Genetic Therapies for Autosomal Dominant Polycystic Kidney Disease

常染色体显性多囊肾病的基因治疗

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要常染色体显性多囊肾病（ADPKD）是一种遗传性疾病，患病率约为千分之一的活产儿。 ADPKD 是一种进行性疾病，患者在其一生中，肾脏中会出现充满液体的囊肿，逐渐丧失肾功能，并且可能会导致肾衰竭。 ADPKD 可由 PKD1 基因（编码多囊蛋白-1 或 PC-1）或 PKD2 基因（编码多囊蛋白-2 或 PC-2）。 PKD1突变约占78% ADPKD 病例数。剩下的病例大部分是由 PKD2 突变引起的。 ADPKD 患者肾脏中形成的囊肿的严重程度会随着患者的一生而增加病人。虽然年轻患者可能没有任何症状，并且可能没有意识到他们患有遗传性易患 ADPKD，老年患者肾功能下降，其特征是总肾功能增加肾体积（TKV）和肾小球滤过率（GFR）降低，最终导致终末期肾病疾病（终末期肾病）。目前 ADPKD 尚无治愈或长期治疗方法。功能丧失的纯合性 PKD1 突变或 PKD2 突变是胚胎致死的。患者谁 PKD 基因突变的杂合子通常会发展为 ADPKD。因此，ADPKD 是一种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 或多囊蛋白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至野生型水平来治疗 ADPKD 是可能的。在隐性遗传病，部分蛋白质可能发生突变或丢失，从而形成野生型蛋白质患者体内产生免疫原性。理论上，这对于 ADPKD 来说不会是问题，因为患者的病情免疫系统对正常的多囊蛋白具有耐受性，这些蛋白在整个生命过程中由未受损的细胞提供。 PKD1 和 PKD2 基因的拷贝。当前的项目提案将尝试将 PKD1 表达恢复为野生状态通过使用辅助依赖性腺病毒 (HD-Ad) 载体递送基因 cDNA 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。