Therapeutic Opportunities in Spinal Muscular Atrophy

描述(申请人提供)：脊髓性肌萎缩症是人类最常见的遗传性运动神经元疾病，发病率为每8,000名活产儿中就有一名。它是导致遗传性婴儿和儿童死亡的主要原因。存活运动神经元1(SMN1)基因的纯合缺失在疾病的发病机制中起主要作用。SMN1基因位于5号染色体上的一个反向重复区域。SMN1的一个几乎相同的拷贝，命名为SMN2，包含一个单核苷酸变化，改变剪接，导致功能蛋白表达减少。然而，大约10%来自SMN1的转录本产生了与SMN1相同的全长SMN mRNA。SMN1基因拷贝数与人类的表型严重程度和SMN1基因敲除小鼠模型中的表型拯救呈负相关。可能存在其他遗传修饰因素，因为家系中具有与受影响兄弟姐妹相同的SMN基因的罕见个体表型正常。已经确定的化合物可以上调SMN2基因的表达，在患者细胞系中表现为中等的疾病表型，并延长SMA小鼠模型的存活时间。研究人员的自然病史数据库包括117名患有SMA的婴儿和儿童，有500多名患者就诊。这个数据库，加上正在进行的涉及80多名儿童的研究，使她处于一个独特的位置，可以询问关于疾病发病机制的具体问题，并研究可能减轻疾病严重程度或进展的治疗方法。据推测，运动神经元功能障碍和丢失是由于运动神经元对低水平SMN蛋白的易感性增加所致。研究人员提出，运动神经元的失神经是随着时间的推移而渐进的；失神经的严重程度与SMN2拷贝数有关；通过上调SMN2基因的表达，神经元中SMN蛋白的表达增加将保留处于危险状态的运动神经元，并促进神经元的萌发和肌肉的再神经支配。她还提出，在疾病过程的早期关键治疗窗口内进行干预将被证明是最有效地缓解疾病严重程度所必需的。为了解决这些假说，研究人员建议：1)确定广泛的SMA儿童失神经和功能运动状态的严重性和时程；2)验证评估失神经严重程度、功能运动状态和疾病生物标记物的不同临床结果指标，以允许评估实验治疗；3)进行试点研究，以评估特定干预措施对神经元萌芽、侧支神经重新支配和功能运动状态的潜在影响；以及4)建立由详细表型信息支持的遗传数据库，以确定疾病修改基因座作为新的治疗干预措施的额外线索。

DESCRIPTION (provided by applicant): Spinal muscular atrophy is the most common inherited motor neuron disease in humans, with an incidence of one in 8,000 live births. It is a leading cause of hereditary infant and childhood mortality. Homozygous deletion of the survival motor neuron 1 (SMN1) gene plays a primary role in disease pathogenesis. The SMN1 gene lies in an inverted duplicated region on chromosome 5. A near identical copy of SMN1, designated SMN2, contains a single nucleotide change which alters splicing, resulting in decreased functional protein expression. However, approximately 10% of the transcripts from SMN2 yield a full length SMN mRNA identical to that produced from SMN1. SMN2 copy number is inversely correlated with phenotypic severity in humans and phenotypic rescue in an SMN1 knock-out mouse model. Other genetic modifiers likely exist, since rare individuals within families with SMN genotypes identical to affected siblings are phenotypically normal. Compounds have been identified which up-regulate SMN2 gene expression, moderate disease phenotype in patient cell lines, and prolong survival in an SMA mouse model. The investigator's natural history database includes 117 infants and children with SMA, with more than 500 patient visits. This database, along with ongoing studies involving over 80 children, put her in a unique position to ask specific questions regarding disease pathogenesis, and to investigate treatments which may attenuate disease severity or progression. It is hypothesized that motor neuron dysfunction and loss are due to an increased vulnerability of motor neurons to low levels of SMN protein. The investigator proposes that motor neuron denervation is progressive over time; that severity of denervation correlates with SMN2 copy number; and that increased expression of SMN protein in neurons via up-regulation of SMN2 gene expression will preserve at risk motor neurons and facilitate neuronal sprouting and reinnervation of muscle. She also proposes that intervention within a critical therapeutic window early in the disease process will prove necessary to most effectively moderate disease severity. To address these hypotheses, the investigator proposes to: 1) determine the severity and time course of denervation and functional motor status in a broad cohort of children with SMA; 2) validate diverse clinical outcome measures which assess severity of denervation, functional motor status, and disease biomarkers to permit the evaluation of experimental treatments; 3) perform pilot studies to evaluate potential effects of specific interventions on neuronal sprouting, collateral re-innervation, and functional motor status, and 4) establish a genetic database supported by detailed phenotypic information to identify disease-modifying loci as additional leads to novel therapeutic interventions.