Studies Of Hereditary Neurological Disease: Clinical Trials

该研究项目的目的是为遗传性神经系统疾病开发安全有效的治疗方法。过去一年的具体研究成果包括：（1）继续进行脊髓和延髓肌萎缩症（SBMA）运动的随机对照试验，（2）继续进行骨骼和心脏成像评估方案，并进行寡核苷酸治疗杜氏肌营养不良症（DMD）的试验。 SBMA是一种X连锁的成人运动神经元疾病。我们即将完成一项研究，以检查SBMA患者运动的安全性和有效性。我们的目标是招募80名基因确诊的SBMA男性。这是一项随机、评价者盲法试验，每个运动组有25名受试者，在知情同意后，受试者接受初步的医疗和身体评估，然后在NIH进行为期两天的门诊访视，进行一系列神经系统检查和血液检查。受试者提供血液工作，用于分析激素水平和评估任何潜在的肌肉损伤。在他们访问的第二天，受试者被随机化并被教导一系列功能性或伸展运动，他们分别作为研究和对照组的一部分参与。在对NIH进行基线访视后，在整个研究期间通过电话联系和其他措施（包括视频记录）监测受试者的进展和依从性。受试者在12周结束时返回NIH，此时重复物理和实验室测试。使用的主要结局指标是成人肌病评估工具。次要结局指标为QMA、定时起身和行走测试、生活质量测量（SF-36 v2）、不良事件问卷、平衡的计算机动态姿势描记评估、运动努力的加速度计测量和渐进式身高坐立测试。正在评估可能受运动影响的几种探索性生物标志物，包括胰岛素样生长因子-1（IGF-1）、IGF结合蛋白3、睾酮、生长激素和肌酸激酶。贝克抑郁量表测试也被用来确定受试者的情绪是否受到锻炼的影响。 DMD是最常见的遗传性致死性儿童疾病。反义寡核苷酸诱导的外显子跳跃是一种有前途的治疗DMD的策略，目前正在临床试验中探索。磁共振成像（MRI）和超声成像方法对营养不良肌肉中的关键过程（如水肿和脂肪浸润）敏感，因此可以作为疾病进展和治疗反应的生物标志物。我们正在完成一项研究方案，以探索这些成像生物标志物用于评估寡核苷酸GSK 2402968在患有DMD的非卧床男孩中的作用的潜力。主要目的是评估接受GSK 2402968或安慰剂治疗的非卧床DMD男孩中反映下肢脂肪和水肿的骨骼肌结构MRI测量的纵向变化。我们招募了9名患有DMD的非卧床男孩。招募了20名年龄范围匹配的健康志愿者/对照男孩，以获得成像研究的比较数据。这项在NIH进行的骨骼肌、心脏和膈肌成像的前瞻性研究，提供给参与一项在患有DMD的非卧床受试者中进行的II期、双盲、探索性平行组、安慰剂对照临床研究的受试者，该DMD是由突变引起的，可以通过GSK 2402968诱导的外显子51跳跃来纠正。受试者在母研究的筛选期与一名家庭成员一起前往NIH进行MRI和超声评估，此外，如果随机化，则在母研究的以下时间点：设盲治疗期的第12周和第24周;最后，治疗后24周完成后（第48周）。如果未随机化，受试者在母研究的筛选期接受一次性评价。还从健康男孩中获得了数据进行比较，以探索DMD非卧床男孩的MRI和超声病理学指标。该研究的主要结局指标是接受GSK 2402968或安慰剂的DMD男孩中下肢骨骼肌脂肪的MRI检测变化。次要结局指标包括接受GSK 2402968或安慰剂治疗的DMD男孩在第12、24和48周时以下结局指标较基线的变化：通过骨骼肌MRI T1成像评估的相对肌肉脂肪/水、通过T2成像评估的肌肉水肿以及通过心脏MRI测量的心脏功能和心肌脂肪和水肿。探索性结局指标包括通过扩散MRI评估的肌肉水扩散率的变化;运动对腿部肌肉中选定MRI指标的影响，肌肉超声监测骨骼肌体积、回声和刚度的变化;以及膈肌运动的MRI评估。

The purpose of this research program is to develop safe and effective treatments for hereditary neurological disorders. Specific research accomplishments in the past year include the following: (1) continuation of a randomized, controlled trial of exercise in spinal and bulbar muscular atrophy (SBMA), (2) continuation of a protocol for evaluation of skeletal and cardiac imaging with a trial of oligonucleotide therapy in Duchenne muscular dystrophy (DMD). SBMA is an X-linked, adult onset motor neuron disease. We are nearing completion of a study to examine the safety and efficacy of exercise in SBMA patients. We aim to enroll 80 men with genetically confirmed SBMA. This is a randomized, evaluator blinded, trial with 25 subjects in each exercise arm. Following informed consent, the subjects undergo initial medical and physical evaluations followed by a series of neurological tests and blood work over a two-day outpatient visit at the NIH. The subjects provide blood work for analysis of hormonal levels and assessment of any potential muscle damage. On the second day of their visit, the subjects are randomized and taught a series of either functional or stretching exercises that they engage in as part of the study and control arms, respectively. Following the baseline visit to NIH, the subjects are monitored throughout the study with telephone contacts and other measures including video recording to monitor their progress and compliance. The subjects return to the NIH at the end of a 12 week period at which time the physical and laboratory testing is repeated. The primary outcome measure used is the Adult Myopathy Assessment Tool . Secondary outcome measures are QMA, the Timed Up and Go test, a quality of life measure (SF-36v2), adverse