Specific Transfection of Inflamed Brain by Macrophages: A New Therapeutic Strategy for Neurodegenerative Diseases
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{"title"=>"Specific Transfection of Inflamed Brain by Macrophages: A New Therapeutic Strategy for Neurodegenerative Diseases", "type"=>"journal", "authors"=>[{"first_name"=>"Matthew J.", "last_name"=>"Haney", "scopus_author_id"=>"37098745700"}, {"first_name"=>"Yuling", "last_name"=>"Zhao", "scopus_author_id"=>"36859196800"}, {"first_name"=>"Emily B.", "last_name"=>"Harrison", "scopus_author_id"=>"55954062100"}, {"first_name"=>"Vivek", "last_name"=>"Mahajan", "scopus_author_id"=>"55581331200"}, {"first_name"=>"Shaheen", "last_name"=>"Ahmed", "scopus_author_id"=>"56465281500"}, {"first_name"=>"Zhijian", "last_name"=>"He", "scopus_author_id"=>"55328716400"}, {"first_name"=>"Poornima", "last_name"=>"Suresh", "scopus_author_id"=>"55262966700"}, {"first_name"=>"Shawn D.", "last_name"=>"Hingtgen", "scopus_author_id"=>"18233565000"}, {"first_name"=>"Natalia L.", "last_name"=>"Klyachko", "scopus_author_id"=>"35579859900"}, {"first_name"=>"R. Lee", "last_name"=>"Mosley", "scopus_author_id"=>"7005483603"}, {"first_name"=>"Howard E.", "last_name"=>"Gendelman", "scopus_author_id"=>"14626299200"}, {"first_name"=>"Alexander V.", "last_name"=>"Kabanov", "scopus_author_id"=>"35494160700"}, {"first_name"=>"Elena V.", "last_name"=>"Batrakova", "scopus_author_id"=>"6701883171"}], "year"=>2013, "source"=>"PLoS ONE", "identifiers"=>{"pmid"=>"23620794", "sgr"=>"84876436797", "doi"=>"10.1371/journal.pone.0061852", "scopus"=>"2-s2.0-84876436797", "pui"=>"368765595", "isbn"=>"1932-6203 (Electronic)\\r1932-6203 (Linking)", "issn"=>"19326203"}, "id"=>"a922480a-978d-339f-aad3-12e0081a9599", "abstract"=>"The ability to precisely upregulate genes in inflamed brain holds great therapeutic promise. Here we report a novel class of vectors, genetically modified macrophages that carry reporter and therapeutic genes to neural cells. Systemic administration of macrophages transfected ex vivo with a plasmid DNA (pDNA) encoding a potent antioxidant enzyme, catalase, produced month-long expression levels of catalase in the brain resulting in three-fold reductions in inflammation and complete neuroprotection in mouse models of Parkinson's disease (PD). This resulted in significant improvements in motor functions in PD mice. Mechanistic studies revealed that transfected macrophages secreted extracellular vesicles, exosomes, packed with catalase genetic material, pDNA and mRNA, active catalase, and NF-kappab, a transcription factor involved in the encoded gene expression. Exosomes efficiently transfer their contents to contiguous neurons resulting in de novo protein synthesis in target cells. Thus, genetically modified macrophages serve as a highly efficient system for reproduction, packaging, and targeted gene and drug delivery to treat inflammatory and neurodegenerative disorders.", "link"=>"http://www.mendeley.com/research/specific-transfection-inflamed-brain-macrophages-new-therapeutic-strategy-neurodegenerative-diseases", "reader_count"=>77, "reader_count_by_academic_status"=>{"Unspecified"=>1, "Professor > Associate Professor"=>5, "Researcher"=>13, "Student > Doctoral Student"=>7, "Student > Ph. D. Student"=>24, "Student > Postgraduate"=>3, "Student > Master"=>6, "Other"=>3, "Student > Bachelor"=>10, "Lecturer"=>1, "Professor"=>4}, "reader_count_by_user_role"=>{"Unspecified"=>1, "Professor > Associate Professor"=>5, "Researcher"=>13, "Student > Doctoral Student"=>7, "Student > Ph. D. Student"=>24, "Student > Postgraduate"=>3, "Student > Master"=>6, "Other"=>3, "Student > Bachelor"=>10, "Lecturer"=>1, "Professor"=>4}, "reader_count_by_subject_area"=>{"Engineering"=>7, "Unspecified"=>3, "Biochemistry, Genetics and Molecular Biology"=>8, "Materials Science"=>1, "Agricultural and Biological Sciences"=>35, "Medicine and Dentistry"=>11, "Neuroscience"=>2, "Pharmacology, Toxicology and Pharmaceutical Science"=>3, "Physics and Astronomy"=>2, "Chemistry"=>4, "Psychology"=>1}, "reader_count_by_subdiscipline"=>{"Engineering"=>{"Engineering"=>7}, "Materials Science"=>{"Materials Science"=>1}, "Medicine and Dentistry"=>{"Medicine and Dentistry"=>11}, "Neuroscience"=>{"Neuroscience"=>2}, "Chemistry"=>{"Chemistry"=>4}, "Physics and Astronomy"=>{"Physics and Astronomy"=>2}, "Psychology"=>{"Psychology"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>35}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>8}, "Unspecified"=>{"Unspecified"=>3}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>3}}, "reader_count_by_country"=>{"United States"=>1, "Brazil"=>1, "France"=>1, "Spain"=>1}, "group_count"=>2}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/1029965"], "description"=>"<p>BALB/c mice were <i>i.c.</i> injected with 6-OHDA. Forty eight hours later, the animals were <i>i.v.</i> injected with catalase-transfected macrophages (bars with diagonal pattern) or PBS (black bars), or empty-transfected macrophages (white bars). Control group was <i>i.c.</i> injected with PBS, and then 48 hours later <i>i.v.</i> injected with PBS (grey bars). Apomorphine (<b>A</b>) and rotaroid (<b>B</b>) tests demonstrated statistically significant improvements in motor functions upon treatment with catalase-transfected macrophages. Number of rotations (<b>A</b>) was significantly decreased in 6-OHDA-intoxicated mice treated with catalase-transfected macrophages compared to non-treated PD mice. No rotations were detected in control PBS-injected mice in apomorphine test. Time spent on the rotarod (<b>B</b>) in 6-OHDA intoxicated mice treated with catalase-transfected macrophages was the same as in healthy non-intoxicated control mice on the seventh week after the intoxication. In contrast, significant decreases were observed in 6-OHDA-intoxicated mice injected with PBS. No effect on motor functions was recorded in 6-OHDA-intoxicated mice treated with empty-transfected macrophages. Statistical significance was calculated using one-way ANOVA test. Values are means ± SEM (<i>N</i> = 10), and <i>p</i><0.05 compared with <sup>a</sup>PBS, and <sup>b</sup>6-OHDA.</p>", "links"=>[], "tags"=>["biotechnology", "immunology", "Immune cells", "Model organisms", "Animal models", "mouse", "Molecular cell biology", "Cellular types", "neuroscience", "Bioengineering", "Clinical research design", "Animal models of disease", "Drugs and devices", "neurology", "Neurodegenerative diseases", "Parkinson disease", "catalase-transfected", "macrophages", "functions", "pd"], "article_id"=>686753, "categories"=>["Medicine", "Engineering", "Biological Sciences"], "users"=>["Matthew J. Haney", "Yuling Zhao", "Emily B. Harrison", "Vivek Mahajan", "Shaheen Ahmed", "Zhijian He", "Poornima Suresh", "Shawn D. Hingtgen", "Natalia L. Klyachko", "R. Lee Mosley", "Howard E. Gendelman", "Alexander V. Kabanov", "Elena V. Batrakova"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0061852.g004", "stats"=>{"downloads"=>1, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Therapeutic_effect_of_catalase_transfected_macrophages_on_motor_functions_in_a_PD_mouse_model_/686753", "title"=>"Therapeutic effect of catalase-transfected macrophages on motor functions in a PD mouse model.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-04-19 01:52:33"}
