Research in Congenital Muscle Disease

先天性肌肉疾病的研究

• 批准号: 10013014
• 负责人: Katherine Meilleur
• 金额: $ 83.52万
• 依托单位: NATIONAL INSTITUTE OF NURSING RESEARCH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10013014
• 关键词: Affect; Antioxidants; Award; Biological; Biological Markers; Blood; CRISPR/Cas technology; Calcium; Calcium Channel; Calibration; Cardiopulmonary; Cells; Cerebral Palsy; Cessation of life; Child; Childhood; Clinic; Clinical; Clinical Investigator; Clinical Protocols; Clinical Research; Clinical Trials; Collaborations; Collagen Type VI; Contracture; Cultured Cells; Data; Data Analyses; Data Collection; Development; Disease; Drug Compounding; Drug Screening; Enrollment; Environment; Exercise stress test; FDA approved; Fatigue; Fishes; Focus Groups; Funding; Future; Genes; Genetic Variation; Goals; Home environment; Human; Image; Individual; Injury; Institution; Intervention; Interview; Laboratories; Laminin; Lead; Left; Libraries; Manuscripts; Measurement; Measures; Merosin; Methods; Modeling; Molecular; Motor; Movement; Mus; Muscle; Muscle Cells; Muscle Fibers; Muscle Weakness; Muscle hypotonia; Muscular Dystrophies; Myoblasts; Myopathy; National Institute of Child Health and Human Development; National Institute of Drug Abuse; National Institute of Neurological Disorders and Stroke; Natural History; Near-Infrared Spectroscopy; Neuromuscular Diseases; Outcome; Outcome Assessment; Outcome Measure; Oxidative Stress; Paralysed; Parents; Participant; Patient Outcomes Assessments; Patients; Peripheral Nervous System; Pharmaceutical Preparations; Pharmacologic Substance; Phenotype; Placebos; Positioning Attribute; Pre-Clinical Model; Preparation; Primary Cell Cultures; Protocols documentation; Proxy; Publishing; Quality of life; Questionnaires; Rare Diseases; Research; Research Personnel; Respiratory Insufficiency; Ryanodine Receptor Calcium Release Channel; Saliva; Sampling; Steroids; Stress; Swimming; Symptoms; Telephone; Testing; Time; Tissues; Translational Research; Travel; United States National Institutes of Health; Universities; Validation; Validity and Reliability; Variant; Vital capacity; Walking; Work; Zebrafish; antioxidant therapy; arm; artery occlusion; base; bench to bedside; burden of illness; cognitive interview; congenital muscle disorder; congenital muscular dystrophy; congenital myopathy; disorder subtype; drug testing; experience; experimental study; healthy volunteer; improved; induced pluripotent stem cell; innovation; insight; meetings; neurogenetics; neuromuscular; novel; novel therapeutics; programs; reduce symptoms; respiratory; response; scoliosis; side effect; symptom science; tenure track; theories; treatment arm; trial design; validation studies; variant of unknown significance

