Long-term neurologic and cardiac correction by intrathecal gene therapy in Pompe disease.
Long-term neurologic and cardiac correction by intrathecal gene therapy in Pompe disease.
复制标题
DOI：
10.1186/s40478-017-0464-2
复制
发表时间：
2017-09-06
影响因子：
7.1
通讯作者：
Colle MA
中科院分区：
文献类型：
--
作者：
Hordeaux J;Dubreil L;Robveille C;Deniaud J;Pascal Q;Dequéant B;Pailloux J;Lagalice L;Ledevin M;Babarit C;Costiou P;Jamme F;Fusellier M;Mallem Y;Ciron C;Huchet C;Caillaud C;Colle MA
庞贝病是由酸α-葡萄糖苷酶（GAA）缺乏引起的溶酶体贮积症，导致糖原贮积。这种疾病表现为致命的婴儿型心肌病。酶替代疗法（ERT）最近延长了这些患者的寿命，揭示了一个新的自然史。一些患者的神经表型和选择性肌无力的持续可归因于未经ERT纠正的中枢神经系统（CNS）储存。GAA- ko 6neo/6neo小鼠在1个月时单次鞘内给予腺相关重组载体（AAV）介导的人GAA基因转移，并对其神经、神经肌肉和心脏功能进行1年的评估。我们证明在治疗动物中，4个月后出现显著的神经功能矫正，9个月后出现神经肌肉改善，12个月时肥厚性心肌病得到矫正。受疾病影响最严重的区域，即脑干、脊髓和左心室壁均表现出酶、生化和组织学上的纠正。肌糖原储存不受治疗影响，因此表明肌肉功能的恢复与中枢神经系统的纠正直接相关。这种前所未有的全球和长期的中枢神经系统和心脏治疗为患者的管理提供了新的视角。本文的在线版本（doi:10.1186/s40478-017-0464-2）包含补充材料，可供授权用户使用。
Pompe disease is a lysosomal storage disorder caused by acid-α-glucosidase (GAA) deficiency, leading to glycogen storage. The disease manifests as a fatal cardiomyopathy in infantile form. Enzyme replacement therapy (ERT) has recently prolonged the lifespan of these patients, revealing a new natural history. The neurologic phenotype and the persistence of selective muscular weakness in some patients could be attributed to the central nervous system (CNS) storage uncorrected by ERT. GAA-KO 6neo/6neo mice were treated with a single intrathecal administration of adeno-associated recombinant vector (AAV) mediated gene transfer of human GAA at 1 month and their neurologic, neuromuscular, and cardiac function was assessed for 1 year. We demonstrate a significant functional neurologic correction in treated animals from 4 months onward, a neuromuscular improvement from 9 months onward, and a correction of the hypertrophic cardiomyopathy at 12 months. The regions most affected by the disease i.e. the brainstem, spinal cord, and the left cardiac ventricular wall all show enzymatic, biochemical and histological correction. Muscle glycogen storage is not affected by the treatment, thus suggesting that the restoration of muscle functionality is directly related to the CNS correction. This unprecedented global and long-term CNS and cardiac cure offer new perspectives for the management of patients. The online version of this article (doi:10.1186/s40478-017-0464-2) contains supplementary material, which is available to authorized users.
登录
查看更多内容
影响因子：
2.8
作者：
Carre-Pierrat, Maite;Lafoux, Aude;Segalat, Laurent
通讯作者：
Segalat, Laurent
DOI：
10.1002/ajmc.31321
发表时间：
2012-02-15
影响因子：
3.1
作者：
Case, Laura E.;Beckemeyer, Alexandra A.;Kishnani, Priya S.
通讯作者：
Kishnani, Priya S.
影响因子：
3.4
作者：
Corti, Manuela;Smith, Barbara K.;Christou, Evangelos A.
通讯作者：
Christou, Evangelos A.
影响因子：
4.2
作者：
Bucher, Thomas;Colle, Marie-Anne;Joussemet, Beatrice
通讯作者：
Joussemet, Beatrice
影响因子：
2.3
作者：
Fuller, David D.;ElMallah, Mai K.;Smith, Barbara K.;Corti, Manuela;Lawson, Lee Ann;Falk, Darin J.;Byrne, Barry J.
通讯作者：
Byrne, Barry J.