Genetic Therapies for Autosomal Dominant Polycystic Kidney Disease

项目摘要/摘要 常染色体显性遗传性多囊肾病(ADPKD)是一种遗传性疾病 大约每千名活产儿中就有一名出生。ADPKD是一种进行性疾病，患者 在他们的一生中，他们的肾脏会出现充满液体的囊性病变，逐渐丧失肾功能， 可能会导致肾衰竭。ADPKD可由PKD1基因(编码多囊蛋白-1)的突变引起 或PKD2基因(编码多囊蛋白-2或PC-2)。PKD1突变约占78% ADPKD病例的比例。PKD2基因突变是其余病例的主要原因。 在ADPKD患者的一生中，发生在肾脏的囊肿的严重程度会增加。 病人。虽然年轻的患者可能没有症状，也可能没有意识到他们是遗传的 易患ADPKD的老年患者出现肾功能下降，其特征是总肾功能增加 肾体积(TKV)和肾小球滤过率(GFR)降低，最终可导致终末期肾脏 疾病(ESRD)。目前，ADPKD尚无治愈或长期治疗方法。 功能丧失的PKD1突变或PKD2突变的纯合子对胚胎是致命的。患者 都是杂合子，因为任何一个PKD基因的突变通常都会发展为ADPKD。正因为如此，ADPKD是一个 有可能通过基因疗法进行治疗。虽然这种疾病被定义为常染色体显性遗传， 最近的研究表明，ADPKD的发病机制可能是由于多囊蛋白-1或多囊蛋白-1的单倍体不足引起的 -2.因此，通过将多囊蛋白基因剂量恢复到野生型水平来治疗ADPKD是可能的。在……里面 隐性遗传病，部分蛋白质可能发生突变或丢失，使野生型蛋白质 患者体内的免疫原性。从理论上讲，这对ADPKD来说不是问题，因为患者的 免疫系统对正常的多囊蛋白耐受，这些蛋白是由未受损的 PKD1和PKD2基因的拷贝数。目前的项目提案将尝试将PKD1的表达恢复到野生状态 通过使用辅助依赖腺病毒(HD-Ad)载体和通过以下方式传递基因的cDNA来表达类型水平 使用腺相关病毒(AAV)和慢病毒(LV)载体递送较小的转录激活剂。

Project Summary/Abstract Autosomal dominant polycystic kidney disease (ADPKD) is an inherited genetic disease with a prevalence of approximately one in one thousand live births. ADPKD is a progressive disease in which patients develop fluid-filled cysts in their kidneys throughout their lifetimes, gradually lose kidney function, and which can end in kidney failure. ADPKD can be caused by mutations in either the PKD1 gene (encoding polycystin-1 or PC-1) or the PKD2 gene (encoding polycystin-2 or PC-2). PKD1 mutations account for approximately 78% of ADPKD cases. Mutations in PKD2 account for most of the remaining cases. The severity of the cysts that develop in the kidneys of an ADPKD patient increases over the lifetime of the patient. While younger patients may experience no symptoms and perhaps not realize they are genetically susceptible to ADPKD, older patients develop decreased renal function characterized by an increase in total kidney volume (TKV) and decreased glomerular filtration rate (GFR), which can culminate in end-stage renal disease (ESRD). There is currently no cure or long-term treatment for ADPKD. Homozygosity for loss of function PKD1 mutations or PKD2 mutations is embryonic lethal. Patients who are heterozygous for mutations in either PKD gene generally develop ADPKD. Because of this, ADPKD is a potential candidate for treatment by gene therapy. While the disease was defined as autosomal dominant, recent studies indicate that ADPKD pathogenesis may be caused by haploinsufficiency of either polycystin-1 or -2. It may therefore be possible to treat ADPKD by restoring polycystin gene dosage to a wild type level. In recessive genetic diseases, portions of proteins may be mutated or lost making the wild-type protein immunogenic in patients. In theory, this will not be a problem for ADPKD due to the fact that the patient's immune system is tolerized to normal polycystin proteins that are provided throughout life by the undamaged copies of PKD1 and PKD2 genes. The current project proposal will attempt to restore PKD1 expression to wild type levels by delivering cDNA of the gene using helper-dependent adenovirus (HD-Ad) vectors and by delivering smaller transcriptional activators using adeno-associated virus (AAV) and lentiviral (LV) vectors.