P23H Rhodopsin Mutant Swine Model of Reninitis Pigmentosa

描述（由申请人提供）：视网膜变性是西方世界失明的主要原因，色素性视网膜炎（RP）是成人生活中遗传性视力丧失的最常见原因。尽管RP的遗传基础已经得到了很好的探索，但由于这组疾病的突变异质性，将这种见解转化为成功的基因治疗一直受到阻碍。除了基因治疗，我们和其他人正在利用干细胞治疗、视网膜假体、生物工程和药理学的最新进展探索替代治疗方法。总之，这些都为RP成功的神经重建带来了希望。在美国密苏里-哥伦比亚大学国家养猪资源研究中心，采用单细胞核移植的方法，用NIH cc单倍型携带突变体Pro23His （P23H）人视紫红质转基因，培育了6只雄性迷你猪。我们的初步数据表明，这些创始人表现出RP的电生理表型特征。由于P23H是人类最常见的常染色体显性突变，我们建议建立一个群体，并对这种新型光感受器变性迷你猪模型的三个独立转基因系进行表征。虽然在这个应用程序的时间框架之外，在不久的将来，它可以被我们和视觉界用于新的治疗干预。

DESCRIPTION (provided by applicant): Retinal degeneration is a leading cause of blindness in the Western world and retinitis pigmentosa (RP) is the most common cause of hereditary visual loss in adult life. Although the genetic basis of RP has been well explored, the translation of this insight into successful genetic therapy has been hindered because of the mutational heterogeneity that underlies this group of diseases. In addition to gene therapy, we and others are exploring alternative therapeutic approaches employing recent advances in stem cell therapy, as well as the retinal prosthesis, bioengineering and pharmacology. Together these hold the promise for successful neural reconstitution in RP. Using the method of single cell nuclear transfer, we produced six male miniature swine (mini-swine) on a NIH cc haplotype carrying a mutant Pro23His (P23H) human rhodopsin transgene at the National Swine Resource Research Center at the University of Missouri-Columbia. Our preliminary data show that these founders exhibited an electrophysiologic phenotype characteristic of RP. Since P23H is the most common autosomal dominant mutation responsible for RP in man, we propose to establish a colony and characterize three independent transgenic lines of this new mini-swine model of photoreceptor degeneration. While outside the time frame of this application, in the near future it can be used by us and the vision community for novel therapeutic interventions. PUBLIC HEALTH RELEVANCE: Using the method of single cell nuclear transfer, we produced six male miniature swine (mini-swine) on a NIH cc haplotype carrying a mutant Pro23His (P23H) human rhodopsin transgene at the National Swine Resource Research Center at the University of Missouri-Columbia. Our preliminary data show that these founders exhibited an electrophysiologic phenotype characteristic of retinitis pigmentosa (RP). Since P23H is the most common autosomal dominant mutation responsible for RP in humans, we propose to establish a colony and characterize three independent transgenic lines of this new mini-swine model of photoreceptor degeneration for future therapeutic interventions.