  • {"files"=>["https://ndownloader.figshare.com/files/1029967"], "description"=>"<p>Exosomes from GFP-transfected cells were collected over two days and evaluated for (<b>A</b>): GFP DNA (<b>1</b>) and RNA (<b>2</b>) by PCR analysis. Exosomes secreted from macrophages transfected with empty vector were used as a control (<b>3</b>). (<b>B</b>): Levels of GFP DNA and RNA in exosomes from GFP-transfected macrophages were compared to those from empty vector-transfected macrophages (<b>1</b>), or non-transfected cells (<b>2</b>) by Real-Time PCR analysis. <b>C</b>: expression levels of GFP (30K) in exosomes from GFP-transfected cells (<b>1</b>) or empty vector-transfected macrophages (<b>2</b>) were examined by western blot and compared to the levels of CD63 (53K). Exosomes released from GFP-transfected macrophages contained four orders of magnitude more of GFP DNA and RNA compared to non-transfected macrophages or those transfected with empty vector (<b>A, B</b>); and 6.1 times greater levels of the expressed protein, GFP (<b>C</b>). Exosomes contain substantially higher levels of NF-kb, a transcription factor that involved in GFP <i>p</i>DNA expression, compared to macrophages as demonstrated by western blot (<b>D</b>). AFM images of exosomes revealed differences between: (<b>E</b>) small donut-shaped (empty) exosomes released from non-transfected macrophages, and (<b>F</b>) large spherical (likely filled with the expressed proteins and genetic material) exosomes from catalase-transfected macrophages. The bar: 200 nm.</p>", "links"=>[], "tags"=>["biotechnology", "immunology", "Immune cells", "Model organisms", "Animal models", "mouse", "Molecular cell biology", "Cellular types", "neuroscience", "Bioengineering", "Clinical research design", "Animal models of disease", "Drugs and devices", "neurology", "Neurodegenerative diseases", "Parkinson disease", "secreted", "gfp-transfected", "macrophages", "gfp", "transcription"], "article_id"=>686755, "categories"=>["Medicine", "Engineering", "Biological Sciences"], "users"=>["Matthew J. Haney", "Yuling Zhao", "Emily B. Harrison", "Vivek Mahajan", "Shaheen Ahmed", "Zhijian He", "Poornima Suresh", "Shawn D. Hingtgen", "Natalia L. Klyachko", "R. Lee Mosley", "Howard E. Gendelman", "Alexander V. Kabanov", "Elena V. Batrakova"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0061852.g005", "stats"=>{"downloads"=>2, "page_views"=>24, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Exosomes_secreted_from_GFP_transfected_macrophages_contain_GFP_DNA_RNA_the_transcription_factor_and_expressed_protein_/686755", "title"=>"Exosomes secreted from GFP-transfected macrophages contain GFP DNA, RNA, the transcription factor, and expressed protein.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-04-19 01:52:35"}
  • {"files"=>["https://ndownloader.figshare.com/files/1029971"], "description"=>"<p><b>A</b>: Cath.A neurons grown on slides were fixed and stained with Anti-NeuN Antibodies (blue, left picture); exosomes were isolated from Raw 264.7 macrophages media, stained with lipophilic fluorescent dye, DIO (green), and added to Cath.A neurons for 24 hours (right picture). <b>B</b>: Raw 264.7 macrophages were transfected with fluorescently-labeled with YOYO-1 tomato protein <i>p</i>DNA (green), and then cultured in complete media. Confocal images of transfected macrophages on day 3 show incorporation of <i>p</i>DNA (green) in the nucleus and expression of tomato protein (red) in the cytoplasm. <b>C</b>: Media from macrophages transfected as described above with tomato protein <i>p</i>DNA (labeled with YOYO-1) was collected over 24 hours, and isolated exosomes were added to Cath.A neurons for various times. Then, the neurons were fixed and stained with Anti-NeuN Antibodies (blue). Confocal images of neurons incubated with exosomal fraction demonstrated relatively constant amount of YOYO-1-labeled <i>p</i>DNA (green), and increasing in time expression levels of tomato protein (red) confirmed by the quantification of green and red fluorescence on confocal images (graph). Co-localization of YOYO-1-labeled genetic material and expressed tomato protein in neurons is manifested by yellow staining. Statistical significance of tomato protein expression levels (shown by asterisk: <i>p</i><0.05) was assessed by a standard t-test compared to day one after transfection. The bar: 20 µm.