Exosome-associated AAV vector as a robust and convenient neuroscience tool
Identifieur interne : 000883 ( Pmc/Curation ); précédent : 000882; suivant : 000884Exosome-associated AAV vector as a robust and convenient neuroscience tool
Auteurs : Eloise Hudry [États-Unis] ; Courtney Martin [États-Unis] ; Sheetal Gandhi [États-Unis] ; Bence György [États-Unis] ; Deborah I. Scheffer [États-Unis] ; Dakai Mu [États-Unis] ; Steven F. Merkel [États-Unis] ; Federico Mingozzi [France] ; Zachary Fitzpatrick [États-Unis] ; Hemi Dimant [États-Unis] ; Marissa Masek [États-Unis] ; Tim Ragan [États-Unis] ; Sisareuth Tan [France] ; Alain R. Brisson [France] ; Servio H. Ramirez [États-Unis] ; Bradley T. Hyman [États-Unis] ; Casey A. Maguire [États-Unis]Source :
- Gene therapy [ 0969-7128 ] ; 2016.
Abstract
Adeno-associated virus (AAV) vectors are showing promise in gene therapy trials and have proven to be extremely efficient biological tools in basic neuroscience research. One major limitation to their widespread use in the neuroscience laboratory is the cost, labor, skill, and time intense purification process of AAV. We have recently shown that AAV can associate with exosomes (exo-AAV) when vector is isolated from conditioned media of producer cells, and the exo-AAV is more resistant to neutralizing anti-AAV antibodies compared to standard AAV. Here we demonstrate that simple pelleting of exo-AAV from media via ultracentrifugation, results in high-titer vector preparations capable of efficient transduction of central nervous system (CNS) cells after systemic injection in mice. We observed that exo-AAV is more efficient at gene delivery to the brain at low vector doses relative to conventional AAV, even when derived from a serotype that does not normally efficiently cross the blood brain barrier. Similar cell types were transduced by exo-AAV and conventionally purified vector. Importantly, no cellular toxicity was noted in exo-AAV transduced cells. We demonstrated the utility and robustness of exo-AAV-mediated gene delivery by detecting direct GFP fluorescence after systemic injection, allowing 3-dimensional reconstruction of transduced Purkinje cells in the cerebellum using
Url:
DOI: 10.1038/gt.2016.11
PubMed: 26836117
PubMed Central: 4824662
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<country xml:lang="fr">États-Unis</country>
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<country xml:lang="fr">États-Unis</country>
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<front><div type="abstract" xml:lang="en"><p id="P1">Adeno-associated virus (AAV) vectors are showing promise in gene therapy trials and have proven to be extremely efficient biological tools in basic neuroscience research. One major limitation to their widespread use in the neuroscience laboratory is the cost, labor, skill, and time intense purification process of AAV. We have recently shown that AAV can associate with exosomes (exo-AAV) when vector is isolated from conditioned media of producer cells, and the exo-AAV is more resistant to neutralizing anti-AAV antibodies compared to standard AAV. Here we demonstrate that simple pelleting of exo-AAV from media via ultracentrifugation, results in high-titer vector preparations capable of efficient transduction of central nervous system (CNS) cells after systemic injection in mice. We observed that exo-AAV is more efficient at gene delivery to the brain at low vector doses relative to conventional AAV, even when derived from a serotype that does not normally efficiently cross the blood brain barrier. Similar cell types were transduced by exo-AAV and conventionally purified vector. Importantly, no cellular toxicity was noted in exo-AAV transduced cells. We demonstrated the utility and robustness of exo-AAV-mediated gene delivery by detecting direct GFP fluorescence after systemic injection, allowing 3-dimensional reconstruction of transduced Purkinje cells in the cerebellum using <italic>ex-vivo</italic>
