Disease Mechanisms in Best Disease

 描述(申请人提供)：最佳疾病，或卵黄状黄斑营养不良，是一种人类黄斑退行性疾病，其特征是进行性和不可逆转的中央视力丧失。这种疾病是由BEST1基因的一系列不同的(主要是错义的)突变引起的。目前，这种情况还没有治疗或治愈的方法。在这项多中心、多PI方案中，我们将使用来自已知BEST1突变患者的诱导多能干细胞(IPSCs)的RPE细胞来评估Best疾病的病理生理学。初步数据显示，这些细胞至少重现了患有Best病的人RPE细胞的部分表型。我们建议进行多学科实验，以更好地了解这种致盲疾病，其中包括：确定Best病患者来源的RPE细胞氯化物电导和细胞电生理的病理；确定不同突变之间以及Best病显性和隐性形式之间的病理关系；以及评估基因治疗/基因组编辑作为Best病的潜在治疗方法。这些重要的研究将为治疗这种疾病的新疗法铺平道路。

 DESCRIPTION (provided by applicant): Best disease, or vitelliform macular dystrophy, is a human macular degenerative disorder characterized by progressive and irreversible central vision loss. The disease is caused by a host of different (largely missense) mutations in the gene BEST1. Currently there is no treatment or cure for this condition. In this multicenter, multi-PI proposal, we will evaluate the pathophysiology of Best disease using RPE cells derived from induced pluripotent stem cells (iPSCs) from patients with known BEST1 mutations. Preliminary data show that these cells recapitulate at least some the phenotypes of human RPE cells with Best disease. We propose multidisciplinary experiments that will lead to a better understanding of this blinding disease, and that include: determining the pathology of Best disease patient-derived RPE cell chloride conductance and cellular electrophysiology; determining the pathological relationship between different mutations, and between dominant and recessive forms of Best disease; and evaluating gene therapy/genome editing as a potential treatment for Best disease. These important studies will pave the way for new treatments for this disorder.