BDNF rs6265 and Response to Dopaminergic Therapy in PD

BDNF rs6265 和 PD 对多巴胺能治疗的反应

基本信息

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
项目类别：
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

项目摘要

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.

项目概要口服左旋多巴（L-dopa）已成为帕金森病（PD）的主要药物治疗方法。虽然治疗帕金森病的运动症状通常有效，但临床反应差异很大。我们争辩口服左旋多巴的功效可能受到受试者基因型的影响。事实上，对抗抑郁药的反应抗精神病药物治疗受到编码脑源性神经营养因子的 Bdnf 基因的影响（BDNF），特别是单核苷酸多态性（SNP）rs6265。 Bdnf SNP rs6265 相对而言常见，携带次要 Met66 等位基因的患病率为 40.6%（Val/Met 或主要/次要 = 35.4%，Met/Met 或次要/次要 = 5.2%，等位基因频率假设 Hardy-Weinberg）。 Met 等位基因的存在会造成干扰活性依赖性 BDNF 的包装和释放。我们最近对早期 PD 患者进行了基因分型，这些患者通过丘脑底核深部脑刺激 (DBS) 或优化药物治疗 (ODT、主要是口服左旋多巴）并参加了范德比尔特 DBS 早期 PD 临床试验（NCT00282152）。审判历时 24 个月。 DBS 的 15 个科目中的 5 个 (33%) 和 13 个科目中的 6 个 (46%) 和ODT治疗组分别携带Bdnf SNP rs6265的Met等位基因。在基线时，所有临床 Bdnf 基因型的终点在统计学上相似 (p > 0.05)。然而，ODT 中的 Met 等位基因携带者手臂在 18 个月 (p = 0.017) 和 24 个月 (p = 与 ODT 相比，12 个月 (p = 0.033) 和 24 个月 (p = 0.018) 时的 PDQ-39 分数显着更高具有最常见基因型 Val/Val 的受试者）。相比之下，没有观察到显着差异，因为在任何时间点接受 DBS 的受试者中任何临床指标的 Met 等位基因状态 (p > 0.05)。我们的发现队列结果表明，拥有 SNP rs6265 的 Met66 等位基因可赋予治疗特异性、在较长的治疗间隔内出现对多巴胺能帕金森病药物的次优反应。验证于有必要对更多接受多巴胺能药物治疗的早期帕金森病受试者进行队列研究，以确定我们是否这种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 的基因分型可作为治疗 PD 的精准医学方法通过医疗或手术干预以及对参加临床的受试者进行分层的方法进行更高效、更有效的临床试验设计。