VALPROIC ACID AND CARNITINE IN PATIENTS WITH SPINAL MUSCULAR ATROPHY

丙戊酸和肉碱治疗脊髓性肌萎缩症患者

• 批准号: 7376480
• 负责人: KATHRYN J. SWOBODA
• 金额: $ 19.39万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2007-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7376480
• 关键词: action potentials; aging; atrophy; carnitine; children; clinical trials; conditioning; gene expression; genetics; hand; infant mortality; innervation; joints; lead; motor neurons; muscle; neural degeneration; phenotype; preschool child (1-5); proteins; university

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.

该子项目是利用 NIH/NCRR 资助的中心拨款提供的资源的众多研究子项目之一。子项目和研究者 (PI) 可能已从另一个 NIH 来源获得主要资金，因此可以在其他 CRISP 条目中得到体现。列出的机构是中心的机构，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遗传性运动神经元疾病，其特征是弥漫性无力和肌肉萎缩。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，但发病和严重程度的临床范围很广，从婴儿先天性关节挛缩和呼吸机依赖到成人近端肌无力发作。这种临床异质性增加了评估有前途的新疗法的临床试验设计的固有挑战。我们和其他人的工作已经证明，SMA 是一种进行性运动神经元疾病，反映在随着时间的推移，远端神经支配的手部肌肉的功能丧失以及最大复合运动动作电位幅度和运动单位数量估计。 1 型 SMA 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 2 型和 3 型 SMA 患者通常表现出更缓慢的进展过程，并在多年内保持稳定的功能。作为当前提案的重要前奏，犹他大学的试点研究已经在一组非走动的坐姿者和走动的 SMA 2 型和 3 型儿童中确定了功能结果测量在至少六个月时间内的稳定性。该方案的主要目的是评估 2-17 岁 SMA 患者口服 VPA 和肉碱联合治疗方案的安全性、耐受性和有效性。 次要目标是完善电生理学和临床技术，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虚弱、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）临床评估，这将有助于准确评估患者的功能性运动结果和力量，2）用于研究和跟踪运动神经元损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，从而拯救运动神经元并允许重新神经支配。