Since November 2016, I have been a Tenure Track Investigator and the Chief of the Neuromuscular Symptoms Unit in the Tissue Injury Branch of the NINR. Prior to that, I was an Assistant Clinical Investigator in the same branch, a position I started in September of 2012. Over the past year, I completed data collection on all three of my clinical protocols. Additionally, the lab component of my program has grown substantially. Data collection for the following three protocols was completed: 1) A study to develop the first proxy motor outcome assessment in young children with neuromuscular disease, entitled Development of a Proxy Motor Outcome Measure in Young Children with Neuromuscular Disease, was completed through Aims 1 and 2. The goal of this study is to use the new scale in future clinical trials to decrease parent stress related to travel to research centers for clinical trials and to improve ecological validity of motor function by utilizing parent insight in the home setting. Aim 1: My team completed all necessary qualitative phone interviews. After a meeting with the focus group of experts, items were developed for the new scale from these interviews. Then, the same focus group was queried via 2 rounds of emailing, using the Delphi method, to finalize the items. This year, we completed the cognitive interviews with parents to assess whether the items captured their intended meaning. The next step will be to finalize the items using qualitative data analysis and then validate them in a future protocol with different parent participants. 2) My team also completed enrollment of participants in a second protocol, The Calibration and Validation of the PROMIS and Neuro-QOL Questionnaires in Cerebral Palsy and Congenital Muscular Dystrophy. This data is currently being cleaned, and preliminary item response theory analyses have begun with Columbia University, the lead institution, to validate these two questionnaires for use in neuromuscular disease patients. 3) A third study, which received the Bench to Bedside Award in 2013, has also completed enrollment over the past year. This was the first clinical trial in the world in any congenital myopathy, including RYR1-related congenital myopathy (RYR1-RM). In this trial of antioxidant therapy in patients with RYR1-RM, 53 participants with this rare disease and 10 healthy volunteers were enrolled since March 2015. We have identified preliminary findings showing increased oxidative stress in humans with RYR1, which are consistent with findings in three preclinical models (mice, zebrafish, human myotubes). This finding is encouraging because the treatment in this trial is a known antioxidant. Data is now locked and under final analysis. We have also been analyzing 6-month natural history data describing from the first part of the study (prior to study drug/placebo administration). We have observed that subjects without treatment are stable over the 6-month time frame of the study, as expected. For example, we recently published a stable 6-month time course, as evaluated by the 6-minute walk test. This suggests that if the trial shows improvement in the treatment arm compared to the placebo arm, the improvement may be attributed to the antioxidant. We continue to analyze natural history data from additional outcomes such as cardiopulmonary exercise testing, arterial occlusion with near infrared spectroscopy, and forced vital capacity. The lab component of my research program has grown substantially, in large part due to my team receiving the Innovation Award last year in collaboration with Drs. Harvey (NIDA) and Bonnemann (NINDS). The aims of the award were to test drug compounds in primary cell culture and zebrafish models of RYR1-related myopathy using a novel calcium channel biomarker, which Dr. Harvey developed. This year, one of the lead FDA approved compounds identified through a drug screen with Dr. Henderson at NCATS showed improvement in our hands in both primary muscle cells from healthy donors and the RYR1 zebrafish model. We are repeating this experiment in the fish and in primary myoblasts from patients as well as testing additional compounds. Additional work in the lab includes the study of variants of uncertain significance in RYR1, which is a very large gene. Many participants in the recently completed NAC trial have genetic variations in the RYR1 gene that are classified as VUS due little or no clinical and/or functional information. My laboratory is setting up a calcium imaging workstation that will allow us to functionally characterize some of these variants, using the base-editing technology of CRISPR-Cas9 to introduce the variations into human iPSCs and HEK-293 cells. I also received the NIH Bench to Bedside award this year to perform a clinical trial of a novel compound over the next two years in collaboration with a pharmaceutical sponsor. Finally, I continue to be an Associate Investigator on an NINDS protocol entitled Clinical and Molecular Manifestations of Neuromuscular and Neurogenetic Disorders of Childhood. As part of this protocol, I took a 5-year project with me from NINDS when I left NINDS and started with NINR. The project was a 5-year natural history and clinical outcome measure validation study in two subtypes of congenital muscular dystrophy, Collagen VI-Related Myopathy and Laminin 2 Related Muscular Dystrophy. The 5-year data is now in final stages of manuscript preparation and describes sensitivity to change of the main outcome measures over the entire 5 years. Another manuscript describing the validation of the PedsQoL is also in final stages of preparation.