serial 2-photon tomography. The ease of isolation combined with the high efficiency of transgene expression in the CNS, may enable widespread use of exo-AAV as a neuroscience research tool. Furthermore, the ability of exo-AAV to evade neutralizing antibodies while still transducing CNS after peripheral delivery is clinically relevant.</p>
</div>
</front>
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</author>
<author><name sortKey="Serrano Pozo, A" uniqKey="Serrano Pozo A">A Serrano-Pozo</name>
</author>
<author><name sortKey="Hyman, Bt" uniqKey="Hyman B">BT Hyman</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Persidsky, Y" uniqKey="Persidsky Y">Y Persidsky</name>
</author>
<author><name sortKey="Fan, S" uniqKey="Fan S">S Fan</name>
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<author><name sortKey="Dykstra, H" uniqKey="Dykstra H">H Dykstra</name>
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<author><name sortKey="Rom, S" uniqKey="Rom S">S Rom</name>
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<author><name sortKey="Ramirez, Sh" uniqKey="Ramirez S">SH Ramirez</name>
</author>
</analytic>
</biblStruct>
</listBibl>
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</TEI>
<pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<pmc-dir>properties manuscript</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-journal-id">9421525</journal-id>
<journal-id journal-id-type="pubmed-jr-id">8603</journal-id>
<journal-id journal-id-type="nlm-ta">Gene Ther</journal-id>
<journal-id journal-id-type="iso-abbrev">Gene Ther.</journal-id>
<journal-title-group><journal-title>Gene therapy</journal-title>
</journal-title-group>
<issn pub-type="ppub">0969-7128</issn>
<issn pub-type="epub">1476-5462</issn>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">26836117</article-id>
<article-id pub-id-type="pmc">4824662</article-id>
<article-id pub-id-type="doi">10.1038/gt.2016.11</article-id>
<article-id pub-id-type="manuscript">NIHMS753186</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Article</subject>
</subj-group>
</article-categories>
<title-group><article-title>Exosome-associated AAV vector as a robust and convenient neuroscience tool</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Hudry</surname>
<given-names>Eloise</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
<xref ref-type="aff" rid="A2">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Martin</surname>
<given-names>Courtney</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
<xref ref-type="aff" rid="A2">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Gandhi</surname>
<given-names>Sheetal</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
<xref ref-type="aff" rid="A2">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>György</surname>
<given-names>Bence</given-names>
</name>
<xref ref-type="aff" rid="A2">2</xref>
<xref ref-type="aff" rid="A3">3</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Scheffer</surname>
<given-names>Deborah I.</given-names>
</name>
<xref ref-type="aff" rid="A3">3</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Mu</surname>
<given-names>Dakai</given-names>
</name>
<xref ref-type="aff" rid="A2">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Merkel</surname>
<given-names>Steven F.</given-names>
</name>
<xref ref-type="aff" rid="A4">4</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Mingozzi</surname>
<given-names>Federico</given-names>
</name>
<xref ref-type="aff" rid="A5">5</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Fitzpatrick</surname>
<given-names>Zachary</given-names>
</name>
<xref ref-type="aff" rid="A2">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Dimant</surname>
<given-names>Hemi</given-names>
</name>
<xref ref-type="aff" rid="A6">6</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Masek</surname>
<given-names>Marissa</given-names>
