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，其发病率 每8,000名活产儿中就有1名。它是导致遗传性婴儿和儿童死亡的主要原因。纯合子 存活运动神经元1(SMN1)基因的缺失在疾病的发病机制中起主要作用。这个 SMN1基因位于5号染色体上的一个反向重复区域。SMN1的拷贝几乎完全相同， 命名为SMN2的基因含有改变剪接的单核苷酸改变，导致减少 功能蛋白的表达。然而，-10%的SMN2转录本产生了全长的SMN mRNA 与SMN1产生的相同。SMN2拷贝数与表型严重程度呈负相关 SMN1基因敲除小鼠模型中的人类和表型救援。可能存在其他遗传修饰物， 由于家系中与受影响兄弟姐妹具有相同SMN基因的罕见个体是表型 很正常。已发现可上调SMN2基因表达的化合物，中度疾病 患者细胞系的表型，并延长SMA小鼠模型的存活时间。我们的自然历史数据库 包括117名患有SMA的婴儿和儿童，有500名患者就诊。该数据库以及正在进行的 涉及80名儿童的研究使我们处于一个独特的位置，可以提出关于疾病的具体问题 研究其发病机制，并研究可减轻疾病严重程度或进展的治疗方法。我们 假设运动神经元功能障碍和丢失是由于运动神经元易损性增加所致 到低水平的SMN蛋白。我们提出运动神经元的去神经作用是随着时间的推移而递进的； 失神经支配的严重程度与SMN拷贝数相关；SMN蛋白表达增加 通过上调SMN2基因表达的神经元将保护处于危险状态的运动神经元，并促进 肌肉的神经元萌发和再神经支配。最后，我们建议在关键时期内进行干预 疾病过程的早期治疗窗口将被证明是最有效地缓解疾病所必需的 严肃性。为了解决这些假设，我们建议：1)确定以下问题的严重性和时间进程 广泛的SMA儿童队列中的失神经和功能运动状态；2)验证不同的临床 评估失神经严重程度、功能运动状态和疾病生物标志的结果指标 允许对实验性治疗进行评估；3)进行试验性研究，以评估 对神经元萌发、侧支神经再支配和功能运动状态的具体干预，最后 4)建立以详细表型信息为支撑的遗传数据库，以识别疾病修饰 作为额外的基因座导致了新的治疗干预措施。

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.