harvard Medical School, MA, Boston, United States.
Sci Rep. 2025 Mar 7;15(1):8051. doi: 10.1038/s41598-025-92273-5.
Primary open angle glaucoma (POAG) and infantile aphakic glaucoma (IAG) are significant contributors of vision loss in adults and infants respectively. Both indications are associated with fibrosis of the trabecular meshwork (TM) that attenuates aqueous humor outflow, elevated intraocular pressure (IOP) and retinal ganglion cell (RGC) death. Transforming growth factor β2 (TGFβ2) is implicated in epithelial to mesenchymal transition (EMT) in both POAG and IAG. A major regulator of TGFβ2 is decorin, a proteoglycan whose expression is reduced in glaucoma patients. In this study we demonstrate highly efficient infection of the murine anterior chamber including ciliary body, corneal stroma, TM and corneal nerves using the adeno-associated virus (AAV) vector AAV-IKV. Intracameral injection of AAV-IKV expressing a constitutively active TGFβ2 (AAV-IKV-TGFβ2) led to fibrosis of the TM in mice and a subsequent increase in IOP and RGC death, modeling pathophysiological features of POAG and IAG. Expression of human decorin from an AAV-IKV vector (AAV-IKV-Decorin) attenuated fibrosis, IOP and RGC death in AAV-IKV-TGFβ2 injected mice, suggesting that AAV-IKV-Decorin may function as a therapy for POAG and IAG respectively. Finally, intracameral injection of an AAV-IKV-GFP vector in a non-human primate led to expression of GFP in the cornea without any discernible toxicity.
原发性开角型青光眼（POAG）和婴儿无晶状体性青光眼（IAG）分别是成人和婴儿视力丧失的重要原因。这两种病症均与小梁网（TM）纤维化有关，小梁网纤维化会减弱房水流出、导致眼压（IOP）升高和视网膜神经节细胞（RGC）死亡。转化生长因子β2（TGFβ2）与POAG和IAG中的上皮-间质转化（EMT）有关。TGFβ2的一个主要调节因子是核心蛋白聚糖，这是一种蛋白聚糖，其在青光眼患者中的表达降低。在本研究中，我们证明了使用腺相关病毒（AAV）载体AAV-IKV可高效感染小鼠前房，包括睫状体、角膜基质、TM和角膜神经。前房内注射表达组成型活性TGFβ2的AAV-IKV（AAV-IKV-TGFβ2）会导致小鼠TM纤维化，随后眼压升高和RGC死亡，模拟了POAG和IAG的病理生理特征。来自AAV-IKV载体（AAV-IKV-核心蛋白聚糖）的人核心蛋白聚糖的表达减轻了注射AAV-IKV-TGFβ2的小鼠的纤维化、眼压和RGC死亡，这表明AAV-IKV-核心蛋白聚糖可能分别作为POAG和IAG的一种治疗方法。最后，在非人类灵长类动物前房内注射AAV-IKV-GFP载体导致角膜中GFP表达，且无任何明显毒性。
