Accelerate Clinical Trials in CMT (ACTCMT) Study

Charcot玛丽牙病（CMT）是一种罕见的遗传性周围神经病。CMT 1A占所有CMT的50%，由17号染色体内的1.4 mB重复引起，导致外周髓磷脂蛋白22 kD（PMP 22）过表达。CMT 1A的特征在于进行性虚弱、不平衡、感觉丧失和步态异常。多种有前景的候选疗法将在3- 5年内准备好进行人体临床试验，包括降低PMP 22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CMT 1A的自然史，并开发了临床结局评估，患者报告结局和CMT儿童功能量表（CMTPedS），显示CMT 1A的反应性。对于CMT 1A试验，必须紧急填补结局指标中的一些关键空白，包括经验证的成人功能结局指标（FDA指南将功能确定为药物批准的关键临床终点）和经验证的疾病进展生物标志物。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CMT 1A成人患者的功能结局（CMT-FOM）以及运动和感觉生物标志物进行多中心验证，解决了这些关键差距。该U 01提案的目标包括以下内容：（1）验证CMT-FOM作为CMT 1A成人的响应性结果指标。CMT-FOM具有高度的患者相关性，因为它结合了患者对功能限制影响的观点。(2)验证肌内脂肪蓄积的定量三点狄克逊MRI作为足下垂和残疾中关键腿部肌肉疾病进展的生物标志物，用于早期CMT 1A试验。(3)验证一种无创和无痛的方法来确定皮肤中迈斯纳小体（一种重要的感觉受体）的密度，作为CMT 1A试验的感觉生物标志物。Dr. D.赫尔曼（U.罗切斯特）将担任总体PI。Herrmann博士开发了CMT-FOM，并将与M博士共同领导AIM 1。Shy（INC Director; U.爱荷华州）和伯恩斯博士（美国。Sydney;谁开发了CMTPedS）。Herrmann博士率先在周围神经病变中使用迈斯纳小体的非侵入性成像，并将领导AIM 3。M博士来自伦敦大学学院的Reilly和J. Thornton博士（物理学家）将领导AIM 2;他们率先使用肌肉MRI作为CMT 1A的生物标志物。S博士谢勒（U. Penn）和D.帕雷森（C. Besta神经学研究所，Milan）领导大型CMT诊所，在评估CMT 1A患者方面拥有丰富的经验。这项研究汇集了一个领先的CMT研究者小组，他们有着长期的成功合作历史，应该会产生一个经过验证的CMT-FOM和生物标志物，这将产生很大的影响，因为这将加速CMT 1A的早期和晚期临床试验，目前还没有疾病修饰治疗。

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.