</p>", "links"=>[], "tags"=>["biotechnology", "immunology", "Immune cells", "Model organisms", "Animal models", "mouse", "Molecular cell biology", "Cellular types", "neuroscience", "Bioengineering", "Clinical research design", "Animal models of disease", "Drugs and devices", "neurology", "Neurodegenerative diseases", "Parkinson disease", "exosomes", "secreted", "macrophages", "neurons"], "article_id"=>686759, "categories"=>["Medicine", "Engineering", "Biological Sciences"], "users"=>["Matthew J. Haney", "Yuling Zhao", "Emily B. Harrison", "Vivek Mahajan", "Shaheen Ahmed", "Zhijian He", "Poornima Suresh", "Shawn D. Hingtgen", "Natalia L. Klyachko", "R. Lee Mosley", "Howard E. Gendelman", "Alexander V. Kabanov", "Elena V. Batrakova"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0061852.g006", "stats"=>{"downloads"=>0, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Accumulation_of_exosomes_secreted_from_macrophages_in_Cath_A_neurons_and_genetic_material_transfer_/686759", "title"=>"Accumulation of exosomes secreted from macrophages in Cath.A neurons and genetic material transfer.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-04-19 01:52:39"}
  • {"files"=>["https://ndownloader.figshare.com/files/1029974"], "description"=>"<p>RAW 264.7 macrophages were transfected with GFP <i>p</i>DNA, cultured in complete media for three days, and then added to Cath.A neurons. To distinguish between the cell types, macrophages were stained with CD11b Ab (Alexa 647). GFP levels in neurons were assessed by FACS as mean fluorescence ± SEM (<i>N</i> = 4). <b>A</b>: The representative FACS plots demonstrating GFP transfer into Cath.A neurons; <b>B</b>: Quantification of GFP levels in macrophages alone (black diamonds), and in co-culture of neurons and macrophages (white squares). GFP expression levels in neurons co-cultured with transfected macrophages increased over 5–12 days. At the same time, protein expression in macrophages at days 5–12 was already diminished, suggesting that along with GFP, its genetic material (<i>p</i>DNA and RNA) was transferred from transfected macrophages into neurons, where the encoded protein (GFP) was synthesized <i>de novo</i>. Statistical significance shown by asterisk (<i>p</i><0.05) was calculated by a one-way ANOVA. The bar: 10 µm.</p>", "links"=>[], "tags"=>["biotechnology", "immunology", "Immune cells", "Model organisms", "Animal models", "mouse", "Molecular cell biology", "Cellular types", "neuroscience", "Bioengineering", "Clinical research design", "Animal models of disease", "Drugs and devices", "neurology", "Neurodegenerative diseases", "Parkinson disease", "neurons", "gfp-transfected"], "article_id"=>686762, "categories"=>["Medicine", "Engineering", "Biological Sciences"], "users"=>["Matthew J. Haney", "Yuling Zhao", "Emily B. Harrison", "Vivek Mahajan", "Shaheen Ahmed", "Zhijian He", "Poornima Suresh", "Shawn D. Hingtgen", "Natalia L. Klyachko", "R. Lee Mosley", "Howard E. Gendelman", "Alexander V. Kabanov", "Elena V. Batrakova"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0061852.g007", "stats"=>{"downloads"=>0, "page_views"=>11, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Transfection_of_Cath_A_neurons_by_GFP_transfected_macrophages_/686762", "title"=>"Transfection of Cath.A neurons by GFP-transfected macrophages.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-04-19 01:52:42"}
