CLINICAL STUDY OF SPINAL MUSCULAR ATROPHY

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 研究中心，而研究中心不一定是研究者所在的机构。 脊髓性肌萎缩症（SMA）是儿童期最具破坏性的神经系统疾病之一。 受影响的婴儿和儿童患有由脊髓和脑干中的下运动神经元变性引起的进行性肌无力。 临床上，根据发病年龄和有史以来达到的最高运动里程碑，在疾病严重程度的连续谱内区分出四种表型。 SMA是由运动神经元存活基因（SMN 1）的纯合缺失引起的。 一个相关的基因，SMN 2，产生低水平的全长SMN蛋白，由于剪接效率低下。 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蛋白水平介导的。 因此，增加全长SMN蛋白的量是一种有前景的治疗策略。 几种靶向剪接效率的药物已在临床前试验中导致SMN蛋白增加，目前正在等待临床试验。 未来的目标是在SMA中进行临床试验，拟定项目有3个具体目标：1）从临床和分子角度描述患者人群的特征;（2）建立基于网络的数据库，用于招募患者人群，并促进未来临床试验的及时招募;和（3）通过（a）制定可靠的结局指标，（B）建立开展有效临床试验所需的基础设施，以及（c）召集参与SMA药物开发的临床前和临床研究人员会议，以选择候选药物，来规划临床试验。 我们已经建立了一个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存储库）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。

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.