</name>
<xref ref-type="aff" rid="A6">6</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Ragan</surname>
<given-names>Tim</given-names>
</name>
<xref ref-type="aff" rid="A6">6</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Tan</surname>
<given-names>Sisareuth</given-names>
</name>
<xref ref-type="aff" rid="A7">7</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Brisson</surname>
<given-names>Alain R.</given-names>
</name>
<xref ref-type="aff" rid="A7">7</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Ramirez</surname>
<given-names>Servio H.</given-names>
</name>
<xref ref-type="aff" rid="A4">4</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Hyman</surname>
<given-names>Bradley T.</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
<xref ref-type="aff" rid="A2">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Maguire</surname>
<given-names>Casey A.</given-names>
</name>
<xref ref-type="aff" rid="A2">2</xref>
<xref ref-type="corresp" rid="cor1">#</xref>
</contrib>
</contrib-group>
<aff id="A1"><label>1</label>
Alzheimer Research Unit, The Massachusetts General Hospital Institute for Neurodegenerative Disease, Charlestown, MA</aff>
<aff id="A2"><label>2</label>
Department of Neurology, The Massachusetts General Hospital, and NeuroDiscovery Center, Harvard Medical School, Boston, USA</aff>
<aff id="A3"><label>3</label>
Department of Neurobiology, Harvard Medical School, Boston, USA</aff>
<aff id="A4"><label>4</label>
Department of Pathology and Laboratory Medicine, Temple University School of Medicine, Philadelphia, PA</aff>
<aff id="A5"><label>5</label>
Genethon, Evry, France</aff>
<aff id="A6"><label>6</label>
TissueVision, Inc., Cambridge, MA</aff>
<aff id="A7"><label>7</label>
UMR-CBMN CNRS-University of Bordeaux, Pessac, France</aff>
<author-notes><corresp id="cor1"><label>#</label>
Correspondence should be addressed to: Casey A. Maguire, Ph.D., Neuroscience Center, The Massachusetts General Hospital, Building 149, 13<sup>th</sup>
Street, Charlestown, MA, 02129 USA. Phone 617-726-5725, Fax 617-724-1537, <email>cmaguire@mgh.harvard.edu</email>
</corresp>
</author-notes>
<pub-date pub-type="nihms-submitted"><day>15</day>
<month>3</month>
<year>2016</year>
</pub-date>
<pub-date pub-type="epub"><day>02</day>
<month>2</month>
<year>2016</year>
</pub-date>
<pub-date pub-type="ppub"><month>4</month>
<year>2016</year>
</pub-date>
<pub-date pub-type="pmc-release"><day>02</day>
<month>8</month>
<year>2016</year>
</pub-date>
<volume>23</volume>
<issue>4</issue>
<fpage>380</fpage>
<lpage>392</lpage>
<pmc-comment>elocation-id from pubmed: 10.1038/gt.2016.11</pmc-comment>
<permissions><license><license-p>Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:<uri xlink:type="simple" xlink:href="http://www.nature.com/authors/editorial_policies/license.html#terms">http://www.nature.com/authors/editorial_policies/license.html#terms</uri>
</license-p>
</license>
</permissions>
<abstract><p id="P1">Adeno-associated virus (AAV) vectors are showing promise in gene therapy trials and have proven to be extremely efficient biological tools in basic neuroscience research. One major limitation to their widespread use in the neuroscience laboratory is the cost, labor, skill, and time intense purification process of AAV. We have recently shown that AAV can associate with exosomes (exo-AAV) when vector is isolated from conditioned media of producer cells, and the exo-AAV is more resistant to neutralizing anti-AAV antibodies compared to standard AAV. Here we demonstrate that simple pelleting of exo-AAV from media via ultracentrifugation, results in high-titer vector preparations capable of efficient transduction of central nervous system (CNS) cells after systemic injection in mice. We observed that exo-AAV is more efficient at gene delivery to the brain at low vector doses relative to conventional AAV, even when derived from a serotype that does not normally efficiently cross the blood brain barrier. Similar cell types were transduced by exo-AAV and conventionally purified vector. Importantly, no cellular toxicity was noted in exo-AAV transduced cells. We demonstrated the utility and robustness of exo-AAV-mediated gene delivery by detecting direct GFP fluorescence after systemic injection, allowing 3-dimensional reconstruction of transduced Purkinje cells in the cerebellum using <italic>ex-vivo</italic>
