Randomized, controlled pilot study of nicotinamide in polycystic kidney disease

烟酰胺治疗多囊肾病的随机对照试验研究

• 批准号: 8807460
• 负责人: Alan S Yu
• 金额: $ 18.88万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-10 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8807460
• 关键词: Adult; Affect; Animal Model; Autosomal Dominant Polycystic Kidney; Biological; Biological Markers; CCL2 gene; Clinical; Clinical Trials; Controlled Clinical Trials; Cyst; Deacetylase; Dilatation - action; Disease; Disease Progression; Dose; Double-Blind Method; Enrollment; Enzyme-Linked Immunosorbent Assay; Epithelial; Epithelial Cells; Goals; Growth; Hereditary Disease; Individual; Injury; Kidney; Kidney Failure; Magnetic Resonance Imaging; Measures; Modeling; Monitor; Morbidity - disease rate; Mus; Niacinamide; Outcome; Pain; Pathogenesis; Patients; Peripheral Blood Mononuclear Cell; Phosphorylation; Pilot Projects; Placebo Control; Play; Polycystic Kidney Diseases; Protein p53; Proteins; Questionnaires; Randomized; Renal tubule structure; Retinoblastoma Protein; Role; Safety; Testing; Tumor Suppressor Proteins; Urine; clinical effect; clinical efficacy; design; dietary supplements; effective therapy; mortality; mouse model; public health relevance; urinary

DESCRIPTION (provided by applicant): Autosomal dominant polycystic kidney disease (PKD) is a common genetic disorder that causes cystic dilatation of the renal tubules and progressive kidney failure. There is currently no effective treatment. Sirtuin 1 is upregulated in the kidney i murine models of PKD and acts as a deacetylase of retinoblastoma protein (Rb, leading to its phosphorylation) and p53, which together drive uncontrolled epithelial proliferation and cystogenesis. Inhibition of SIRT1 with nicotinamide, a component of vitamin B3, retards progression of PKD in mice. The overarching hypothesis of this proposal is that nicotinamide can inhibit SIRT1 deacetylase activity and safely and effectively retard cyst enlargement and disease progression in patients with PKD. Nicotinamide is a particularly attractive candidate for treatment of PKD because it has a well-established safety profile and, as a nutritional supplement, it does not require FDA approval. Thus, if it can be proven to be effective, PKD patients would have access to its use immediately. The goal of this pilot study is to provide initial estimates of the biological and clinical efficacy of nicotinamide in patients with PKD. The resulting estimates will provide critical information to determine if we can detect any hint of a beneficial clinical effect on cyst progression and provide a plausible range of effect sizes for th design of a subsequent, larger, confirmatory trial. We propose to enroll 30 adult subjects with PKD in a double blind, randomized, placebo-controlled clinical trial of nicotinamide, 30 mg/kg/d orally. Our specific aims are to estimate the effect of nicotinamide on: 1) SIRT1 deacetylase activity, and 2) biomarkers of PKD progression. To measure SIRT1 activity, peripheral blood mononuclear cells will be isolated and acetylated and total p53, and phosphorylated and total Rb will be measured by ELISA. To monitor PKD progression, MRI of the kidneys will be performed to determine total kidney volume, kidney pain will be measured with a questionnaire, and urine MCP1, KIM1, NGAL and other biomarkers will be measured. Positive outcomes in this pilot study would lay the groundwork for a larger confirmatory trial that could definitively tst whether nicotinamide ameliorates disease progression in individuals with PKD.

描述(申请人提供)：常染色体显性遗传性多囊肾病(PKD)是一种常见的遗传性疾病，可导致肾小管囊性扩张和进行性肾功能衰竭。目前还没有有效的治疗方法。Sirtuin 1在PKD小鼠肾脏模型中表达上调，作为视网膜母细胞瘤蛋白(Rb)的脱乙酰酶，导致其磷酸化，并共同推动失控的上皮细胞增殖和囊变。用维生素B3的一种成分烟酰胺抑制SIRT1可以延缓小鼠PKD的进展。这一建议的主要假设是烟酰胺可以抑制SIRT1脱乙酰酶活性，并安全有效地延缓PKD患者的囊肿胀大和疾病进展。烟酰胺是治疗PKD的一种特别有吸引力的候选药物，因为它具有良好的安全性，而且作为营养补充剂，它不需要FDA的批准。因此，如果它被证明是有效的，PKD患者将可以立即使用它。这项先导性研究的目的是对烟酰胺对PKD患者的生物学和临床疗效提供初步估计。这个 由此产生的评估将提供关键信息，以确定我们是否可以检测到任何有益于囊性病变的临床效果的迹象，并为随后的更大规模的验证性试验的设计提供一个可信的效果大小范围。我们建议招募30名成年PKD受试者参加烟酰胺30 mg/kg/d口服的双盲、随机、安慰剂对照临床试验。我们的具体目的是评估烟酰胺对以下方面的影响：1)SIRT1脱乙酰酶活性，2)PKD进展的生物标志物。为测定SIRT1活性，分离外周血单个核细胞，乙酰化和总P53，磷酸化和总Rb用ELISA法测定。为了监测PKD的进展，将进行肾脏磁共振成像以确定肾脏总体积，将通过问卷测量肾脏疼痛，并将测量尿液MCP1、KIM1、NGAL和其他生物标志物。这项初步研究的积极结果将为一项更大规模的验证性试验奠定基础，该试验可以确定烟酰胺是否改善了PKD患者的疾病进展。