自2016年11月以来，我一直是终身跟踪研究员和NINR组织损伤分支神经肌肉症状部门的负责人。在此之前，我是同一分支的助理临床研究者，我于2012年9月开始担任该职位。 在过去的一年里，我完成了所有三个临床方案的数据收集。此外，我的项目的实验室部分也大幅增长。 完成了以下三个方案的数据收集： 1)通过目标1和2完成了一项研究，以开发第一个神经肌肉疾病幼儿代理运动结果评估，题为神经肌肉疾病幼儿代理运动结果测量的开发。 本研究的目的是在未来的临床试验中使用新的量表，以减少与前往研究中心进行临床试验相关的父母压力，并通过在家庭环境中利用父母的洞察力来提高运动功能的生态有效性。 目标1：我的团队完成了所有必要的定性电话访谈。 在与专家焦点小组举行会议后，根据这些访谈为新的量表制定了项目。然后，使用德尔菲方法，通过2轮电子邮件询问同一焦点组，以最终确定项目。今年，我们完成了对父母的认知访谈，以评估这些项目是否抓住了他们的意图。下一步将是使用定性数据分析最终确定项目，然后在未来的方案中与不同的父母参与者进行验证。 2)我的团队还完成了第二个方案的参与者招募，即脑性瘫痪和先天性肌营养不良的PROMIS和神经QOL量表的校准和验证。这些数据目前正在清理，初步的项目反应理论分析已经开始与哥伦比亚大学，牵头机构，以验证这两个问卷用于神经肌肉疾病患者。 3)第三项研究在2013年获得了“从板凳到床边奖”，在过去的一年里也完成了招募。这是世界上第一个针对任何先天性肌病的临床试验，包括RYR 1相关的先天性肌病（RYR 1-RM）。在这项针对RYR 1-RM患者的抗氧化治疗试验中，自2015年3月以来招募了53名患有这种罕见疾病的参与者和10名健康志愿者。我们已经确定了初步的研究结果，显示RYR 1在人类中的氧化应激增加，这与三种临床前模型（小鼠，斑马鱼，人类肌管）的研究结果一致。这一发现令人鼓舞，因为该试验中的治疗是一种已知的抗氧化剂。数据现已锁定，正在进行最终分析。 我们还分析了研究第一部分（研究药物/安慰剂给药前）描述的6个月自然史数据。我们观察到未接受治疗的受试者在研究的6个月时间范围内稳定，与预期一致。例如，我们最近发表了一个稳定的6个月时间过程，通过6分钟步行测试进行评估。这表明，如果试验显示治疗组与安慰剂组相比有所改善，则这种改善可能归因于抗氧化剂。我们继续分析其他结果的自然病史数据，如心肺运动试验、近红外光谱动脉闭塞和用力肺活量。 我的研究计划的实验室部分已经大幅增长，在很大程度上是由于我的团队获得了创新奖，去年与博士合作。该奖项的目的是使用Harvey博士开发的新型钙通道生物标志物在原代细胞培养和RYR 1相关肌病的斑马鱼模型中测试药物化合物。今年，通过与NCATS的亨德森博士进行的药物筛选，FDA批准的一种主要化合物在我们手中的健康供体和RYR 1斑马鱼模型的原代肌细胞中都有改善。 我们正在鱼和患者的原代成肌细胞中重复这项实验，并测试其他化合物。 实验室的其他工作包括研究RYR 1中不确定意义的变体，RYR 1是一个非常大的基因。最近完成的NAC试验中的许多参与者在RYR 1基因中具有遗传变异，由于很少或没有临床和/或功能信息而被归类为VUS。我的实验室正在建立一个钙成像工作站，这将使我们能够功能性地表征其中一些变体，使用CRISPR-Cas9的碱基编辑技术将这些变体引入人类iPSC和HEK-293细胞。 今年，我还获得了NIH Bench to Bedside奖，与制药赞助商合作，在未来两年内对一种新型化合物进行临床试验。 最后，我继续担任NINDS方案的助理研究员，该方案题为儿童神经肌肉和神经遗传性疾病的临床和分子表现。 作为该协议的一部分，当我离开NINDS并开始NINR时，我从NINDS开始了一个为期5年的项目。该项目是一项为期5年的自然史和临床结果测量验证研究，研究对象是两种亚型的先天性肌营养不良症，胶原VI相关肌病和层粘连蛋白2相关肌营养不良症。5年数据目前处于手稿准备的最后阶段，描述了整个5年内主要结局指标变化的敏感性。描述PedsQoL验证的另一份手稿也处于最后准备阶段。

项目成果

Review of RyR1 pathway and associated pathomechanisms.

• DOI: 10.1186/s40478-016-0392-6
• 发表时间: 2016-11-17
• 期刊: Acta neuropathologica communications
• 影响因子: 7.1
• 作者: Witherspoon JW;Meilleur KG
• 通讯作者: Meilleur KG

Ryanodine Receptor 1-Related Myopathies: Diagnostic and Therapeutic Approaches.

• DOI: 10.1007/s13311-018-00677-1
• 发表时间: 2018-10
• 期刊: Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics
• 作者: Lawal TA;Todd JJ;Meilleur KG
• 通讯作者: Meilleur KG