VALPROIC ACID AND CARNITINE IN PATIENTS WITH SPINAL MUSCULAR ATROPHY

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。脊髓性肌萎缩症（SMA）是一种常染色体隐性运动神经元疾病，以弥漫性虚弱和肌肉萎缩为特征。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，但临床发病和严重程度很广泛，从先天性关节挛缩和呼吸机依赖的婴儿到近端肌肉无力的成人发病。这种临床异质性增加了评估有希望的新疗法的临床试验设计的固有挑战。我们和其他人的研究表明，SMA是一种进行性运动神经元疾病，随着时间的推移，远端神经支配的手部肌肉的功能丧失、最大复合运动动作电位振幅和运动单位数估计都反映了这一点。1型SMA患儿在达到稳定但明显较弱的终点之前，疾病进展迅速，而2型和3型SMA患者通常表现出更缓慢的进展过程，多年来功能保持稳定。作为当前提案的重要前奏，犹他大学的试点研究已经在非活动看护和活动SMA 2型和3型儿童的队列中建立了至少6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和肉碱联合方案的安全性、耐受性和有效性。次要目标是完善电生理和临床技术，以帮助我们更好地跟踪SMA患者的病程，特别是因为它与导致无力、运动神经元功能障碍和丧失的原发疾病过程有关。这些包括：1)有助于准确评估患者功能性运动结果和力量的临床评估，2)研究和跟踪运动神经元丢失过程的电生理技术，以及3)影响表型严重程度的遗传机制的研究。我们假设VPA治疗通过上调SMN2基因表达来增加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.