Controlling AAV Tropism in the Nervous System with Natural and Engineered Capsids

Castle, Michael J.; Turunen, Heikki; Vandenberghe, Luk; Wolfe, John H.

doi:10.1007/978-1-4939-3271-9_10

Cited by 112 publications

(106 citation statements)

References 133 publications

(163 reference statements)

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“…With translational studies in mind, it is important to demonstrate consistent tropism of a particular rAAV, as examples where the tropism of a given rAAV capsid does not remain consistent in rodents and higher animals have been described [7]. In the current study, we observed that the affinity of Olig001 to transduce oligodendroglia was conserved between species.…”

Section: Discussionsupporting

confidence: 49%

Novel oligodendroglial alpha synuclein viral vector models of multiple system atrophy: studies in rodents and nonhuman primates

Mandel

Marmion

Kirik

et al. 2017

acta neuropathol commun

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Multiple system atrophy (MSA) is a horrible and unrelenting neurodegenerative disorder with an uncertain etiology and pathophysiology. MSA is a unique proteinopathy in which alpha-synuclein (α-syn) accumulates preferentially in oligodendroglia rather than neurons. Glial cytoplasmic inclusions (GCIs) of α-syn are thought to elicit changes in oligodendrocyte function, such as reduced neurotrophic support and demyelination, leading to neurodegeneration. To date, only a murine model using one of three promoters exist to study this disease. We sought to develop novel rat and nonhuman primate (NHP) models of MSA by overexpressing α-syn in oligodendroglia using a novel oligotrophic adeno-associated virus (AAV) vector, Olig001. To establish tropism, rats received intrastriatal injections of Olig001 expressing GFP. Histological analysis showed widespread expression of GFP throughout the striatum and corpus callosum with >95% of GFP+ cells co-localizing with oligodendroglia and little to no expression in neurons or astrocytes. We next tested the efficacy of this vector in rhesus macaques with intrastriatal injections of Olig001 expressing GFP. As in rats, we observed a large number of GFP+ cells in gray matter and white matter tracts of the striatum and the corpus callosum, with 90–94% of GFP+ cells co-localizing with an oligodendroglial marker. To evaluate the potential of our vector to elicit MSA-like pathology in NHPs, we injected rhesus macaques intrastriatally with Olig001 expressing the α-syn transgene. Histological analysis 3-months after injection demonstrated widespread α-syn expression throughout the striatum as determined by LB509 and phosphorylated serine-129 α-syn immunoreactivity, all of which displayed as tropism similar to that seen with GFP. As in MSA, Olig001-α-syn GCIs in our model were resistant to proteinase K digestion and caused microglial activation. Critically, demyelination was observed in the white matter tracts of the corpus callosum and striatum of Olig001-α-syn but not Olig001-GFP injected animals, similar to the human disease. These data support the concept that this vector can provide novel rodent and nonhuman primate models of MSA.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-017-0451-7) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 49%

Novel oligodendroglial alpha synuclein viral vector models of multiple system atrophy: studies in rodents and nonhuman primates

Mandel

Marmion

Kirik

et al. 2017

acta neuropathol commun

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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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“…2, b). As our viral vector, we chose AAV9, a serotype of AAV with favorable tropism for neurons and large spatial spread after direct intracranial delivery 30 . This vector encoded the DREADD receptor hM4Di, fused to the fluorescent reporter mCherry to facilitate histological visualization.…”

Section: Anatomical and Genetic Targeting Of Dreaddsmentioning

confidence: 99%

Acoustically targeted chemogenetics for the non-invasive control of neural circuits

et al. 2018

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Neurological and psychiatric diseases often involve the dysfunction of specific neural circuits in particular regions of the brain. Existing treatments, including drugs and implantable brain stimulators, aim to modulate the activity of these circuits, but are typically not cell type-specific, lack spatial targeting or require invasive procedures. Here, we introduce an approach to modulating neural circuits noninvasively with spatial, cell-type and temporal specificity. This approach, called acoustically targeted chemogenetics, or ATAC, uses transient ultrasonic opening of the blood brain barrier to transduce neurons at specific locations in the brain with virally-encoded engineered G-protein-coupled receptors, which subsequently respond to systemically administered bio-inert compounds to activate or inhibit the activity of these neurons. We demonstrate this concept in mice by using ATAC to noninvasively modify and subsequently activate or inhibit excitatory neurons within the hippocampus, showing that this enables pharmacological control of memory formation. This technology allows a brief, noninvasive procedure to make one or more specific brain regions capable of being selectively modulated using orally bioavailable compounds, thereby overcoming some of the key limitations of conventional brain therapies.

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Controlling AAV Tropism in the Nervous System with Natural and Engineered Capsids

Cited by 112 publications

References 133 publications

Novel oligodendroglial alpha synuclein viral vector models of multiple system atrophy: studies in rodents and nonhuman primates

Novel oligodendroglial alpha synuclein viral vector models of multiple system atrophy: studies in rodents and nonhuman primates

Viral vectors for therapy of neurologic diseases

Acoustically targeted chemogenetics for the non-invasive control of neural circuits

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