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Regeneration of pigment cells and basic and clinical study for treatment of age-related macular degeneration

色素细胞再生及治疗年龄相关性黄斑变性的基础与临床研究

基本信息

批准号：
06404061
负责人：
TAMAI Makoto
金额：
$ 16.26万
依托单位：
Tohoku University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
1994
资助国家：
日本
起止时间：
1994 至 1996
项目状态：
已结题

项目摘要

Age-related macular degeneration is one of the most serious diseases in the elderly people. Even if submacular and choroidal neovascular membrane could be surgically excised, severe damage or evacuation of retinal pigment epithelium are innevitable in the operated area. Pigmentary dystrophy is also a devastating hereditary eye disease with severe visual disturbance. Up to now, we have no effective treatments for both of them. We have conducted basic experiments of retinal pigment epithelium (RPE) culture, their transplantation to subretinal space of animals, especially, the royal college of surgeon's (RCS) rat, a model of hereditary retinal degeneration and observed their rescue effects for photoreceptor cell death.1) With the retinal dystrophic RCS rat, we transplanted RPE from Long Evans rat, human, and bovine and could observe the retardation of the photoreceptor cell death.2) RPE cells from eye bank eye or fetus eye were easily obtained and cultured. They were transplanted as fresh … More or cultured with primary or multiple passage. We also tried cryopreservation of these cells up to 3 months. Their characteristics were well preserved at least in the viewpoints of several gene expression. In the future, if we could keep these RPE cells in deep-freezed condition, we could use them clinically in appropriate time and number of cells for patients just as "RPE bank".3) In experimental animals, they did not show any immunological reaction. But transplantation of human RPE cells with collagen sheet into the anterior chamber in rabbit showed difinite reaction like suppression of electroretinogram and macrophage infiltration in the subretinal space, not only in the operated but contralateral non-operated eye. These results suggest we must be cautious in clinical application of heterogenous RPE transplantation. It was an interesting observation that the expression of MHC class II cells were observed in the course of photoreceptor cell degeneration in the RCS rat but supressed if they were rescued by the transplantation of human cultured RPE in these animals.4) If we cpnsider clinical application of this technique, it is natural the autograft is much better than the xeno-or allograft. We tried to use the iris pigment epithelium (IPE) for transplantation because they were neural origin, pigmented cells and easily and enough amount of them were obtained by peripheral iridectomy. IPE of rat were cultured the vector (pCNX2) with cDNA of rat bFGF were transfected and transplanted into the subretinal space of RCS rat. These transfected cells expressed strong mRNA of bFGF.The photoreceptors were well preserved and no immunological reaction. If we could use IPE,either wild or modified with molecular technique, they were applicable for patients, much safer and easier. Less

视网膜相关性黄斑变性是老年人最严重的疾病之一。即使手术切除黄斑下和脉络膜新生血管膜，手术区域内的视网膜色素上皮也不可避免地会有严重的损伤或清除。色素营养不良也是一种严重的视力障碍的毁灭性遗传性眼病。到目前为止，我们对这两种疾病都没有有效的治疗方法。本研究进行了视网膜色素上皮细胞（retinal pigment epithelium，RPE）培养、移植到动物视网膜下腔的基础实验，特别是以遗传性视网膜变性的动物模型皇家外科学院（Royal College of Surgeon's，RCS）大鼠为研究对象，观察了RPE对视网膜光感受器细胞死亡的挽救作用。2）眼库眼和胎眼的RPE细胞易于获得和培养。它们被移植到 ...更多信息或者用原代或多次传代培养。我们还尝试将这些细胞冷冻保存长达3个月。它们的特征至少在几个基因表达的观点上得到了很好的保留。将来，如果能将这些RPE细胞深冻保存，就可以在适当的时间和数量将其作为“RPE库”用于临床。3）在实验动物中，它们没有表现出任何免疫反应。但将人RPE细胞与胶原膜一起移植到兔前房内，不仅在手术眼，而且在对侧非手术眼，都出现了视网膜电图抑制和视网膜下腔巨噬细胞浸润等明显反应。提示临床应用异种RPE移植时应慎重。在RCS大鼠视网膜光感受器细胞变性过程中，观察到MHC Ⅱ类细胞的表达，但在这些动物中，如果通过移植人培养的RPE来拯救它们，则MHC Ⅱ类细胞的表达受到抑制。4）如果我们考虑到这种技术的临床应用，自体移植物自然比异种或同种异体移植物好得多。由于虹膜色素上皮细胞是神经源性的色素细胞，且容易通过周边虹膜切除术获得足够数量的色素细胞，因此我们尝试将其用于移植。培养大鼠IPE，将大鼠bFGF的cDNA载体（pCNX 2）转染RCS大鼠视网膜下腔。这些转染细胞表达强碱性成纤维细胞生长因子mRNA，光感受器保存良好，无免疫反应。如果我们能使用野生型或分子技术修饰的IPE，它们将适用于患者，更安全，更容易。少