event questionnaires, a Computerized Dynamic Posturography assessment of balance, accelerometer measurements of exercise effort, and progressive height sit-to-stand testing. Several exploratory biomarkers that may be affected by exercise are being evaluated, including insulin-like growth factor-1 (IGF-1), IGF binding protein 3, testosterone, growth hormone, and creatine kinase. Beck Depression Inventory testing is also being used to determine if the subjects mood is affected by exercise. DMD is the most frequent inherited fatal childhood disease. Antisense oligonucleotide-induced exon skipping is a promising therapeutic strategy for DMD that is currently being explored in clinical trials. Magnetic resonance imaging (MRI) and ultrasound imaging methods are sensitive to key processes in dystrophic muscle such as edema and fat infiltration and therefore could serve as a biomarker of disease progression and therapeutic response. We are completing a study protocol to explore the potential of these imaging biomarkers for assessing the effects of the oligonucleotide GSK2402968 in ambulatory boys with DMD. The primary objective is to assess longitudinal changes in skeletal muscle structural MRI measures reflecting fat and edema in the lower extremities in ambulatory boys with DMD receiving GSK2402968 or placebo. We have enrolled 9 ambulatory boys with DMD. 20 healthy volunteer/control boys matched for the age-range have been recruited to obtain comparative data for the imaging studies. This prospective study of skeletal muscle, cardiac, and diaphragm imaging at the NIH was offered to subjects participating in a phase 2, double blind, exploratory parallel-group, placebo-controlled clinical study in ambulatory subjects with DMD resulting from a mutation that can be corrected by exon 51 skipping induced by GSK2402968. Subjects traveled with a family member to the NIH for MRI and ultrasound assessments during the screening phase of the parent study and additionally, if randomized, then at the following time points in the parent study: at 12 weeks, and 24 weeks during the blinded treatment period; and finally, after completion of 24 weekpost-treatment phase (at 48 weeks). If not randomized, the subjects had a one-time evaluation during the screening phase of the parent study. Data has also been obtained from healthy boys for comparisons to allow exploration of MRI and ultrasound measures specific to pathology in the ambulatory boys with DMD. The primary outcome measure for the study is MRI-detected change in skeletal muscle fat in the lower extremities from baseline in boys with DMD receiving GSK2402968 or placebo. Secondary outcome measures include changes in the following outcome measures at 12, 24, and 48 weeks from baseline in boys with DMD receiving GSK2402968 or placebo: relative muscle fat/water assessed by skeletal muscle MRI T1 imaging, muscle edema assessed by T2 imaging, and cardiac function and myocardial fat and edema as measured by cardiac MRI. Exploratory outcome measures include changes in muscle water diffusivity as assessed by diffusion MRI; the effects of exercise on selected MRI measures in leg muscles, muscle ultrasound to monitor changes in skeletal muscle volume, echogenicity, and stiffness; and MRI assessment of diaphragm motion.