Gene therapy using p21WAF-1/CIP-1 to modulate wound healing after glaucoma trabeculectomy surgery in a primate model of ocular hypertension
Gene therapy using p21WAF-1/CIP-1 to modulate wound healing after glaucoma trabeculectomy surgery in a primate model of ocular hypertension
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DOI：
10.1038/sj.gt.3302253
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发表时间：
2004-06-01
期刊：
影响因子：
5.1
通讯作者：
Nickells, RW
中科院分区：
文献类型：
--
作者：
Heatley, G;Kiland, J;Nickells, RW
青光眼是一种与眼压升高相关的常见眼病。降低眼压是青光眼唯一可接受的治疗方法，可以减缓疾病的进展。滤过手术通过巩膜引入一个有保护的造口进入眼睛前房，使房水逸出，是有效降低IOP的最可靠方法。这种手术的成功受到造口疤痕的限制，因此这种手术通常伴随着抗代谢物的使用，如丝裂霉素C (MMC)，以阻止伤口愈合反应。虽然抗代谢物在预防瘢痕形成方面是有效的，但它也会产生不良的副作用，如由于细胞破坏而引起的低密度和组织变性。本研究提出了一种替代抗代谢物的方法，通过基因治疗引入人类p21基因（WAF-1/cip-1） （p21），从而导致周围细胞的细胞周期阻滞，而不是破坏它们。在这个过程中，用重组腺病毒将p21传递到眼压高的猴子眼睛。这些眼睛随后接受了滤过手术。结果显示，用p21治疗的眼睛在功能和组织学标准上都表现出开放的手术造口，并且没有出现与用MMC治疗的对照动物相同的任何副作用。
Glaucoma is a common eye disease associated with elevated intraocular pressure (IOP). Lowering IOP is the only acceptable therapy for glaucoma and slows progression of the disease. Filtration surgery, which introduces a guarded ostomy through the sclera into the anterior chamber of the eye to allow the escape of aqueous humor, is the most reliable method for effective IOP lowering. Success of this surgery is limited by scarring of the ostomy, so this procedure is often accompanied by the use of antimetabolites, such as mitomycin C (MMC), to block the wound healing response. Although effective in preventing scarring, antimetabolites also yield unwanted side effects, such as hypotony and tissue degeneration due to cellular destruction. This study presents an alternative to antimetabolites by using gene therapy to introduce the human gene for p21(WAF-1/cip-1) (p21) to cause cell cycle arrest of surrounding cells rather than their destruction. In this procedure, p21 was delivered using a recombinant adenovirus to ocular hypertensive monkey eyes. These eyes then underwent filtration surgery. Results show that eyes treated with p21 exhibited open surgical ostomies by both functional and histological criteria, and did not display any side effects seen in control animals that were treated with MMC.