Genetic Therapies for Autosomal Dominant Polycystic Kidney Disease

项目总结/摘要 常染色体显性多囊肾病（ADPKD）是一种遗传性遗传病， 患病率约为千分之一。ADPKD是一种进行性疾病， 在他们的一生中，肾脏会出现充满液体的囊肿，逐渐失去肾功能， 会导致肾衰竭ADPKD可由PKD1基因（编码多囊蛋白-1）突变引起 或PC-1）或PKD 2基因（编码多囊蛋白-2或PC-2）。PKD1突变约占78% ADPKD病例。PKD2突变占其余病例的大部分。 在ADPKD患者的肾脏中发展的囊肿的严重程度在其一生中增加。 病人虽然年轻的患者可能没有症状，也许没有意识到他们是遗传性的， 易患ADPKD，老年患者出现肾功能下降，其特征是总 肾体积（TKV）和肾小球滤过率（GFR）降低，最终可导致终末期肾功能衰竭。 疾病（ESRD）。目前还没有治愈或长期治疗ADPKD的方法。 PKD1突变或PKD2突变的功能丧失的纯合性是胚胎致死性的。的患者 对于任一PKD基因中的突变为杂合子的人通常发展为ADPKD。因此，ADPKD是一种 基因治疗的潜在候选者。虽然该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多囊蛋白-1或 -2.因此，可能通过将多囊蛋白基因剂量恢复到野生型水平来治疗ADPKD。在 在隐性遗传疾病中，蛋白质的一部分可能突变或丢失，从而产生野生型蛋白质。 免疫原性。理论上，这对ADPKD来说不是问题，因为患者的 免疫系统耐受正常的多囊蛋白，这些蛋白在整个生命过程中由未受损的 PKD 1和PKD 2基因的拷贝。目前的项目建议将试图恢复PKD 1表达野生 通过使用辅助依赖性腺病毒（HD-Ad）载体递送基因的cDNA和通过 使用腺相关病毒（AAV）和慢病毒（LV）载体递送较小的转录激活因子。

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.