Genetic Therapies for Autosomal Dominant Polycystic Kidney Disease

常染色体显性多囊肾病的基因治疗

• 批准号: 10025375
• 负责人: Jeffrey D Rubin
• 金额: $ 3.88万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-30 至 2021-06-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10025375
• 关键词: Adenovirus Vector; Adenoviruses; Affect; Alleles; Attenuated; Autosomal Dominant Polycystic Kidney; Biology; Cell Culture Techniques; Cells; Clustered Regularly Interspaced Short Palindromic Repeats; Complementary DNA; Cyst; DNA; Dependovirus; Disease; Embryo; End stage renal failure; FDA approved; Gene Activation; Gene Delivery; Gene Dosage; Gene Transduction Agent; Genes; Genetic Diseases; Genetic Transcription; Glomerular Filtration Rate; Hereditary Disease; Human; Immune system; Individual; Injections; Kidney; Kidney Failure; Lentivirus Vector; Life; Liquid substance; Live Birth; Messenger RNA; Methods; Modeling; Mus; Mutate; Mutation; PKD1 gene; PKD2 gene; PKD2 protein; Pathogenesis; Patients; Pharmaceutical Preparations; Prevalence; Progressive Disease; Proteins; Renal function; Severities; Symptoms; System; Technology; Testing; Time; Transcription Coactivator; Transgenic Mice; Translating; United States; Ureter; Work; adeno-associated viral vector; capsule; comparative efficacy; data tools; dosage; experience; gene product; gene repair; gene therapy; gutless adenoviral vector; immunogenic; in vivo; kidney cell; loss of function; mouse model; mutant; older patient; overexpression; polycystic kidney disease 1 protein; recessive genetic trait; reduce symptoms; repaired; small molecule; theories; tolvaptan; tool; vector; viral gene delivery

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.

项目摘要/摘要 常染色体显性多囊性肾脏疾病（ADPKD）是一种遗传性遗传疾病 大约一千分之一的活产率。 ADPKD是一种进行性疾病，患者 在一生中，在肾脏中发展液体囊肿，逐渐失去肾脏功能，并且 可以以肾衰竭结束。 ADPKD可能是由PKD1基因突变引起的（编码Polycystin-1 或PC-1）或PKD2基因（编码Polycystin-2或PC-2）。 PKD1突变约为78％ ADPKD案件。 PKD2中的突变占其余大多数情况。 在ADPKD患者的肾脏中发育的囊肿的严重程度在一生中增加 病人。虽然年轻的患者可能没有症状，但也许没有意识到自己是遗传的 容易受到ADPKD的影响，老年患者的肾功能降低，其特征是总数增加 肾脏体积（TKV）和肾小球滤过率（GFR）降低，该肾脏可以达到末期肾脏 疾病（ESRD）。目前尚无治愈或长期治疗ADPKD。 功能丧失PKD1突变或PKD2突变的纯合性是胚胎致死的。患者 对于两个PKD基因中的突变而言是杂合的，通常会发展为ADPKD。因此，ADPKD是 通过基因疗法治疗的潜在候选者。虽然该疾病被定义为常染色体显性症，但 最近的研究表明，ADPKD发病机理可能是由多囊这或多囊蛋白1或 -2。因此，可以通过将多囊基因剂量恢复到野生型水平来治疗ADPKD。在 隐性遗传疾病，蛋白质的一部分可能突变或丢失，使野生型蛋白 患者的免疫原性。从理论上讲，这不是ADPKD的问题，因为患者的 免疫系统被耐受性多囊蛋白蛋白耐受性耐受 PKD1和PKD2基因的副本。当前的项目建议将尝试将PKD1表达恢复为野生 通过使用辅助腺病毒（HD-AD）向量传递基因cDNA的类型水平，并通过 使用腺相关病毒（AAV）和慢病毒（LV）载体传递较小的转录激活剂。