Randomized, controlled pilot study of nicotinamide in polycystic kidney disease

烟酰胺治疗多囊肾病的随机对照初步研究

• 批准号: 9136856
• 负责人: Alan S Yu
• 金额: $ 22.65万
• 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 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9136856
• 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; Health; Hereditary Disease; Individual; Injury; Kidney; Kidney Failure; LCN2 gene; Magnetic Resonance Imaging; Measures; 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; TP53 gene; Testing; Tumor Suppressor Proteins; Urine; clinical effect; clinical efficacy; design; dietary supplements; effective therapy; mortality; mouse model; 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（由申请人提供）：常染色体显性多囊性肾脏疾病（PKD）是一种常见的遗传疾病，可引起肾小管囊性扩张和进行性肾脏衰竭。目前没有有效的治疗方法。 Sirtuin 1在PKD的肾脏I鼠模型中被上调，并充当视网膜细胞瘤蛋白的脱乙酰基酶（RB，导致其磷酸化）和p53，它们共同驱动了不受控制的上皮增殖和囊肿。用烟酰胺（维生素B3的成分）抑制SIRT1抑制小鼠PKD的进展。该提案的总体假设是烟酰胺可以抑制SIRT1脱乙酰基酶活性，并安全有效地阻碍PKD患者的囊肿增大和疾病进展。烟酰胺是PKD治疗的特别有吸引力的候选人，因为它具有完善的安全性，并且作为营养补充剂，它不需要FDA批准。因此，如果证明它是有效的，PKD患者将立即使用其使用。 这项初步研究的目的是提供烟酰胺对PKD患者的生物学和临床功效的初步估计。这 最终的估计值将提供关键信息，以确定我们是否可以检测到对囊肿进展的有益临床作用的任何暗示，并为随后的，更大的确认性试验的设计提供了合理的效应范围。我们建议将30名成人受试者纳入烟酰胺的双盲，随机，安慰剂对照的临床试验，30 mg/kg/d口服。我们的具体目的是估计烟酰胺对：1）SIRT1脱乙酰基酶活性，以及​​2）PKD进展的生物标志物。为了测量SIRT1活性，将分离出外周血单核细胞并乙酰化和总p53，并通过ELISA测量磷酸化和总RB。为了监测PKD的进展，将执行肾脏的MRI以确定总肾脏体积，将通过问卷调查测量肾脏疼痛，将测量尿液MCP1，KIM1，NGAL和其他生物标志物。 这项试验研究的积极结果将为更大的确认试验奠定基础，该试验可能会确定烟酰胺是否可以改善PKD患者的疾病进展。