Biomarkers and additive therapies to enhance symptomatic treatment of Spinal Muscular Atrophy

增强脊髓性肌萎缩症对症治疗的生物标志物和附加疗法

• 批准号: 9524746
• 负责人: ARTHUR H. M. BURGHES
• 金额: $ 42.22万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-20 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9524746
• 关键词: Action Potentials; Age; Aging; Alleles; Antisense Oligonucleotides; Biological Markers; Blood specimen; CRISPR/Cas technology; Calcium; Cessation of life; Clinic; Clinical; Clinical Treatment; Clinical Trials; Comb animal structure; Data; Defect; Dependovirus; Disease; Disease Progression; Electrophysiology (science); Elements; Enhancers; Enrollment; Exons; Family suidae; Follistatin; Future; Genes; Genetic; Genome; Hand Strength; Incidence; Infant; Infant Mortality; Injury; Introns; Lead; Length; Live Birth; Maintenance; Measures; Modeling; Monitor; Motor; Motor Neurons; Mus; Muscle; Muscle Contraction; Muscle function; Mutation; Nerve; Neurodegenerative Disorders; Nucleotides; Paralysed; Patients; Pharmacodynamics; Phase; Phenotype; Plasma; Plasma Proteins; Prediction of Response to Therapy; Prognostic Marker; RNA; RNA Splicing; Reagent; Research Design; SMN protein (spinal muscular atrophy); SMN2 gene; Safety; Sampling; Severity of illness; Site; Spinal Muscular Atrophy; Structure; System; Testing; Therapeutic; Therapeutic Effect; Time; Troponin C; Werdnig-Hoffmann Disease; Work; adeno-associated viral vector; base; bench to bedside; biomarker identification; combinatorial; effective therapy; enhancing factor; experimental study; gene therapy; gene therapy clinical trial; improved; in vivo; infant death; innovation; motor neuron function; muscle form; neuron loss; outcome forecast; partial response; pharmacodynamic biomarker; phase 1 study; postnatal; preclinical study; prognostic; protein biomarkers; repaired; response; restoration; symptom treatment; therapeutic target; treatment response; treatment strategy

Project Summary/Abstract Spinal muscular atrophy (SMA) is a neurodegenerative disease that causes loss of motor neurons, results in paralysis, and in the most severe forms leads to death. The incidence of SMA is 1 in 10,000 live births, making this disease one of the leading causes of infant mortality. SMA is caused by low levels of the survival motor neuron (SMN) protein. Recent experiments have shown a remarkable rescue of phenotype in SMA mice upon delivery of SMN using scAAV9. Likewise, correction of SMN2 splicing using antisense oligonucleotides (ASO) can expand survival and rescue electrophysiology defects. Such promising pre-clinical studies have led to several clinical trials for the treatment of SMA. It is crucial that biomarkers are established for SMA that can help predict treatment response and to measure therapeutic effect. A panel of protein markers known as SMA- MAP shows correlation with function in SMA patients. Yet, it is unknown if these markers can quantify therapeutic response. A subset of these plasma markers are both abnormal in SMA mice and normalize in SMA mice treated presymptomatically with anti-sense oligonucleotides (ASO) to increase SMN. The ability of these markers to quantify treatment response following treatment with ASO to increase SMN will be tested in SMA mice treated at different disease stages. These findings will be further investigated by testing the SMA- MAP panel in blood samples from treated SMA type I infants enrolled in the phase 1 gene therapy clinical trial at our center. These samples will be compared with samples from untreated SMA type 1 infants, matched for age and SMN2 copy number, from the NeuroNext clinical trial to allow determination of the markers that respond to treatment. While SMN therapies are very effective when given early, they are less effective late in the course of disease. In aim 2, combinatorial therapies to improve muscle function in combination with SMN therapies, will be tested in SMA mice. Mutations in the troponin C gene that result in increased calcium sensitivity will be delivered using adeno associated virus (AAV) vectors and tested for an effect on muscle contraction force even with reduced motor neuron input. Self-complementary AAV follistatin will be used to increase muscle mass to determine if there is an additive effect of increased muscle size when combined with SMN. In these combinatorial therapy experiments, mice will be treated with ASOs to increase SMN at different disease stages to mimic the clinical trial situation. We will monitor muscle force and electrophysiological measures of motor unit function in these mice. Finally, aim 3 will investigate whether higher levels of SMN can enhance motor neuron repair and improve therapeutic response in post symptomatically treated mice. Lastly intron 6 and 7 will be investigated using the CRISPR/Cas9 system to find new regulatory sites that control splicing of exon 7. Identification of new sites will expand therapeutic targets that can be used with ASOs and open the possibility of using AAV vector to make a permeant change in SMN2.

项目摘要/摘要 脊柱肌肉萎缩（SMA）是一种导致运动神经元丧失的神经退行性疾病，导致 瘫痪，最严重的形式导致死亡。 SMA的发病率是10,000个活生生中的1个 这种疾病是婴儿死亡率的主要原因之一。 SMA是由低水平的生存电机引起的 神经元（SMN）蛋白。最近的实验表明，在SMA小鼠中对表型的显着营救 使用SCAAV9交付SMN。同样，使用反义寡核苷酸（ASO）校正SMN2剪接 可以扩大生存和挽救电生理缺陷。这种有希望的临床前研究导致 几项用于治疗SMA的临床试验。至关重要的是，为SMA建立生物标志物可以 有助于预测治疗反应并测量治疗作用。一个称为sma-的蛋白质标记面板 地图显示了SMA患者的功能的相关性。但是，未知这些标记是否可以量化 治疗反应。这些等离子体标记的子集在SMA小鼠中均异常，并且在 SMA小鼠用抗义寡核苷酸（ASO）进行了预测，以增加SMN。能力 这些标记以量化使用ASO治疗后增加SMN后的治疗反应的标记将进行测试 在不同疾病阶段接受治疗的SMA小鼠。这些发现将通过测试SMA-进一步研究 从1阶段基因治疗临床试验中入学的SMA I型婴儿的血液样本中的地图面板 在我们的中心。这些样本将与未经治疗的SMA 1型婴儿的样本进行比较，与 年龄和SMN2拷贝数，来自Neuronext临床试验，以确定标记 应对治疗。虽然SMN疗法在提早给予时非常有效，但它们在晚期的有效性较低 疾病进程。在AIM 2中，组合疗法可改善肌肉功能与SMN结合 疗法将在SMA小鼠中进行测试。肌钙蛋白C基因的突变导致钙增加 灵敏度将使用adeno相关病毒（AAV）向量传递，并测试对肌肉产生影响 即使减少了运动神经元输入，收缩力也是如此。自我平衡的AAV follistatin将用于 增加肌肉质量以确定与 SMN。在这些组合治疗实验中，将使用ASO治疗小鼠以增加不同的SMN 疾病阶段以模仿临床试验状况。我们将监测肌肉力和电生理学 这些小鼠的运动单位功能的度量。最后，AIM 3将调查较高水平的SMN是否可以 增强运动神经元修复并改善症状后治疗的小鼠的治疗反应。最后 内含子6和7将使用CRISPR/CAS9系统进行研究，以找到控制的新调节站点 外显子7的剪接。识别新站点将扩展可以与ASO一起使用的治疗靶标的 打开使用AAV矢量在SMN2中进行统计更改的可能性。