Therapeutic Opportunities in Spinal Muscular Atrophy

描述（由申请人提供）：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1/8，000活产婴儿。 它是遗传性婴儿和儿童死亡率的主要原因。 运动神经元存活基因1（SMN 1）的纯合缺失在疾病发病机制中起主要作用。 SMN 1基因位于5号染色体上的反向重复区域。 一个几乎相同的SMN 1拷贝，命名为SMN 2，含有一个改变剪接的单核苷酸变化，导致功能蛋白表达降低。 然而，大约10%的SMN 2转录产物产生与SMN 1相同的全长SMN mRNA。 SMN 2拷贝数与人类表型严重程度和SMN 1敲除小鼠模型中的表型挽救呈负相关。 可能存在其他遗传修饰因子，因为与受影响的兄弟姐妹相同的SMN基因型家族中的罕见个体表型正常。 已鉴定出可上调SMN 2基因表达、缓解患者细胞系疾病表型并延长SMA小鼠模型存活期的化合物。 研究者的自然史数据库包括117名SMA婴儿和儿童，超过500名患者就诊。 这个数据库，沿着正在进行的研究，涉及80多名儿童，把她放在一个独特的位置，问有关疾病发病机制的具体问题，并调查治疗，可能会减轻疾病的严重程度或进展。 据推测，运动神经元功能障碍和损失是由于运动神经元对低水平SMN蛋白的脆弱性增加。 研究者提出，运动神经元去神经化随时间推移而进行;去神经化的严重程度与SMN 2拷贝数相关;通过上调SMN 2基因表达增加神经元中SMN蛋白的表达将保护处于风险中的运动神经元，并促进神经元发芽和肌肉的神经再支配。 她还提出，在疾病过程早期的关键治疗窗口内进行干预将被证明是最有效地减轻疾病严重程度所必需的。 为了解决这些假设，研究者建议：1）确定广泛SMA儿童队列中去神经支配和功能性运动状态的严重程度和时间进程; 2）验证评估去神经支配严重程度、功能性运动状态和疾病生物标志物的多种临床结局指标，以允许评价实验性治疗; 3）进行试点研究，以评估特定干预对神经元发芽、侧支再神经支配和功能性运动状态的潜在影响，和4）建立由详细的表型信息支持的遗传数据库，以鉴定疾病修饰基因座作为新的治疗干预的额外线索。

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.