title: A codon-optimized Mecp2 transgene corrects breathing deficits and improves survival in a mouse model of Rett syndrome.
abstract: Rett syndrome (RTT) is a severe X-linked neurodevelopmental disorder that is primarily caused by mutations in the methyl CpG binding protein 2 gene (MECP2). RTT is the second most prevalent cause of intellectual disability in girls and there is currently no cure for the disease. The finding that the deficits caused by the loss of Mecp2 are reversible in the mouse has bolstered interest in gene therapy as a cure for RTT. In order to assess the feasibility of gene therapy in a RTT mouse model, and in keeping with translational goals, we investigated the efficacy of a self-complementary AAV9 vector expressing a codon-optimized version of Mecp2 (AAV9-MCO) delivered via a systemic approach in early symptomatic Mecp2-deficient (KO) mice. Our results show that AAV9-MCO administered at a dose of 2×1011viral genome (vg)/mouse was able to significantly increase survival and weight gain, and delay the occurrence of behavioral deficits. Apneas, which are one of the core RTT breathing deficits, were significantly decreased to WT levels in Mecp2 KO mice after AAV9-MCO administration. Semi-quantitative analysis showed that AAV9-MCO administration in Mecp2 KO mice resulted in 10 to 20% Mecp2 immunopositive cells compared to WT animals, with the highest Mecp2 expression found in midbrain regions known to regulate cardio-respiratory functions. In addition, we also found a cell autonomous increase in tyrosine hydroxylase levels in the A1C1 and A2C2 catecholaminergic Mecp2+ neurons in treated Mecp2 KO mice, which may partly explain the beneficial effect of AAV9-MCO administration on apneas occurrence.
authors.affiliation: Aix Marseille Univ, INSERM, GMGF, UMR_S 910, 13385 Marseille, France.
authors.forename: Valerie
authors.initials: V
authors.lastname: Matagne
authors.affiliation: Aix Marseille Univ, INSERM, GMGF, UMR_S 910, 13385 Marseille, France.
authors.forename: Yann
authors.initials: Y
authors.lastname: Ehinger
authors.affiliation: Aix Marseille Univ, INSERM, GMGF, UMR_S 910, 13385 Marseille, France.
authors.forename: Lydia
authors.initials: L
authors.lastname: Saidi
authors.affiliation: Aix Marseille Univ, INSERM, GMGF, UMR_S 910, 13385 Marseille, France.
authors.forename: Ana
authors.initials: A
authors.lastname: Borges-Correia
authors.affiliation: Center of Research on Myology, FRE 3617 Centre National de la Recherche Scientifique, UMRS 974 INSERM, French Institute of Myology, Pierre and Marie Curie University Paris, France.
authors.forename: Martine
authors.initials: M
authors.lastname: Barkats
authors.affiliation: Aix Marseille Univ, INSERM, GMGF, UMR_S 910, 13385 Marseille, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Bartoli
authors.affiliation: Aix Marseille Univ, INSERM, GMGF, UMR_S 910, 13385 Marseille, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Villard
authors.affiliation: Aix Marseille Univ, INSERM, GMGF, UMR_S 910, 13385 Marseille, France. Electronic address: Jean-christophe.roux@univ-amu.fr.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Roux
mesh_terms: D000588:Amines; D000818:Animals; D001049:Apnea / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D003062:Codon; D003509:Cyclohexanecarboxylic Acids; D000229:Dependovirus; D004195:Disease Models, Animal; D018450:Disease Progression; D000077206:Gabapentin; D015316:Genetic Therapy; D005822:Genetic Vectors; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D008636:Mesencephalon / Q000378:metabolism / Q000473:pathology; D051783:Methyl-CpG-Binding Protein 2 / Q000008:administration & dosage* / Q000235:genetics / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012119:Respiration; D015518:Rett Syndrome / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D016019:Survival Analysis; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D015430:Weight Gain; D005680:gamma-Aminobutyric Acid
chemical_list: D000588:Amines; D003062:Codon; D003509:Cyclohexanecarboxylic Acids; D051783:Methyl-CpG-Binding Protein 2; D049452:Green Fluorescent Proteins; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin; D014446:Tyrosine 3-Monooxygenase
keywords: AAV9; Animal model; Gene therapy; Mecp2; Rett syndrome