serial 2-photon tomography. The ease of isolation combined with the high efficiency of transgene expression in the CNS, may enable widespread use of exo-AAV as a neuroscience research tool. Furthermore, the ability of exo-AAV to evade neutralizing antibodies while still transducing CNS after peripheral delivery is clinically relevant.</p>
</abstract>
</article-meta>
</front>
<floats-group><fig id="F1" orientation="portrait" position="float"><label>Figure 1</label>
<caption><title>Overview of the distribution of GFP throughout the central nervous system (CNS) after i.v. injection of AAV9-CBA-GFP and exo-AAV9-CBA-GFP</title>
<p id="P48">Representative images of GFP fluorescence over three different coronal sections across the brain (<bold>a</bold>
) and of the spinal cord (<bold>b</bold>
) after intravenous injection of the same self-complementary genome vector copy (g.c.) numbers (1.5×10<sup>11</sup>
g.c.) of AAV9 (left panels) and exo-AAV9 (right panel). A widespread signal was observed for both vectors within the cortex (ctx), hippocampus (hpc), striatum (str) and cerebellum (crbl). Within the spinal cord, GFP transduced cells could be observed in the ventral (vh) and dorsal (dh) horns. Scale bar: 1000µm.</p>
</caption>
<graphic xlink:href="nihms753186f1"></graphic>
</fig>
<fig id="F2" orientation="portrait" position="float"><label>Figure 2</label>
<caption><title>Detection of direct GFP fluorescence by <italic>in vivo</italic>
two-photon imaging and <italic>ex vivo</italic>
serial two-photon tomography (STP)</title>
<p id="P49">BALB/c mice were injected with 7×10<sup>11</sup>
g.c. of exo-AAV9-CBA-GFP. After 3 weeks, the GFP fluorescent signal was detected <italic>in vivo</italic>
by multiphoton imaging or ex vivo by STP (in absence of immunostaining). (<bold>a</bold>
) Representative 2-photon images of a GFP transduced astrocyte (white arrow, identified with the astrocytic marker SR101 topically applied on the brain) in the living animal after cranial window implantation. Numerous surrounding astrocytes do not express detectable GFP (blue arrow). Scale bar: 100µm. (<bold>b</bold>
) Three-dimensional reconstruction of the entire cerebellum by post-mortem STP tomography imaging, showing the whole vascular tree as well as the direct fluorescent signal across this particular region of the brain. On the right panel, numerous GFP transduced cells could be identified on a higher magnification image of a small region of the cerebellum. Scale bar: 1000µm (<bold>c</bold>
) GFP signal detected in one section of the cerebellum imaged by 2-photon before 3D-reconstruction. Scale bar: 1000µm. On the right, two cropped regions of the initial image show GFP positive astrocytes (yellow arrow), vascular endothelium (blue arrow) and Purkinje cells (purple arrow). Scale bar: 200µm.</p>
</caption>
<graphic xlink:href="nihms753186f2"></graphic>
</fig>
<fig id="F3" orientation="portrait" position="float"><label>Figure 3</label>
<caption><title>Astrocytes and neurons as preferentially targeted by peripherally administered AAV9 and exo-AAV9</title>
<p id="P50">Double immunostainings were performed in order to determine the main neural cell types transduced by both exo-AAV9 and AAV9 (white arrows). (<bold>a</bold>
) Representative images of GFP positive astrocytes and neurons, respectively identified by the markers Glutamine synthetase (GS) and NeuN, in the cortex of injected mice. Astrocytes and neurons were predominantly transduced in the brain. (<bold>b</bold>
