Therapeutic Opportunities in Spinal Muscular Atrophy

脊髓性肌萎缩症是人类最常见的遗传性运动神经元疾病， 每8,000个活产婴儿中就有一个。它是遗传性婴儿和儿童死亡率的主要原因。纯合 运动神经元存活基因1（SMN 1）的缺失在疾病发病机制中起主要作用。的 SMN 1基因位于5号染色体上的一个反向重复区域。一个几乎相同的SMN 1拷贝， 命名为SMN 2，包含一个改变剪接的单核苷酸变化，导致减少 功能性蛋白表达。然而，来自SMN 2的约10%的转录物产生全长SMN mRNA。 与由SMN 1产生的相同。SMN 2拷贝数与表型严重程度呈负相关， 人和SMN 1敲除小鼠模型中的表型拯救。可能存在其他遗传修饰剂， 由于在具有与受累同胞相同的SMN基因型的家族中， 正常已鉴定出上调SMN 2基因表达的化合物， 表型，并延长SMA小鼠模型中的存活。我们的自然历史数据库 包括117名SMA婴儿和儿童，患者就诊次数> 500次。这个数据库，沿着正在进行的 涉及80多名儿童的研究，使我们处于一个独特的位置，可以提出有关疾病的具体问题， 发病机制，并研究可以减轻疾病严重程度或进展的治疗。我们 假设运动神经元功能障碍和丧失是由于运动神经元的脆弱性增加 低水平的SMN蛋白。我们认为运动神经元的去神经支配是随着时间的推移而进行的， 去神经支配严重程度与SMN 2拷贝数相关; 通过上调SMN 2基因表达，神经元将保留处于危险中的运动神经元， 神经元发芽和肌肉的神经再支配。最后，我们建议在一个关键的 在疾病过程早期的治疗窗口将被证明是最有效地缓和疾病所必需的 严重性。为了解决这些假设，我们建议：1）确定的严重程度和时间进程 SMA儿童广泛队列的去神经支配和功能性运动状态; 2）验证各种临床 评估失神经支配严重程度、功能性运动状态和疾病标志物的结果指标 允许对实验性治疗进行评估; 3）进行试点研究，以评估 对神经元发芽、侧支神经再支配和功能性运动状态的特定干预， 4)建立一个由详细的表型信息支持的遗传数据库，以识别疾病修饰基因 基因座作为额外的导致新的治疗干预。

Spinal muscular atrophy is the most common inherited motor neuron disease in humans, with an incidence of 1 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, -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 knockout 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. Our natural history database includes 117 infants and children with SMA, with > 500 patient visits. This database, along with ongoing studies involving > 80 children, put us in a unique position to ask specific questions regarding disease pathogenesis, and to investigate treatments which may attenuate disease severity or progression. We hypothesize that motor neuron dysfunction and loss are due to an increased vulnerability of motor neurons to low levels of SMN protein. We propose 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. Finally, we propose 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, we propose 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 biomarkersto 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 finally 4) Establish a genetic database supported by detailed phenotype information to identify disease-modifying loci as additional leads to novel therapeutic interventions.