Widespread neuron-specific transgene expression in brain and spinal cord following synapsin promoter-driven AAV9 neonatal intracerebroventricular injection

McLean, Jesse R.; Smith, Gaynor A.; Rocha, Emily M.; Hayes, Melissa A.; Beagan, Jonathan A.; Hallett, Peter; Isacson, Ole

doi:10.1016/j.neulet.2014.05.044

Cited by 78 publications

(76 citation statements)

References 36 publications

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“…36 The use of the synapsin promoter permitted long-term neuron-specific tropism of the FMRP transgene protein. This is important because FMRP is expressed predominantly in neurons throughout all regions of the adult mouse CNS.…”

Section: Discussionmentioning

confidence: 99%

FMRP Expression Levels in Mouse Central Nervous System Neurons Determine Behavioral Phenotype

et al. 2016

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Fragile X mental retardation protein (FMRP) is absent or highly reduced in Fragile X Syndrome, a genetic disorder causing cognitive impairment and autistic behaviors. Previous proof-of-principle studies have demonstrated that restoring FMRP in the brain using viral vectors can improve pathological abnormalities in mouse models of fragile X. However, unlike small molecule drugs where the dose can readily be adjusted during treatment, viral vector–based biological therapeutic drugs present challenges in terms of achieving optimal dosing and expression levels. The objective of this study was to investigate the consequences of expressing varying levels of FMRP selectively in neurons of Fmr1 knockout and wild-type (WT) mice. A wide range of neuronal FMRP transgene levels was achieved in individual mice after intra-cerebroventricular administration of adeno-associated viral vectors coding for FMRP. In all treated knockout mice, prominent FMRP transgene expression was observed in forebrain structures, whereas lower levels were present in more caudal regions of the brain. Reduced levels of the synaptic protein PSD-95, elevated levels of the transcriptional modulator MeCP2, and abnormal motor activity, anxiety, and acoustic startle responses in Fmr1 knockout mice were fully or partially rescued after expression of FMRP at about 35–115% of WT expression, depending on the brain region examined. In the WT mouse, moderate FMRP over-expression of up to about twofold had little or no effect on PSD-95 and MeCP2 levels or on behavioral endophenotypes. In contrast, excessive over-expression in the Fmr1 knockout mouse forebrain (approximately 2.5–6-fold over WT) induced pathological motor hyperactivity and suppressed the startle response relative to WT mice. These results delineate a range of FMRP expression levels in the central nervous system that confer phenotypic improvement in fragile X mice. Collectively, these findings are pertinent to the development of long-term curative gene therapy strategies for treating Fragile X Syndrome and other neurodevelopmental disorders.

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Section: Discussionmentioning

confidence: 99%

FMRP Expression Levels in Mouse Central Nervous System Neurons Determine Behavioral Phenotype

et al. 2016

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“…New born pups (P1) were cryo-anesthetized by placing them at 0°C for 3 min before injection as described (Kim et al, 2013; McLean et al, 2014; Passini and Wolfe, 2001). Then 1.2 μl (10 6 –10 7 pfu/ml) of GFP (Green Fluorescent Protein) conjugated lentiviral particles of either HDAC4 RNAi or control RNAi (n = 9) were slowly injected into the cortex of each hemisphere located anteroposterior −2.0 mm, lateral +1.5 mm and vertical −1.5mm to a depth of 1mm.…”

Section: Methodsmentioning

confidence: 99%

Isoflurane-induced inactivation of CREB through histone deacetylase 4 is responsible for cognitive impairment in developing brain

Sen

2016

Neurobiology of Disease

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Anesthetics including isoflurane are known to induce neuronal dysfunction in the developing brain, however, the underlying mechanism is mostly unknown. The transcriptional activation of CREB (cyclic AMP response element binding protein) and the alterations in acetylation of histones modulated by several histone deacetylases such as HDAC4 (histone deacetylase 4) are known to contribute to synaptic plasticity in the brain. Here we have shown that administration of isoflurane (1.4%) for 2h leads to transcriptional inactivation of CREB which results in loss of dendritic outgrowth and decreased expression level of proteins essential for memory and cognitive functions, such as bdnf, and c-fos in the developing brain of mice at postnatal day 7 (PND7). To elucidate the molecular mechanism, we found that exposure to isoflurane leads to an increase in nuclear translocation of HDAC4, which interacts with CREB in the nucleus. This event, in turn, results in a decrease in interaction between an acetyltransferase, CBP, and CREB that ultimately leads to transcriptional inactivation of CREB. As a result, the expression level of bdnf, and cfos were significantly down-regulated after administration of isoflurane in PND7 brain. Depletion of HDAC4 in PND7 brain rescues the transcriptional activation of CREB along with augmentation in the level of the expression level of bdnf and c-fos. Moreover, administration of lentiviral particles of HDAC4 RNAi in primary neurons rescues neurite outgrowth following isoflurane treatment. Taken together, our study suggests that HDAC4- induced transcriptional inactivation of CREB is responsible for isoflurane-induced cognitive dysfunction in the brain.

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“…Infusion into the lateral ventricles (ICV) in adult mice primarily results in transduction of the surrounding ependymal cell layer (Davidson et al, 2000) which can be extended to the brain parenchyma by intravenous co-administration of mannitol to raise osmolarity and thereby open up junctions between ependymal cells. ICV injection of AAV into neonatal mice provides a means of widespread gene delivery of many cell types throughout the brain and spinal cord (Kim et al, 2014; McLean et al, 2014). On the other hand, IT injection into the CSF, either at the subarachnoid space in the cisterna magna or into the intervertebral cistern in the lumbar spinal cord, is less invasive than ICV delivery and results in robust and widespread transduction of spinal cord motor neurons, as well as dorsal root ganglia (DRG) in mice (Snyder et al, 2011).…”

Section: Deliver the Vector The More The Better (Modes And Sites mentioning

confidence: 99%

Viral vectors for therapy of neurologic diseases

et al. 2017

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Neurological disorders – disorders of the brain, spine and associated nerves – are a leading contributor to global disease burden with a shockingly large associated economic cost. Various treatment approaches – pharmaceutical medication, device-based therapy, physiotherapy, surgical intervention, among others – have been explored to alleviate the resulting extent of human suffering. In recent years, gene therapy using viral vectors – encoding a therapeutic gene or inhibitory RNA into a “gutted” viral capsid and supplying it to the nervous system – has emerged as a clinically viable option for therapy of brain disorders. In this Review, we provide an overview of the current state and advances in the field of viral vector-mediated gene therapy for neurological disorders. Vector tools and delivery methods have evolved considerably over recent years, with the goal of providing greater and safer genetic access to the central nervous system. Better etiological understanding of brain disorders has concurrently led to identification of improved therapeutic targets. We focus on the vector technology, as well as preclinical and clinical progress made thus far for brain cancer and various neurodegenerative and neurometabolic disorders, and point out the challenges and limitations that accompany this new medical modality. Finally, we explore the directions that neurological gene therapy is likely to evolve towards in the future.

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Widespread neuron-specific transgene expression in brain and spinal cord following synapsin promoter-driven AAV9 neonatal intracerebroventricular injection

Cited by 78 publications

References 36 publications

FMRP Expression Levels in Mouse Central Nervous System Neurons Determine Behavioral Phenotype

FMRP Expression Levels in Mouse Central Nervous System Neurons Determine Behavioral Phenotype

Isoflurane-induced inactivation of CREB through histone deacetylase 4 is responsible for cognitive impairment in developing brain

Viral vectors for therapy of neurologic diseases

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