Systemic Delivery of MeCP2 Rescues Behavioral and Cellular Deficits in Female Mouse Models of Rett Syndrome
Systemic Delivery of MeCP2 Rescues Behavioral and Cellular Deficits in Female Mouse Models of Rett Syndrome
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DOI：
10.1523/jneurosci.1854-13.2013
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发表时间：
2013-08-21
影响因子：
5.3
通讯作者：
Mandel, Gail
中科院分区：
文献类型：
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作者：
Garg, Saurabh K.;Lioy, Daniel T.;Mandel, Gail
编码转录因子甲基-CpG结合蛋白2（MECP 2）的X连锁基因的从头突变是神经系统疾病Rett综合征（RTT）的最常见原因。半合子雄性通常死于新生儿脑病。杂合子雌性存活至成年，但表现出严重的症状，包括小头畸形，有目的的手部动作和言语的丧失，以及运动异常，这些症状在明显正常发育一段时间后出现。大多数研究都集中在雄性小鼠模型上，因为这些小鼠的潜伏期较短，症状严重，但这些小鼠在受影响的雌性小鼠中模仿疾病的程度尚不清楚。很少有针对女性的治疗方法，这是更适合性别的模式。在这里，我们表明，自身互补的AAV 9，承载MeCP 2 cDNA的控制下，其自身的启动子（scAAV 9/MeCP 2）的片段，是能够显着稳定或逆转症状时，全身给药到雌性RTT小鼠。据我们所知，这是第一个潜在的基因治疗女性患有RTT。
De novo mutations in the X-linked gene encoding the transcription factor methyl-CpG binding protein 2 (MECP2) are the most frequent cause of the neurological disorder Rett syndrome (RTT). Hemizygous males usually die of neonatal encephalopathy. Heterozygous females survive into adulthood but exhibit severe symptoms including microcephaly, loss of purposeful hand motions and speech, and motor abnormalities, which appear after a period of apparently normal development. Most studies have focused on male mouse models because of the shorter latency to and severity in symptoms, yet how well these mice mimic the disease in affected females is not clear. Very few therapeutic treatments have been proposed for females, the more gender-appropriate model. Here, we show that self-complementary AAV9, bearing MeCP2 cDNA under control of a fragment of its own promoter (scAAV9/MeCP2), is capable of significantly stabilizing or reversing symptoms when administered systemically into female RTT mice. To our knowledge, this is the first potential gene therapy for females afflicted with RTT.