Axonal transport of adeno-associated viral vectors is serotype-dependent

Salegio, Ernesto A.; Samaranch, Lluı́s; Kells, Adrian P.; Mittermeyer, Gabriele; Sebastián, Waldy San; Zhou, Shangzhen; Beyer, Janine; Forsayeth, John; Bankiewicz, Krystof S.

doi:10.1038/gt.2012.27

Cited by 139 publications

(133 citation statements)

References 19 publications

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“…58 Thus, FP+ cell bodies found at greater distances from the injection site are labeled retrogradely via transduced fibers entering the injection site. The retrograde capacity of rAAV2 vectors was previously shown by Towne et al 59 and Zhang et al 60 Since the dLGN is bidirectionally connected with area V1, we hypothesized that this thalamic nucleus could contain both anterogradely labeled FP+ axon terminals and retrogradely labeled FP+ cell bodies.…”

Section: Projections To the Dorsal Lateral Geniculate Nucleusmentioning

confidence: 98%

Serotype-dependent transduction efficiencies of recombinant adeno-associated viral vectors in monkey neocortex

et al. 2015

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Abstract. Viral vector-mediated expression of genes (e.g., coding for opsins and designer receptors) has grown increasingly popular. Cell-type specific expression is achieved by altering viral vector tropism through crosspackaging or by cell-specific promoters driving gene expression. Detailed information about transduction properties of most recombinant adeno-associated viral vector (rAAV) serotypes in macaque cortex is gradually becoming available. Here, we compare transduction efficiencies and expression patterns of reporter genes in two macaque neocortical areas employing different rAAV serotypes and promoters. A short version of the calmodulin-kinase-II (CaMKIIα0.4) promoter resulted in reporter gene expression in cortical neurons for all tested rAAVs, albeit with different efficiencies for spread: rAAV2/5>>rAAV2/7>rAAV2/8>rAAV2/9>>rAAV2/1 and proportion of transduced cells: rAAV2/1>rAAV2/5>rAAV2/7=rAAV2/9>rAAV2/8. In contrast to rodent studies, the cytomegalovirus (CMV) promoter appeared least efficient in macaque cortex. The human synapsin-1 promoter preceded by the CMV enhancer (enhSyn1) produced homogeneous reporter gene expression across all layers, while two variants of the CaMKIIα promoter resulted in different laminar transduction patterns and cell specificities. Finally, differences in expression patterns were observed when the same viral vector was injected in two neocortical areas. Our results corroborate previous findings that reporter-gene expression patterns and efficiency of rAAV transduction depend on serotype, promoter, cortical layer, and area. © The Authors. Published by SPIE under a Creative Commons Attribution 3.0 Unported License. Distribution or reproduction of this work in whole or in part requires full attribution of the original publication, including its DOI.

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Section: Projections To the Dorsal Lateral Geniculate Nucleusmentioning

confidence: 98%

Serotype-dependent transduction efficiencies of recombinant adeno-associated viral vectors in monkey neocortex

et al. 2015

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“…1, D-I). Some AAV vectors have been shown to produce retrograde transfection of cells projecting to the injection site (2,44). Based on a previous study (6), we inspected the nucleus of the solitary tract (NTS) for GFP-positive cells in brain stems from rats injected in the SFO with either shSCM (n ϭ 7) or shAT1aR (n ϭ 8) that were euthanized 4 wk after the injections.…”

Section: Viral Delivery and Transfection In The Sfomentioning

confidence: 99%

Angiotensin II type 1a receptors in subfornical organ contribute towards chronic intermittent hypoxia-associated sustained increase in mean arterial pressure

