In Vitro and In Vivo Efficacy of SYL040012, a Novel siRNA Compound for Treatment of Glaucoma
In Vitro and In Vivo Efficacy of SYL040012, a Novel siRNA Compound for Treatment of Glaucoma
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DOI：
10.1038/mt.2013.216
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发表时间：
2014-01-01
影响因子：
12.4
通讯作者：
Isabel Jimenez, Ana
中科院分区：
文献类型：
--
作者：
Martinez, Tamara;Victoria Gonzalez, Maria;Isabel Jimenez, Ana
青光眼是一种以视神经退化和不可逆的视野丧失为特征的进行性眼部综合征。眼压升高是青光眼的主要危险因素。IOP升高是房水（AH）合成和流出失衡的结果。阻断- 2肾上腺素能受体（ADRB2）可通过减少睫状体（CB） AH的产生来降低IOP。SYL040012是一种siRNA，旨在特异性沉默ADRB2，目前正在开发用于青光眼治疗。在这里，我们发现SYL040012特异性地降低ADRB2在细胞培养和眼组织中的表达。该化合物在滴眼液给药后不久进入眼睛，并迅速分布在眼睛前段的结构中。此外，SYL040012被CB细胞积极吸收，但不被全身器官（如肺）的细胞吸收，在这些器官中，抑制ADRB2可能会引起不良的副作用。此外，SYL040012在正常血压和高血压动物模型中降低IOP，效果似乎是持久的，局部和全身耐受性都非常好。
Glaucoma is a progressive ocular syndrome characterized by degeneration of the optic nerve and irreversible visual field loss. Elevated intraocular pressure (IOP) is the main risk factor for glaucoma. Increased IOP is the result of an imbalance between synthesis and outflow of aqueous humor (AH). Blocking beta 2 adrenergic receptor (ADRB2) has shown to reduce IOP by decreasing production of AH at the ciliary body (CB). SYL040012 is a siRNA designed to specifically silence ADRB2 currently under development for glaucoma treatment. Here, we show that SYL040012 specifically reduces ADRB2 expression in cell cultures and eye tissues. The compound enters the eye shortly after administration in eye drops and is rapidly distributed among structures of the anterior segment of the eye. In addition, SYL040012 is actively taken up by cells of the CB but not by cells of systemic organs such as the lungs, where inhibition of ADRB2 could cause undesirable side effects. Moreover, SYL040012 reduces IOP in normotensive and hypertensive animal models and the effect appears to be long lasting and extremely well tolerated both locally and systemically.