Clinical Trial Readiness for Children 0-5 years with Congenital Muscular Dystrophy Secondary to LAMA2 Mutations

该提案的总体目标是加快5岁以下先天性肌营养不良继发于层粘连蛋白α2相关营养不良（LAMA2-RD）突变儿童的药物开发。不同严重程度的优秀小鼠模型提高了对LAMA2-RD发病机制的理解。治疗策略，包括蛋白质替代和细胞凋亡抑制（第一阶段），连接基因转移和补偿性基因上调（临床前概念证明），都处于不同的发展阶段，但预计将在2-3年内进入临床试验。虽然所有这些进展都很有希望，但目前，对于LAMA2-RD < 5岁的儿童，还没有经过验证的临床结果评估（COA）。因此，对于遗传上确诊为LAMA2-RD的儿童（小于5岁），迫切需要验证结果测量和生物标志物。成功地翻译任何治疗都必须包括这些最小的孩子，因为针对年龄较大的“合作儿童”设计的基于力量或功能的方法对他们不起作用。为婴幼儿做好临床试验准备尤为重要，因为治疗干预措施如果成功，在早期给予可能会产生最佳反应。我们建议的具体目标是1)验证运动功能作为LAMA2-RD儿童的COA， 2)通过将其锚定在临床总体印象量表上，建立运动COA的最小临床重要差异，3)确定哪些队列特征将最好地告知临床试验资格，4)验证新的生物标志物（通过超声横断面测量肱二头肌和股直肌）和肌酸激酶水平随时间的变化。为了实现这些目标，我们提出了一项14个地点的多中心前瞻性2年研究，纳入44名5岁以下的儿童。每个合作地点至少有两名临床评估人员将在牵头机构全国儿童医院（national Children 's Hospital）接受详细培训，培训时间为入学前和第三学年。我们根据他们在小儿神经肌肉临床试验方面的专业知识选择了这些地点。LAMA2-RD极为罕见，这些儿童通常在医学上很脆弱。因此，我们也选择了地理上不同的地点，以尽量减少旅行和试验参与的负担。在COVID-19大流行期间，有必要开发一种新的COA，即对所有运动功能COA进行视频评估，进一步减少儿童的旅行。我们与包括Cure CMD（先天性肌肉萎缩症）和肌肉萎缩症协会在内的倡导团体建立了伙伴关系，这将使我们能够使用辐条和枢纽模式成功招募儿童。该提案将开发和验证5岁以下LAMA2-RD儿童的coa，并将为未来的临床试验设计和解释提供信息。此外，一旦得到验证，这些coa很可能成功用于患有其他罕见疾病的儿童，这些疾病会影响婴儿期早期的运动发育。

This proposal’s overall goal is to hasten drug development for children < 5 years with congenital muscular dystrophy secondary to laminin α2-related dystrophies (LAMA2-RD) mutations. Excellent mouse models of differing severity improved the understanding of pathogenesis in LAMA2-RD. Therapeutic strategies, including protein replacement and apoptosis inhibition (Phase 1), linker gene transfer, and compensatory gene upregulation (pre- clinical proof of concept), are all at various developmental stages but are expected to come to clinical trials in 2-3 years. While all these advances are promising, currently, no validated clinical outcome assessments (COA) are available for children with LAMA2-RD < 5 years. Thus, the need to validate outcome measures and biomarkers is urgent for children (< 5 years) with genetically confirmed LAMA2-RD. Successfully translating any therapy must include these youngest children for whom strength or function-based approaches designed for older “cooperative children” do not work. Clinical trial readiness for infants and young children is particularly critical since therapeutic interventions, if successful, are likely to have the best response when given early. The specific aims of our proposal are to 1) Validate motor function as COA for children with LAMA2-RD, 2) Establish minimal clinically important differences for motor COAs by anchoring them to the clinical global impressions scale, 3) Determine what cohort characteristics will best inform clinical trial eligibility, and 4) Validate novel biomarkers (cross-sectionally measure biceps and rectos femoris by ultrasound) and creatine kinase levels over time. To achieve these aims, we propose a 14-site multicenter prospective 2-year study of 44 children < 5 years at enrollment. Detailed training of at least two clinical evaluators from each collaborating site will take place at the lead institution, Nationwide Children’s Hospital, before enrollment and again in Year 3. We selected the sites based on their expertise in pediatric neuromuscular clinical trials. LAMA2-RD is ultra-rare, and these children are often medically fragile. Therefore, we also selected geographically diverse locations to minimize travel and burden of trial participation. A novel COA developed by necessity during the COVID-19 Pandemic is video assessments of all motor function COAs, further allowing less travel for children. Our partnerships with advocacy groups, including Cure CMD (Congenital Muscular Dystrophy) and the Muscular Dystrophy Association, will allow us to successfully recruit children using a spoke and hub model. The proposal will develop and validate COAs for children < 5 years with LAMA2-RD and will inform future clinical trial design and interpretation. Furthermore, once validated, these COAs are very likely to be successful for children with other rare disorders affecting motor development in early infancy.