CLINICAL STUDY OF SPINAL MUSCULAR ATROPHY

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。脊髓性肌萎缩症(SMA)是儿童时期最具破坏性的神经系统疾病之一。受影响的婴儿和儿童由于脊髓和脑干中下运动神经元的退化而导致进行性肌肉无力。临床上，根据发病年龄和达到的最高运动里程碑，在疾病严重程度的连续谱中可区分四种表型。SMA是由存活运动神经元-1(SMN1)基因纯合缺失引起的。由于剪接效率低下，相关基因SMN2产生的全长SMN蛋白水平较低。SMN拷贝数和疾病严重程度之间存在负相关，推测是由全长SMN蛋白水平调节的。因此，增加全长SMN蛋白的量是一种有前途的治疗策略。几种靶向剪接效率的药物在临床前检测中导致SMN蛋白增加，目前正在等待临床测试。根据未来在SMA进行临床试验的目标，拟议的项目有3个具体目标：1)从临床和分子角度确定患者群体的特征；(2)建立一个基于网络的数据库，该数据库将用于登记患者群体，并将促进为未来的临床试验及时招募；以及(3)通过(A)制定可靠的结果衡量标准，(B)建立进行有效临床试验所需的基础设施，以及(C)召开参与SMA药物开发的临床前和临床研究人员会议，选择候选药物，以规划临床试验。我们已经建立了儿科神经肌肉临床研究网络(PNCR)，以评估三个地点的患者：纽约、波士顿和费城。数据管理(包括完全基于网络的数据储存库)和统计分析将在罗切斯特大学由一个在神经肌肉疾病临床试验方面经验丰富的小组进行。我们会改变

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Spinal Muscular Atrophy (SMA) is one of the most devastating neurological diseases of childhood. Affected infants and children suffer from progressive muscle weakness caused by degeneration of lower motor neurons in the spinal cord and brainstem. Clinically, four phenotypes are distinguished within the continuous spectrum of disease severity based on the age of onset and the highest motor milestone ever achieved. SMA is caused by homozygous deletion of the survival motor neuron-1 (SMN1) gene. A related gene, SMN2, produces low levels of full-length SMN protein due to inefficient splicing. There is an inverse correlation between SMN copy number and disease severity, presumably mediated by levels of full-length SMN protein. Therefore, increasing the amount of full-length SMN protein is a promising treatment strategy. Several drugs targeting splicing efficiency have resulted in increased SMN protein in preclinical assays and are now awaiting clinical testing. With the future objective to conduct clinical trials in SMA, the proposed project has 3 specific aims: 1) to characterize the patient population from a clinical and molecular point of view; (2) to establish a web-based database that will serve to enroll the patient population and that will facilitate timely recruitment for future clinical trials; and (3) to plan for clinical trials by (a) developing reliable outcome measures, (b) establishing the infrastructure needed to carry out efficient clinical trials, and (c) convening meetings of preclinical and clinical researchers involved in SMA drug development to select candidate drugs. We have established a Pediatric Neuromuscular Clinical Research Network (PNCR) to evaluate patients at three sites: New York, Boston and Philadelphia. Data management (including fully web-based data repository) and statistical analyses will be carried out at the University of Rochester by a group experienced in clinical trials of neuromuscular disease. We will cha