) By contrast, no microglial cells (identified by Iba1 labeling) and rare oligodendrocytes (expressing Olig2) were observed. Scale bar: 50µm</p>
</caption>
<graphic xlink:href="nihms753186f3"></graphic>
</fig>
<fig id="F4" orientation="portrait" position="float"><label>Figure 4</label>
<caption><title>Neuronal sub-types transduced after peripheral injection of AAV9 and exo-AAV9</title>
<p id="P51">Representative images of co-labeling experiments performed to characterize the transduction profile of peripherally injected exo-AAV9 and AAV9 in various neuronal sub-types. The colocalization between GFP with CamKII (<bold>a</bold>
) or GAD67 (<bold>b</bold>
) markers demonstrates efficient targeting of excitatory and inhibitory neurons, respectively. (<bold>c</bold>
) Interestingly, few GFP/Tyrosine hydroxylase (TH) positive dopaminergic neurons were observed after exo-AAV9 injection, but not with conventional AAV9. (<bold>d</bold>
) In the cerebellum, numerous Purkinje cells, identified with the marker calbindin, express GFP after AAV9 and exo-AAV9 transduction. (<bold>e</bold>
) In the spinal cord, GFP positive motor neurons expressing the choline acetyltransferase (ChAT) were observed. Scale bar: 50µm.</p>
</caption>
<graphic xlink:href="nihms753186f4"></graphic>
</fig>
<fig id="F5" orientation="portrait" position="float"><label>Figure 5</label>
<caption><title>Stereology-based study of the percentage of AAV9 and exo-AAV9 transduced neurons</title>
<p id="P52">BALB/c mice were sacrificed 4 weeks after intravenous injection of 1.5×10<sup>11</sup>
g.c of conventional AAV9 or exo-AAV9. To evaluate the percentage of neuronal transduction, an unbiased stereological analysis of the total number of neurons (identified using the NeuN marker) and of the total number of transduced neurons (NeuN/GFP double positive cells) was achieved by random sampling of the cortex, striatum and hippocampus, following the protocol detailed in the Materials and Methods section. (<bold>a</bold>
) GFP positive neurons were evenly distributed across the cortex (left panel) and the striatum (right panel) and showed a significant increased percentage of transduction after exo-AAV9 administration (cortex: 5.11±0.28%; striatum: 5.31±0.27%) as compared with AAV9 (cortex: 2.87±0.12%; striatum: 2.79±0.18%). (<bold>b</bold>
) By contrast, transduction variability was observed in the hippocampus, with both CA3 and the dentate gyrus (DG) being preferentially targeted by AAV9 and exo-AAV9 as compared with CA1–2. The mice injected with exo-AAV9 presented a higher density of NeuN/GFP neurons in each hippocampal sub-division than AAV9 (for AAV9: CA1/2: 2.66±0.46%; CA3: 4.37±0.84% and DG: 3.15±0.34% and for exo-AAV9: CA1/2: 5.45±0.57%; CA3: 7.93±0.54% and DG: 6.19±0.79%). n= 4 mice per group (3 sections analyzed per mouse); non-parametric Mann Whitney test; ***p<0.0001; **p<0.005; *p<0.5. Scale bar: 100µm</p>
</caption>
<graphic xlink:href="nihms753186f5"></graphic>
</fig>
<fig id="F6" orientation="portrait" position="float"><label>Figure 6</label>
<caption><title>Stereology-based study of the percentage of AAV9 and exo-AAV9 transduced astrocytes</title>
<p id="P53">BALB/c mice were sacrificed 4 weeks after intravenous injection of 1.5×10<sup>11</sup>
g.c of conventional AAV9 or exo-AAV9. To evaluate the percentage of transduced astrocytes, an unbiased stereological analysis of the total number of astrocytes (identified Glutamine synthetase positive cells) and of the total number of transduced astrocytes (GS/GFP double positive cells) was achieved by random sampling of the cortex, striatum and hippocampus, following the protocol detailed in the Materials and Methods section. The percentage of GFP positive astrocytes was significant higher after i.v. injection of exo-AAV9 as compared with AAV9 in both cortex (<bold>a:</bold>
AAV9: 9.3±1.2% and exo-AAV9: 15.37±0.7%) and striatum (<bold>b</bold>
