TY - JOUR
T1 - Systemic delivery of MeCP2 rescues behavioral and cellular deficits in female mouse models of Rett syndrome
AU - Garg, Saurabh K.
AU - Lioy, Daniel T.
AU - Cheval, Hélène
AU - McGann, James C.
AU - Bissonnette, John M.
AU - Murtha, Matthew J.
AU - Foust, Kevin D.
AU - Kaspar, Brian K.
AU - Bird, Adrian
AU - Mandel, Gail
PY - 2013
Y1 - 2013
N2 - 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 focus edon 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.
AB - 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 focus edon 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.
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U2 - 10.1523/JNEUROSCI.1854-13.2013
DO - 10.1523/JNEUROSCI.1854-13.2013
M3 - Article
C2 - 23966684
AN - SCOPUS:84882718651
SN - 0270-6474
VL - 33
SP - 13612
EP - 13620
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 34
ER -