Saxena

Little

Nedungadi

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

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Saxena A, Little JT, Nedungadi TP, Cunningham JT. Angiotensin II type 1a receptors in subfornical organ contribute towards chronic intermittent hypoxia-associated sustained increase in mean arterial pressure. Am J Physiol Heart Circ Physiol 308: H435-H446, 2015. First published December 24, 2014 doi:10.1152/ajpheart.00747.2014.-Sleep apnea is associated with hypertension. The mechanisms contributing to a sustained increase in mean arterial pressure (MAP) even during normoxic awake-state remain unknown. Rats exposed to chronic intermittent hypoxia for 7 days, a model of the hypoxemia associated with sleep apnea, exhibit sustained increases in MAP even during the normoxic dark phase. Activation of the renin-angiotensin system (RAS) has been implicated in chronic intermittent hypoxia (CIH) hypertension. Since the subfornical organ (SFO) serves as a primary target for the central actions of circulating ANG II, we tested the effects of ANG II type 1a receptor (AT1aR) knockdown in the SFO on the sustained increase in MAP in this CIH model. Adeno-associated virus carrying green fluorescent protein (GFP) and small-hairpin RNA against either AT1aR or a scrambled control sequence (SCM) was stereotaxically injected in the SFO of rats. After recovery, MAP, heart rate, respiratory rate, and activity were continuously recorded using radiotelemetry. In the normoxic groups, the recorded variables did not deviate from the baseline values. Both CIH groups exhibited significant increases in MAP during CIH exposures (P Ͻ 0.05). During the normoxic dark phase in the CIH groups, only the SCMinjected group exhibited a sustained increase in MAP (P Ͻ 0.05). The AT1aR-CIH group showed significant decreases in FosB/⌬FosB staining in the median preoptic nucleus and the paraventricular nuclei of the hypothalamus compared with the SCM-CIH group. Our data indicate that AT1aRs in the SFO are critical for the sustained elevation in MAP and increased FosB/⌬FosB expression in forebrain autonomic nuclei associated with CIH. angiotensin receptor; subfornical organ; chronic intermittent hypoxia; obstructive sleep apnea; AT1aR SLEEP APNEA (SA) is increasingly being recognized as a cause of neurogenic and treatment-resistant hypertension (12,19,32,37,52). SA is associated with a sustained increase in sympathetic nerve activity (SNA) and mean arterial pressure (MAP) even during periods of wakefulness and normoxia (4, 33). Animal models of chronic intermittent hypoxia (CIH), such as the one introduced by Fletcher at al. (17), produce cardiovascular sequelae similar to sleep apnea (11). Together, it appears that CIH episodes lead to pathophysiological adaptations that may generate and sustain a heightened basal MAP, which is partially dependent on increased SNA.The renin-angiotensin system (RAS) is activated during CIH (11,16,54), and it contributes to CIH hypertension (11, 16). For example, in rats exposed to CIH, peripheral administration of losartan, an angiotensin II (ANG II) type 1 receptor (AT1R) antagonist, has been shown to prevent the increase ...

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“…Nevertheless, these fi ndings suggest that AAV vectors can be conferred the appropriate tropism and that genetic modifi cation of the based on the ability of locally transduced cells to effect the secretion and cross-correction of nearby, as well as distal, cells through diffusion and axonal transport of both the enzyme and the AAV vector. AAV vectors transported to distal sites in this manner could, in turn, correct additional areas of the brain, thereby providing broader therapeutic coverage than may be expected from a localized injection ( 39,(110)(111)(112)(113). Despite this phenomenon, effi cacy in animal models of LSDs has only been demonstrated using multiple bilateral intracranial injections of the AAV vectors ( 38,46 ).…”

Section: Effi Cacy Of Intracranial Delivery Of Aav Vectors For Neuropmentioning

confidence: 99%

Gene therapy for the neurological manifestations in lysosomal storage disorders

Cheng¹

2014

Journal of Lipid Research

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precise mechanistic links between these altered biochemical and cellular states and disease pathophysiology and pathogenesis remain unclear. Typically, disease severity is correlated with the level of residual activity, with individuals harboring lower levels presenting with more aggressive and severe disease manifestations. A large percentage of individuals, particularly those with signifi cantly diminished lysosomal function, also exhibit CNS involvement, the extent of which is dependent on the nature of the specifi c storage metabolites and the differential sensitivity of the resident cell types to the accumulated substrates. Although individually each LSD may be relatively rare, as a group, these disorders have an incidence of approximately 1 per 5,000 live births ( 4, 5 ).Of the approximately 50 LSDs that have been identifi ed thus far, the majority (greater than 70%) exhibit significant CNS involvement ( 6 ). This fi nding is not surprising given that lysosomes and related organelles are ubiquitously present in most cell types and are involved not only in recycling cellular debris but also in maintaining cellular homeostasis ( 7-9 ). Irrespective of the LSD, these CNS diseases are typically characterized by generalized infl ammation and neurodegeneration in multiple brain regions. In a subset of the diseases, altered calcium homeostasis and oxidative stress may also contribute to the overall pathology ( 10 ). Moreover, each specifi c disease may initially present with a unique temporal and spatial alteration that is dictated by the nature of the storage metabolites prior to the development of a more generalized global derangement ( 11 ). In some diseases, the symptoms are evident in neonates, whereas in others, they become apparent only in early childhood. Consequently, some LSDs may require early therapeutic intervention to affect broad and potentially all regions of the CNS. The lysosomal storage disorders (LSDs) are a heterogeneous group of inherited metabolic diseases that result from a defi ciency in one or more of the 80 enzymes or transporters that normally reside within the lysosomal compartment ( 1-3 ). A reduction or loss of one or more of these activities results in the progressive and relentless accumulation of undegraded macromolecules, a consequent derangement of proper lysosomal and autophagosomal functions, and ultimately, cellular demise. However, the

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Axonal transport of adeno-associated viral vectors is serotype-dependent

Cited by 139 publications

References 19 publications

Serotype-dependent transduction efficiencies of recombinant adeno-associated viral vectors in monkey neocortex

Serotype-dependent transduction efficiencies of recombinant adeno-associated viral vectors in monkey neocortex

Angiotensin II type 1a receptors in subfornical organ contribute towards chronic intermittent hypoxia-associated sustained increase in mean arterial pressure

Gene therapy for the neurological manifestations in lysosomal storage disorders

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