: AAV9: 7.02±1.05% and exo-AAV9: 12.64±0.91%). However, the difference did not reach significance in the hippocampus (<bold>c</bold>
: AAV9: 5.56±1.41% and exo-AAV9: 8.91±1.74%). n= 4 mice per group (3 sections analyzed per mouse); non-parametric Mann Whitney test; **p<0.0001; **p<0.005; *p<0.5.</p>
</caption>
<graphic xlink:href="nihms753186f6"></graphic>
</fig>
<fig id="F7" orientation="portrait" position="float"><label>Figure 7</label>
<caption><title>Kinetics of exo-AAV8 and standard AAV8 luciferase (FLuc) expression after systemic injection</title>
<p id="P54">BALB/c mice were injected i.v. with 5×10<sup>10</sup>
g.c. of either standard AAV8-FLuc or exo-AAV8-FLuc. (<bold>a</bold>
) Representative images of bioluminescence intensity of head and liver region in mice 7 days post-injection for AAV8 and exo-AAV8. (<bold>b</bold>
) Bioluminescent signal quantitation in head region one week post injection. Kinetics of FLuc bioluminescence over 4 weeks in head (<bold>c</bold>
) and liver (<bold>d</bold>
) region. (<bold>e</bold>
) Luciferase levels in brain homogenates isolated from mice injected i.v. with AAV8-FLuc or exo-AAV8-FLuc.</p>
</caption>
<graphic xlink:href="nihms753186f7"></graphic>
</fig>
<fig id="F8" orientation="portrait" position="float"><label>Figure 8</label>
<caption><title>exo-AAV8 enhances GFP reporter expression over standard AAV8 at low vector doses</title>
<p id="P55">(<bold>a</bold>
) BALB/c mice were injected i.v. with 4 × 10<sup>11</sup>
g.c. of either AAV8 (left panels) or exo-AAV8 (right panels) constructs and two weeks later, sacrificed, and cryosections immunostained with an anti-GFP antibody. Representative images of a coronal section after immunostaining show no difference in the intensity of GFP signal between both vectors (upper panels). Scale bar: 1000µm. At higher magnification (<bold>b</bold>
), transduced cells with morphological features of astrocytes (white arrows), neurons (yellow arrows) as well as cerebral vasculature (blue arrows) could be detected. Scale bar: 100µm. (<bold>c</bold>
) In order to decipher the discrepancy between our GFP and Luc data, BALB/c mice were then injected i.v. with the indicated doses of single-stranded AAV8-GFP or exo-AAV8-GFP. Two weeks post injection mice were sacrificed and genomic and virus vector DNA isolated and subjected to an AAV-specific qPCR. n=2 per dose. (<bold>d</bold>
) Brain homogenates of mice injected at the lowest dose (5×10<sup>10</sup>
g.c.) were subjected to immunoblot detection of GFP. GAPDH was shown as loading control. M1 and M2 refer to two separate animals in each group (mouse 1 and mouse 2) analyzed for GFP expression. (<bold>e</bold>
) Densitometry was performed on GFP bands and normalized to the GAPDH bands.</p>
</caption>
<graphic xlink:href="nihms753186f8"></graphic>
</fig>
<fig id="F9" orientation="portrait" position="float"><label>Figure 9</label>
<caption><title>exo-AAV cross a blood-brain barrier model</title>
<p id="P56">bEnd.3 cells, a cell line generated from mouse cortical endothelial cells, were seeded on cell culture inserts and grown to confluence in order to establish an <italic>in vitro</italic>
blood-brain barrier model. Standard AAV or exo-AAV (1.6×10<sup>10</sup>
genome copies) were suspended in media and dispensed into the upper chamber (apical side of cell culture inserts), while vector-free media was added to the lower chamber (below the inserts). After 24 hours, media was collected from the lower chamber to determine the number of AAV genomes present in the media by qPCR. (<bold>a</bold>
) Data are presented as the mean of total AAV genome copies below the cell culture insert ± standard deviation. n=4 transwell assays per group; t-test between standard AAV and exo-AAV for each serotype; *p<0.05.</p>
</caption>
<graphic xlink:href="nihms753186f9"></graphic>
</fig>
</floats-group>
</pmc>
</record>
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