VALPROIC ACID AND CARNITINE IN PATIENTS WITH 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)是一种以弥漫性无力和肌肉萎缩为特征的常染色体隐性运动神经元病。它是最常见的神经肌肉疾病之一，也是遗传性婴儿死亡的主要原因。患者最常出现在婴儿期和幼儿期，但临床起病和严重程度范围很广，从先天性关节痉挛和呼吸机依赖的婴儿到成人起病的近端肌肉无力。这种临床异质性增加了评估有前景的新疗法的临床试验设计的内在挑战。我们和其他人的工作表明，SMA是一种进行性运动神经元病，反映在远端神经支配的手部肌肉中，随着时间的推移，功能丧失以及最大复合运动动作电位幅度和运动单位数估计。SMA 1型婴儿在达到稳定但明显较弱的终点之前，疾病进展可能会迅速发生，而SMA 2型和3型患者通常表现出较慢的进展过程，多年来保持稳定的功能。作为目前这一提议的重要前奏，犹他大学的试点研究已经在一组非卧床保姆和SMA 2型和3型儿童中建立了至少六个月时间内功能结果测量的稳定性。该方案的主要目的是评估2-17岁SMA患者口服VPA和肉碱的联合方案的安全性、耐受性和有效性。次要目标是改进电生理和临床技术，以帮助我们更好地跟踪SMA患者的病程，特别是当它与导致虚弱、运动神经元功能障碍和丢失的原发疾病过程有关时。这些包括：1)有助于准确评估患者功能运动结果和强度的临床评估；2)研究和跟踪运动神经元丢失过程的电生理学技术；3)影响表型严重程度的遗传机制的研究。我们推测，VPA通过上调SMN基因的表达来增加SMN蛋白的表达，从而挽救运动神经元，并允许再神经支配。

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 an autosomal recessive motor neuron disease characterized by diffuse weakness and muscular atrophy. It is one of the most common neuromuscular conditions, and a leading cause of hereditary infant mortality. Patients most frequently present in infancy and early childhood, but the clinical spectrum of onset and severity is broad, ranging from the infant with congenital joint contractures and ventilator dependence to adult onset of proximal muscle weakness. This clinical heterogeneity increases the inherent challenges in clinical trial design for the evaluation of promising new therapies. Our work and that of others have demonstrated that SMA is a progressive motor neuron disease, as reflected by loss of function as well as maximum compound motor action potential amplitudes and motor unit number estimates in a distally innervated hand muscle over time. Disease progression can occur rapidly in SMA type 1 infants prior to reaching a stable albeit significantly weak endpoint, while patients with SMA types 2 and 3 often demonstrate a more slowly progressive course, with stable function preserved over many years. As an important prelude to this current proposal, pilot studies at the University of Utah have established stability of functional outcome measures over at least a six month time period in a cohort of non-ambulatory sitters and ambulatory SMA type 2 and 3 children. The primary objective of this protocol is to assess the safety, tolerability, and efficacy of a combined regimen of oral VPA and carnitine in SMA patients 2-17 years of age. Secondary objectives are to refine electrophysiological and clinical techniques to help us better follow the course of patients with SMA, particularly as it relates to the primary disease process causing weakness, motor neuron dysfunction and loss. These include: 1) clinical assessments which will help accurately assess functional motor outcome and strength of patients, 2) electrophysiologic techniques to study and follow the course of motor neuron loss, and 3) investigation of genetic mechanisms which influence the severity of phenotype. We hypothesize that treatment with VPA increases expression of SMN protein via up-regulation of SMN2 gene expression, resulting in the rescue of motor neurons and allowing re-innervation.