Preventing Photoreceptor Degeneration: The Role of ALG-2

描述：(申请者摘要)导致视网膜的眼部疾病 退化是人类遗传性失明的最常见原因。 其中最突出的是视网膜色素变性(RP)，每3000人中就有1人患病。 人民。RP由一组临床上和遗传上不同的 疾病。在超过50%的患者中，分子缺陷没有 意志坚定，而且没有有效的治疗方法。 大多数形式的视网膜变性涉及光感受器的凋亡。 细胞。视网膜变性的动物模型正在被用来测试不同的 修复遗传缺陷或阻止感光细胞的策略 细胞凋亡。尽管基因修复至少部分有效，但这一策略 受RP基因缺陷的异质性所限制。 因此，抢救感光细胞的方法是通过预防 细胞凋亡有望影响多种形式的疾病。 大量证据表明，钙离子在细胞凋亡中起着关键作用。 光感受器细胞，但其机制尚不清楚。ALG-2的研究报告 提供了一个更好地理解光感受器如何 细胞死亡和钙在这一过程中的作用。此外，一种基因疗法 靶向ALG-2的方法可能使不同的遗传病在 一种单一的时尚。 具体目的包括：1.传递ALG-2核酶或反义ALG-2构建物 通过腺相关病毒载体转导RD/RD/Tg+细胞 以干扰小鼠ALG-2的合成，阻断细胞凋亡。2. 证明从ALG-2序列衍生的多肽可以阻断 形成功能所需的ALG-2二聚体。向媒体传送 构建编码多肽的结构，扰乱功能，将加强对 损害ALG-2的合成，并提供另一种治疗方法。

DESCRIPTION: (Applicant's Abstract) Eye diseases leading to retinal degeneration are the most common cause of hereditary blindness in humans. Prominent among these is retinitis pigmentosa (RP) affecting about 1 in 3000 people. RP consists of a clinically and genetically heterogeneous group of diseases. In more than 50% of the patients the molecular defect has not been determined, and there is no effective treatment available. Most forms of retinal degeneration involve the apoptosis of photoreceptor cells. Animal models of retinal degeneration are being used to test different strategies to either repair the genetic defect or to prevent photoreceptor cell apoptosis. Although gene repair is at least partially effective, this strategy is limited by the heterogeneity of the genetic defects underlying RP. Therefore, the rescue of photoreceptor cells through the prevention of apoptosis holds the promise of effecting multiple forms of the disease. Ample evidence indicates that Ca++ plays a pivotal role in the apoptosis of photoreceptor cells, but the mechanisms are unclear. Studies of ALG-2 presented in this proposal provide an opportunity to better understand how photoreceptor cells die and the role of Ca in this process. In addition, a gene therapy approach targeting ALG-2 may allow disparate genetic diseases to be treated in a single fashion. Specific Aims Include: 1. Deliver ALG-2 ribozymes or antisense ALG-2 constructs via an adeno-associated virus vector to photoreceptor cells of the rd/rd/tg+ mouse in order to interfere with the synthesis of ALG-2 and block apoptosis. 2. Demonstrate that a peptide derived from the ALG-2 sequence can block the formation of an ALG-2 dimer required for function. Vector delivery of a construct encoding the peptide, disrupting function, will augment studies of impaired ALG-2 synthesis and offer an alternative therapeutic approach.