BDNF rs6265 and Response to Dopaminergic Therapy in PD

BDNF rs6265 和 PD 对多巴胺能治疗的反应

• 批准号: 9195187
• 负责人: JOHN L GOUDREAU
• 金额: $ 29.35万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9195187
• 关键词: Alleles; Antidepressive Agents; Antipsychotic Agents; Beck depression inventory; Brain; Brain-Derived Neurotrophic Factor; Clinical; Clinical Data; Clinical Trials; Clinical Trials Design; Code; Cognition; DNA; Deep Brain Stimulation; Deposition; Development; Disease; Enrollment; Exhibits; Gene Frequency; Genes; Genomic DNA; Genotype; Goals; Inferior; Institutes; Levodopa; Light; Longitudinal Studies; Medical; Medical Research; Memory; Methods; Minor; National Institute of Neurological Disorders and Stroke; Operative Surgical Procedures; Oral; Outcome; Outcome Measure; Parkinson Disease; Participant; Patient Care; Patients; Pharmaceutical Preparations; Pharmacotherapy; Population; Prevalence; Sampling; Single Nucleotide Polymorphism; Staging; Stratification; Structure of subthalamic nucleus; Sum; Surgical Management; Symptoms; Therapeutic; Time; United States National Institutes of Health; Validation; Variant; Work; arm; base; cohort; dopaminergic neuron; experience; genetic variant; meetings; methionylmethionine; motor symptom; novel; precision medicine; predicting response; primary outcome; prospective; response; secondary outcome; tool

Project Summary Oral levodopa (L-dopa) has become the mainstay pharmacotherapy for Parkinson's disease (PD). Although generally effective in treating the motor symptoms of PD, the clinical response is highly variable. We contend that the efficacy of oral L-dopa may be influenced by subject genotype. Indeed, response to antidepressant and antipsychotic pharmacotherapy is influenced by the Bdnf gene coding for brain-derived neurotrophic factor (BDNF), specifically the single nucleotide polymorphism (SNP) rs6265. The Bdnf SNP rs6265 is relatively common with a 40.6% prevalence of carrying the minor Met66 allele (Val/Met or Major/Minor = 35.4%, Met/Met or Minor/Minor = 5.2%, allelic frequency assuming Hardy-Weinberg). Presence of the Met allele disrupts packaging and release of activity-dependent BDNF. We recently genotyped early-stage PD patients who were treated with either deep brain stimulation of the subthalamic nucleus (DBS) or optimized drug therapy (ODT, predominantly oral L-dopa) and enrolled in the Vanderbilt DBS in Early Stage PD clinical trial (NCT00282152). The trial occurred over a period of 24 months. Five of 15 subjects (33%) and 6 of 13 subjects (46%) in the DBS and ODT treatment arms, respectively, carried the Met allele of the Bdnf SNP rs6265. At baseline, all clinical endpoints were statistically similar across Bdnf genotype (p > 0.05). However, Met allele carriers in the ODT arm exhibited significantly higher (worse) UPDRS scores ON medications at 18 (p = 0.017) and 24 months (p = 0.019) and significantly higher PDQ-39 scores at 12 (p = 0.033) and 24 months (p = 0.018, compared to ODT subjects with the most common genotype Val/Val). In contrast, no significant differences were observed due to Met allele status in subjects receiving DBS at any time point with any clinical metric (p > 0.05). Our discovery cohort results suggest that possession of the Met66 allele of the SNP rs6265 confers a treatment-specific, suboptimal response to dopaminergic PD medication that emerges over long treatment intervals. Validation in a larger cohort of early PD subjects treated with dopaminergic medication is warranted to establish whether our phenomenon is truly generalizable to the PD population as a whole. Our ultimate goal is to determine whether genotyping for the Bdnf SNP rs6265 could be used as a precision medicine approach for the treatment of PD by either medical or surgical interventions as well as a method for stratification of subjects enrolled in clinical trials for more efficient and effective clinical trial design.

项目摘要 口服左旋多巴（L-DOPA）已成为帕金森氏病（PD）的主要药物治疗。虽然 通常在治疗PD的运动症状时有效，临床反应高度可变。我们认为 口服L-DOPA的功效可能受主体基因型的影响。确实，对抗抑郁药的反应 抗精神病药物药物疗法受脑衍生的神经营养因子编码的BDNF基因的影响 （BDNF），特别是单核苷酸多态性（SNP）rs6265。 BDNF SNP RS6265相对 携带MET66等位基因的40.6％患病率（Val/Met或Major/Minor = 35.4％，Met/MET）常见于40.6％ 或假设Hardy-Weinberg）或次要/次要= 5.2％，等位基因频率）。 MET等位基因的存在破坏 活动依赖性BDNF的包装和释放。我们最近对早期PD患者进行了基因分型 用深脑核核（DBS）或优化的药物治疗（ODT， 主要是口服L-DOPA），并在早期PD临床试验（NCT00282152）中招募了Vanderbilt DBS。 试验发生在24个月的时间内。 DBS中的15个受试者中有5名（33％）和13个受试者中的6名（46％） 和ODT治疗臂分别带有BDNF SNP RS6265的MET等位基因。在基线时，所有临床 在BDNF基因型中，终点在统计学上相似（p> 0.05）。但是，在ODT中遇到了等位基因载体 ARM在18（p = 0.017）和24个月的药物上表现出明显更高（恶化）的UPDRS评分（P = 0.019）在12（p = 0.033）和24个月时的PDQ-39分数明显更高（与ODT相比，P = 0.018 具有最常见的基因型val/val的受试者。相反，由于 在任何临床指标（p> 0.05）的任何时间点接收DBS的受试者中遇到了等位基因状态。我们的发现 队列的结果表明，SNP RS6265的Met66等位基因拥有特定于治疗的特定于治疗的等位基因 对多巴胺能PD药物的次级反应在长时间的治疗间隔内出现。验证IN 有必要确定我们是否有多巴胺能药物治疗的早期PD受试者 现象确实可以推广到整个PD人群。我们的最终目标是确定是否 BDNF SNP RS6265的基因分型可以用作治疗PD的精确医学方法 通过医学或手术干预措施以及一种分层临床受试者的方法 试验，以进行更有效，有效的临床试验设计。