A large animal model of spinal muscular atrophy and correction of phenotype.
A large animal model of spinal muscular atrophy and correction of phenotype.
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DOI：
10.1002/ana.24332
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发表时间：
2015-03
影响因子：
11.2
通讯作者：
Burghes, Arthur H. M.
中科院分区：
文献类型：
--
作者：
Duque, Sandra I.;Arnold, W. David;Odermatt, Philipp;Li, Xiaohui;Porensky, Paul N.;Schmelzer, Leah;Meyer, Kathrin;Kolb, Stephen J.;Schuemperli, Daniel;Kaspar, Brian K.;Burghes, Arthur H. M.
脊髓性肌萎缩症（SMA）是由SMN水平降低导致运动神经元丢失引起的。增加SMN水平的治疗策略，包括药物化合物、反义寡核苷酸或scAAV 9基因治疗，已证明在小鼠中有效。我们希望在大型动物模型中确定出生后运动神经元中SMN的减少是否导致SMA，SMA是否可以在肌无力发展后得到纠正以及临床相关生物标志物的反应。使用鞘内递送表达靶向猪SMN 1的shRNA的scAAV 9，出生后运动神经元中的SMN被敲低至SMA水平。这导致了代表SMA的第一个大型动物模型的SMA表型。在不同时间点用表达人SMN的scAAV 9（scAAV 9-SMN）进行SMN的恢复，并进行电生理学测量和病理学检查。出生后运动神经元中SMN的敲除导致明显的近端无力、肌电图（EMG）上的纤维化（表明主动去神经支配）以及复合肌肉动作电位（CMAP）和运动单位数量估计（MUNE）降低，与人类SMA相似。神经病理显示运动神经元和运动轴突的损失。scAAV 9-SMN的症状前递送预防了SMA症状，表明所有变化都是SMN依赖性的。症状发作后scAAV 9-SMN的递送对表型、电生理测量和病理学具有显著影响。高SMN水平对出生后运动神经元至关重要，SMN减少会导致SMA表型依赖SMN。重要的是，临床相关生物标志物（包括CMAP和MUNE）对SMN恢复有反应，即使在症状发作后也可以实现表型的消除。
Spinal muscular atrophy (SMA) is caused by reduced levels of SMN which results in motoneuron loss. Therapeutic strategies to increase SMN levels including drug compounds, antisense oligonucleotides or scAAV9 gene therapy have proved effective in mice. We wished to determine whether reduction of SMN in postnatal motoneurons resulted in SMA in a large animal model, whether SMA could be corrected after development of muscle weakness and the response of clinically relevant biomarkers. Using intrathecal delivery of scAAV9 expressing a shRNA targeting pig SMN1, SMN was knocked down in motoneurons postnatally to SMA levels. This resulted in an SMA phenotype representing the first large animal model of SMA. Restoration of SMN was performed at different time points with scAAV9 expressing human SMN (scAAV9-SMN) and electrophysiology measures and pathology were performed. Knockdown of SMN in postnatal motoneurons results in overt proximal weakness, fibrillations on electromyography (EMG) indicating active denervation, and reduced compound muscle action potential (CMAP) and motor unit number estimates (MUNE), like human SMA. Neuropathology showed loss of motoneurons and motor axons. Pre-symptomatic delivery of scAAV9-SMN prevented SMA symptoms indicating all changes are SMN dependent. Delivery of scAAV9-SMN after symptom onset had a marked impact on phenotype, electrophysiological measures and pathology. High SMN levels are critical in postnatal motoneurons and reduction of SMN results in a SMA phenotype which is SMN dependent. Importantly, clinically relevant biomarkers including CMAP and MUNE are responsive to SMN restoration and abrogation of phenotype can be achieved even after symptom onset.
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影响因子：
64.5
作者：
LEFEBVRE, S;BURGLEN, L;MELKI, J
通讯作者：
MELKI, J
影响因子：
46.9
作者：
通讯作者：
--
影响因子：
30.8
作者：
Lefebvre, S;Burlet, P;Melki, J
通讯作者：
Melki, J
用于针对小儿疾病的脊髓，大脑和周围组织的大物种中的全身基因递送。
DOI：
10.1038/mt.2011.157
发表时间：
2011-11
期刊：
Molecular therapy : the journal of the American Society of Gene Therapy
影响因子：
--
作者：
通讯作者：
--
影响因子：
3.5
作者：
Coovert, DD;Le, TT;Burghes, AHM
通讯作者：
Burghes, AHM