Accelerate Clinical Trials in CMT (ACTCMT) Study

Charcot Marie Tooth病(CMT)是一种罕见的遗传性周围神经病。CMT1a占所有CMT的50%，是由17号染色体上1.4MB的重复导致外周髓鞘蛋白22kD(PMP22)过表达所致。CMT1a的特征是进行性虚弱、失衡、感觉丧失和步态异常。多种有希望的候选疗法将在3-5年内准备好用于人类临床试验，包括减少PMP22表达并纠正啮齿动物模型表型的反义寡核苷酸疗法。我们在遗传性神经病联盟罕见疾病临床研究网络(INC RDCRN)中定义了CMT1A的自然历史，并开发了临床结果评估、患者报告的结果和CMT儿童功能量表(CMTPedS)，以显示CMT1A的反应性。对于CMT1A试验，必须紧急填补结果测量中的一些关键空白，包括针对成人的经过验证的功能结果测量(FDA指南确定其功能是药物批准的关键临床终点)，以及经过验证的疾病进展生物标记物。这项名为“加速CMT临床试验(ACTCMT)”的研究通过利用INC RDCRN的专业知识和多中心基础设施对患有CMT1A的成年人进行功能结果(CMT-FOM)以及运动和感觉生物标记物的多中心验证，从而解决了这些关键差距。这项U01提案的目的包括以下几点：(1)CMT-FOM作为成人CMT1A患者的反应性结局测量工具的有效性。CMT-FOM具有很高的患者相关性，因为它结合了对功能限制有影响的患者视角。(2)用于早期CMT1A试验的定量三点Dixon MRI对肌肉内脂肪堆积作为关键腿部肌肉疾病进展的生物标记物的验证，该生物标记物用于足下垂和残疾。(3)验证了一种非侵入性和无痛的方法来确定皮肤中触觉小体(一种重要的感觉受体)的密度作为CMT1A试验的感觉生物标记物。D.Herrmann博士(U·罗切斯特)将担任总PI。赫尔曼博士开发了CMT-FOM，并将与M.Shy博士(Inc.董事，爱荷华州大学)和J.Burns博士(悉尼大学，开发了CMTPedS)共同领导AIM 1。赫尔曼博士率先将迈斯纳小体的非侵入性成像用于周围神经病，他还将领导AIM 3。来自该大学的M.Reilly博士和J.Thornton博士(物理学家)。将领导AIM 2；他们率先在CMT1A中使用肌肉磁共振作为生物标记物。S.Scherer博士(宾夕法尼亚大学)和D.Pareyson博士(米兰C.Besta神经病学研究所)领导大型CMT诊所，并在评估CMT1A患者方面拥有丰富的经验。这项研究汇集了具有长期成功合作历史的CMT研究人员领导小组，应该会产生有效的CMT-FOM和将产生重大影响的生物标记物，因为这将加速CMT1A的早期和晚期临床试验，目前还没有可用的疾病修改治疗方法。

Charcot Marie Tooth disease (CMT) is a family of rare inherited peripheral neuropathies. CMT1A accounts for 50% of all CMT and is caused by a 1.4 mB duplication within chromosome 17 that results in the overexpression of peripheral myelin protein 22 kD (PMP22). CMT1A is characterized by progressive weakness, imbalance, sensory loss, and gait abnormalities. Multiple promising candidate therapies will be ready for human clinical trials within 3- 5 years, including antisense oligonucleotide therapy that decreases PMP22 expression and corrects the phenotype of rodent models. We in the Inherited Neuropathies Consortium Rare Disease Clinical Research Network (INC RDCRN) have defined the natural history of CMT1A, and developed clinical outcome assessments, patient reported outcomes, and a functional scale for children with CMT (CMTPedS), that shows responsiveness in CMT1A. For CMT1A trials, some critical gaps in outcome measures must be urgently filled, including a validated functional outcome measure for adults (the FDA guidance identifies function as a key clinical endpoint for drug approval), and validated, disease-progression biomarkers. This study, “Accelerate Clinical Trials in CMT (ACTCMT)”, addresses these key gaps by leveraging the expertise and multicenter infrastructure of the INC RDCRN to conduct a multicenter validation of a functional outcome (CMT-FOM), and motor and sensory biomarkers in adults with CMT1A. The aims of this U01 proposal include the following: (1) Validation of the CMT-FOM as a responsive outcome measure in adults with CMT1A. The CMT-FOM has high patient relevance, as it incorporates the patient perspective on which functional limitations are impactful. (2) Validation of a quantitative three-point Dixon MRI of intramuscular fat accumulation as a biomarker of disease progression in key leg muscles invoked in foot drop and disability for use in early phase CMT1A trials. (3) Validation of a non-invasive and painless way to determine the density of Meissner corpuscles (an important kind of sensory receptor) in the skin as a sensory biomarker for CMT1A trials. Dr. D. Herrmann (U. Rochester), will serve as overall PI. Dr. Herrmann developed CMT-FOM and will co-lead AIM 1 with Dr. M. Shy (INC Director; U. Iowa) and Dr. J. Burns (U. Sydney; who developed the CMTPedS). Dr. Herrmann pioneered the use of non-invasive imaging of Meissner corpuscles in peripheral neuropathy, and will also lead AIM 3. Dr. M. Reilly and Dr. J. Thornton (physicist), both from the Univ. College of London, will lead AIM 2; they pioneered the use of muscle MRI as a biomarker in CMT1A. Drs. S. Scherer (U. Penn) and D. Pareyson (C. Besta Neurological Inst., Milan) lead large CMT clinics and have considerable experience in evaluating CMT1A patients. This study brings together a leading group of CMT investigators who have a long history of successfully collaborating, and should yield a validated CMT-FOM and biomarkers that will have high impact because this will accelerate early and late phase clinical trials in CMT1A, for which no disease-modifying treatment is yet available.