Widespread Central Nervous System Gene Transfer and Silencing After Systemic Delivery of Novel AAV-AS Vector

Choudhury, Sourav; Harris, Anne F; Cabral, Damien J.; Keeler, Allison M.; Sapp, Ellen; Ferreira, Jennifer S; Gray‐Edwards, Heather L.; Johnson, Jacob A.; Johnson, Aime K.; Su, Qin; Stoica, Lorelei; DiFiglia, Marian; Aronin, Neil; Martin, Douglas R.; Gao, Guangping; Sena‐Esteves, Miguel

doi:10.1038/mt.2015.231

Cited by 100 publications

(76 citation statements)

References 64 publications

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“…An AAV capsid that can reach the CNS after peripheral administration, such as AAV9 (Foust et al, 2009; Wang et al, 2010; Miyake et al, 2011) or other natural AAV serotypes (Miyake et al, 2011; Snyder et al, 2011; Samaranch et al, 2013; Yang et al, 2014; Jackson et al, 2015b) is advantageous for a relatively non-invasive administration that yields wide-scale expression. Now there are several engineered capsids with increased neuronal transduction efficiency (Choudhury et al, 2016a,b; Deverman et al, 2016). Here we tested AAV-PHP.B described in Deverman et al (2016) in rats for the first time in order to achieve greater gene transfer efficiency and potentially for improved neuronal targeting as well.…”

Section: Introductionmentioning

confidence: 99%

Better Targeting, Better Efficiency for Wide-Scale Neuronal Transduction with the Synapsin Promoter and AAV-PHP.B

Jackson

Dayton

Deverman

et al. 2016

Front. Mol. Neurosci.

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Widespread genetic modification of cells in the central nervous system (CNS) with a viral vector has become possible and increasingly more efficient. We previously applied an AAV9 vector with the cytomegalovirus/chicken beta-actin (CBA) hybrid promoter and achieved wide-scale CNS transduction in neonatal and adult rats. However, this method transduces a variety of tissues in addition to the CNS. Thus we studied intravenous AAV9 gene transfer with a synapsin promoter to better target the neurons. We noted in systematic comparisons that the synapsin promoter drives lower level expression than does the CBA promoter. The engineered adeno-associated virus (AAV)-PHP.B serotype was compared with AAV9, and AAV-PHP.B did enhance the efficiency of expression. Combining the synapsin promoter with AAV-PHP.B could therefore be advantageous in terms of combining two refinements of targeting and efficiency. Wide-scale expression was used to model a disease with widespread pathology. Vectors encoding the amyotrophic lateral sclerosis (ALS)-related protein transactive response DNA-binding protein, 43 kDa (TDP-43) with the synapsin promoter and AAV-PHP.B were used for efficient CNS-targeted TDP-43 expression. Intracerebroventricular injections were also explored to limit TDP-43 expression to the CNS. The neuron-selective promoter and the AAV-PHP.B enhanced gene transfer and ALS disease modeling in adult rats.

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Section: Introductionmentioning

confidence: 99%

Better Targeting, Better Efficiency for Wide-Scale Neuronal Transduction with the Synapsin Promoter and AAV-PHP.B

Jackson

Dayton

Deverman

et al. 2016

Front. Mol. Neurosci.

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“…47 In the future, it may be possible to enhance neuronal targeting even further by combining the transcriptional targeting described here with neuron-targeted AAV capsids. 48 …”

Section: Discussionmentioning

confidence: 99%

Tailored transgene expression to specific cell types in the central nervous system after peripheral injection with AAV9

Dashkoff

Lerner

Truong

et al. 2016

Molecular Therapy - Methods & Clinical Development

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The capacity of certain adeno-associated virus (AAV) vectors to cross the blood–brain barrier after intravenous delivery offers a unique opportunity for noninvasive brain delivery. However, without a well-tailored system, the use of a peripheral route injection may lead to undesirable transgene expression in nontarget cells or organs. To refine this approach, the present study characterizes the transduction profiles of new self-complementary AAV9 (scAAV9) expressing the green fluorescent protein (GFP) either under an astrocyte (glial fibrillary acidic (GFA) protein) or neuronal (Synapsin (Syn)) promoter, after intravenous injection of adult mice (2 × 1013 vg/kg). ScAAV9-GFA-GFP and scAAV9-Syn-GFP robustly transduce astrocytes (11%) and neurons (17%), respectively, without aberrant expression leakage. Interestingly, while the percentages of GFP-positive astrocytes with scAAV9-GFA-GFP are similar to the performances observed with scAAV9-CBA-GFP (broadly active promoter), significant higher percentages of neurons express GFP with scAAV9-Syn-GFP. GFP-positive excitatory as well as inhibitory neurons are observed, as well as motor neurons in the spinal cord. Additionally, both activated (GFAP-positive) and resting astrocytes (GFAP-negative) express the reporter gene after scAAV9-GFA-GFP injection. These data thoroughly characterize the gene expression specificity of AAVs fitted with neuronal and astrocyte-selective promoters after intravenous delivery, which will prove useful for central nervous system (CNS) gene therapy approaches in which peripheral expression of transgene is a concern.

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“…The other major concern is that the presence of neutralizing antibodies to AAV in monkeys and humans can severely limit the extent of gene transfer by systemic infusion (Gray et al, 2011; Samaranch et al, 2012). Recent efforts at capsid reengineering (Castle et al, 2016) have led to the generation of two AAV capsid variants, AAV-AS (Choudhury et al, 2015) and AAV-PHP.B (Deverman et al, 2016). Both vectors are superior to the current standard AAV9 at transducing the CNS, with high efficiency of gene transfer to neurons.…”

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 Central Nervous System Gene Transfer and Silencing After Systemic Delivery of Novel AAV-AS Vector

Cited by 100 publications

References 64 publications

Better Targeting, Better Efficiency for Wide-Scale Neuronal Transduction with the Synapsin Promoter and AAV-PHP.B

Better Targeting, Better Efficiency for Wide-Scale Neuronal Transduction with the Synapsin Promoter and AAV-PHP.B

Tailored transgene expression to specific cell types in the central nervous system after peripheral injection with AAV9

Viral vectors for therapy of neurologic diseases

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