Adeno-associated virus mediated delivery of a non-membrane targeted human soluble CD59 attenuates some aspects of diabetic retinopathy in mice.
Adeno-associated virus mediated delivery of a non-membrane targeted human soluble CD59 attenuates some aspects of diabetic retinopathy in mice.
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腺相关病毒介导的非膜靶标CD59的递送减弱了小鼠糖尿病性视网膜病的某些方面。
DOI：
10.1371/journal.pone.0079661
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Kumar-Singh R
中科院分区：
文献类型：
--
作者：
Adhi M;Cashman SM;Kumar-Singh R
糖尿病视网膜病变是导致工作成年人视觉功能障碍的主要原因，并归因于视网膜血管和神经细胞损伤。最近的研究已经描述了在糖尿病视网膜病变患者的视网膜中以及在该疾病的动物模型中膜攻击复合物（MAC）的水平升高和膜相关补体调节剂（包括CD 55和CD 59）的水平降低。我们之前已经描述了可溶性膜非依赖性形式的CD 59（sCD 59）的开发，当使用腺相关病毒载体（AAV 2/8-sCD 59）通过基因治疗方法递送至小鼠眼睛时，其可以阻断MAC沉积和脉络膜新血管形成。在这里，我们研究了链脲佐菌素（STZ）诱导的糖尿病后，AAV 2/8-sCD 59介导的MAC沉积的衰减和随后的补体介导的对小鼠视网膜的损伤。我们观察到，相对于注射阴性对照病毒的糖尿病眼睛，预先注射AAV 2/8-sCD 59的糖尿病眼睛中视网膜血管渗漏减少60%。注射AAV 2/8-sCD 59的眼睛也表现出对视网膜血管的非灌注的保护。此外，相对于用对照病毒预注射的糖尿病眼睛，在用AAV 2/8-sCD 59预注射的糖尿病眼睛中记录了视网膜神经节细胞凋亡减少200%和MAC沉积减少40%。这是第一项研究，其特征在于在糖尿病视网膜病变模型中靶向MAC的病毒基因治疗干预。使用AAV 2/8-sCD 59作为晚期糖尿病视网膜病变的潜在疗法值得进一步探索。
Diabetic retinopathy is the leading cause of visual dysfunction in working adults and is attributed to retinal vascular and neural cell damage. Recent studies have described elevated levels of membrane attack complex (MAC) and reduced levels of membrane associated complement regulators including CD55 and CD59 in the retina of diabetic retinopathy patients as well as in animal models of this disease. We have previously described the development of a soluble membrane-independent form of CD59 (sCD59) that when delivered via a gene therapy approach using an adeno-associated virus vector (AAV2/8-sCD59) to the eyes of mice, can block MAC deposition and choroidal neovascularization. Here, we examine AAV2/8-sCD59 mediated attenuation of MAC deposition and ensuing complement mediated damage to the retina of mice following streptozotocin (STZ) induced diabetes. We observed a 60% reduction in leakage of retinal blood vessels in diabetic eyes pre-injected with AAV2/8-sCD59 relative to negative control virus injected diabetic eyes. AAV2/8-sCD59 injected eyes also exhibited protection from non-perfusion of retinal blood vessels. In addition, a 200% reduction in retinal ganglion cell apoptosis and a 40% reduction in MAC deposition were documented in diabetic eyes pre-injected with AAV2/8-sCD59 relative to diabetic eyes pre-injected with the control virus. This is the first study characterizing a viral gene therapy intervention that targets MAC in a model of diabetic retinopathy. Use of AAV2/8-sCD59 warrants further exploration as a potential therapy for advanced stages of diabetic retinopathy.
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影响因子：
7.7
作者：
Lieth, E;Barber, AJ;Strother, JM
通讯作者：
Strother, JM
影响因子：
4.4
作者：
Bora, Nalini S.;Kaliappan, Sankaranarayanan;Bora, Puran S.
通讯作者：
Bora, Puran S.
影响因子：
4.4
作者：
Feit-Leichman, RA;Kinouchi, R;Chen, DF
通讯作者：
Chen, DF
影响因子：
4.4
作者：
Bossi, F;Fischetti, F;Tedesco, F
通讯作者：
Tedesco, F
从体内腺病毒表达的可溶性CD59是对鼠肝血管内皮的补体沉积的有效抑制剂。
影响因子：
3.7
作者：
Gandhi J;Cashman SM;Kumar-Singh R
通讯作者：
Kumar-Singh R