CNS-dominant human FMRP isoform rescues seizures, fear, and sleep abnormalities in Fmr1-KO mice.

Fragile X syndrome is a neurodevelopmental disorder caused by the absence of the mRNA-binding protein fragile X messenger ribonucleoprotein (FMRP). Because FMRP is a highly pleiotropic protein controlling the expression of hundreds of genes, viral vector-mediated gene replacement therapy is viewed as a potential viable treatment to correct the fundamental underlying molecular pathology inherent in the disorder. Here, we studied the safety profile and therapeutic effects of a clinically relevant dose of a self-complementary adeno-associated viral (AAV) vector containing a major human brain isoform of FMRP after intrathecal injection into wild-type and fragile X-KO mice. Analysis of the cellular transduction in the brain indicated primarily neuronal transduction with relatively sparse glial expression, similar to endogenous FMRP expression in untreated wild-type mice. AAV vector-treated KO mice showed recovery from epileptic seizures, normalization of fear conditioning, reversal of slow-wave deficits as measured via electroencephalographic recordings, and restoration of abnormal circadian motor activity and sleep. Further assessment of vector efficacy by tracking and analyzing individual responses demonstrated correlations between the level and distribution of brain transduction and drug response. These preclinical findings further demonstrate the validity of AAV vector-mediated gene therapy for treating the most common genetic cause of cognitive impairment and autism in children.

Sexually dimorphic patterns in electroencephalography power spectrum and autism-related behaviors in a rat model of fragile X syndrome.

Fragile X syndrome (FXS), a neurodevelopmental disorder with autistic features, is caused by the loss of the fragile X mental retardation protein. Sex-specific differences in the clinical profile have been observed in FXS patients, but few studies have directly compared males and females in rodent models of FXS. To address this, we performed electroencephalography (EEG) recordings and a battery of autism-related behavioral tasks on juvenile and young adult Fmr1 knockout (KO) rats. EEG analysis demonstrated that compared to wild-type, male Fmr1 KO rats showed an increase in gamma frequency band power in the frontal cortex during the sleep-like immobile state, and both male and female KO rats failed to show an increase in delta frequency power in the sleep-like state, as observed in wild-type rats. Previous studies of EEG profiles in FXS subjects also reported abnormally increased gamma frequency band power, highlighting this parameter as a potential translatable biomarker. Both male and female Fmr1 KO rats displayed reduced exploratory behaviors in the center zone of the open field test, and increased distance travelled in an analysis of 24-h home cage activity, an effect that was more prominent during the nocturnal phase. Reduced wins against wild-type opponents in the tube test of social dominance was seen in both sexes. In contrast, increased repetitive behaviors in the wood chew test was observed in male but not female KO rats, while increased freezing in a fear conditioning test was observed only in the female KO rats. Our findings highlight sex differences between male and female Fmr1 KO rats, and indicate that the rat model of FXS could be a useful tool for the development of new therapeutics for treating this debilitating neurodevelopmental disorder.

Sexually Divergent Mortality and Partial Phenotypic Rescue After Gene Therapy in a Mouse Model of Dravet Syndrome.

Dravet syndrome (DS) is a neurodevelopmental genetic disorder caused by mutations in the SCN1A gene encoding the α subunit of the NaV1.1 voltage-gated sodium channel that controls neuronal action potential firing. The high density of this mutated channel in GABAergic interneurons results in impaired inhibitory neurotransmission and subsequent excessive activation of excitatory neurons. The syndrome is associated with severe childhood epilepsy, autistic behaviors, and sudden unexpected death in epilepsy. Here, we compared the rescue effects of an adeno-associated viral (AAV) vector coding for the multifunctional ß1 sodium channel auxiliary subunit (AAV-NaVß1) with a control vector lacking a transgene. We hypothesized that overexpression of NaVß1 would facilitate the function of residual voltage-gated channels and improve the DS phenotype in the Scn1a+/- mouse model of DS. AAV-NaVß1 was injected into the cerebral spinal fluid of neonatal Scn1a+/- mice. In untreated control Scn1a+/- mice, females showed a higher degree of mortality than males. Compared with Scn1a+/- control mice, AAV-NaVß1-treated Scn1a+/- mice displayed increased survival, an outcome that was more pronounced in females than males. In contrast, behavioral analysis revealed that male, but not female, Scn1a+/- mice displayed motor hyperactivity, and abnormal performance on tests of fear and anxiety and learning and memory. Male Scn1a+/- mice treated with AAV-NaVß1 showed reduced spontaneous seizures and normalization of motor activity and performance on the elevated plus maze test. These findings demonstrate sex differences in mortality in untreated Scn1a+/- mice, an effect that may be related to a lower level of intrinsic inhibitory tone in female mice, and a normalization of aberrant behaviors in males after central nervous system administration of AAV-NaVß1. The therapeutic efficacy of AAV-NaVß1 in a mouse model of DS suggests a potential new long-lasting biological therapeutic avenue for the treatment of this catastrophic epilepsy.

Amphiphile-like self assembly of metal organic polyhedra having both polar and non-polar groups.

Mixed linker metal-organic polyhedra (MOPs) with polar and non-polar groups on the same MOP have been synthesized. This yields two types of MOPs, one where the ligands are evenly and symmetrically distributed over each polyhedron, as confirmed crystallographically and the other where respective groups segregate. The segregation is confirmed by the amphiphile-like behavior of the latter MOP in different polarity solvents, as seen through transmission electron microscopy (TEM) even though the anchor points of the functional groups are ∼10 Šapart on the MOP surface.