  • {"files"=>["https://ndownloader.figshare.com/files/1029975"], "description"=>"<p>Three possible ways of therapeutic effects of catalase-transfected macrophages in PD mouse model: <b><i>Pathway I</i></b>: macrophages transfected with catalase encoding pDNA cross the BBB and release catalase and its genetic material in SNpc; <b><i>Pathway II</i></b>: catalase and its genetic material are released from transfected macrophages in exosomes to the blood stream and bypass the BBB independently of the cell-carriers; <b><i>Pathway III</i></b>: gene and drug-incorporating exosomes released in the periphegral organs (liver, spleen, <i>etc.</i>) or in the blood are taken by residential macrophages, monocytes, T-cells, or dendritic cells suppressing peripheral leukocyte activation that may result in decrease of inflammation in the brain.</p>", "links"=>[], "tags"=>["biotechnology", "immunology", "Immune cells", "Model organisms", "Animal models", "mouse", "Molecular cell biology", "Cellular types", "neuroscience", "Bioengineering", "Clinical research design", "Animal models of disease", "Drugs and devices", "neurology", "Neurodegenerative diseases", "Parkinson disease", "pictorial", "cell-based"], "article_id"=>686763, "categories"=>["Medicine", "Engineering", "Biological Sciences"], "users"=>["Matthew J. Haney", "Yuling Zhao", "Emily B. Harrison", "Vivek Mahajan", "Shaheen Ahmed", "Zhijian He", "Poornima Suresh", "Shawn D. Hingtgen", "Natalia L. Klyachko", "R. Lee Mosley", "Howard E. Gendelman", "Alexander V. Kabanov", "Elena V. Batrakova"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0061852.g008", "stats"=>{"downloads"=>1, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_A_pictorial_scheme_for_cell_based_gene_and_drug_delivery_/686763", "title"=>"A pictorial scheme for cell-based gene and drug delivery.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-04-19 01:52:43"}
  • {"files"=>["https://ndownloader.figshare.com/files/1029976"], "description"=>"a<p>BALB/c mice were i.c. injected with 6-OHDA. Forty eight hours later, the animals were <i>i.v.</i> injected with various macrophage-based formulations or PBS. Control group was <i>i.c.</i> injected with PBS, and then 48 hours later <i>i.v.</i> injected with PBS.</p>b<p>Total number of neurons was calculated in ipsilateral hemisphere.</p>c<p>Statistical significance is shown by asterisk: <i>p</i><0.05 (*), and <i>p</i><0.005 (**) compared to mice with <i>i.c.</i> PBS injections followed by <i>i.v.</i> PBS injections (healthy controls); or <i>p</i><0.05 (#),compared to mice with <i>i.c.</i> 6-OHDA injections followed by <i>i.v.</i> PBS injections (PD controls); was performed by a1+standard t-test. Errors are mean ± SEM, <i>N</i> = 7.</p>", "links"=>[], "tags"=>["biotechnology", "immunology", "Immune cells", "Model organisms", "Animal models", "mouse", "Molecular cell biology", "Cellular types", "neuroscience", "Bioengineering", "Clinical research design", "Animal models of disease", "Drugs and devices", "neurology", "Neurodegenerative diseases", "Parkinson disease", "catalase-transfected", "macrophages", "inflammation", "neurodegeneration", "mice", "pd"], "article_id"=>686764, "categories"=>["Medicine", "Engineering", "Biological Sciences"], "users"=>["Matthew J. Haney", "Yuling Zhao", "Emily B. Harrison", "Vivek Mahajan", "Shaheen Ahmed", "Zhijian He", "Poornima Suresh", "Shawn D. Hingtgen", "Natalia L. Klyachko", "R. Lee Mosley", "Howard E. Gendelman", "Alexander V. Kabanov", "Elena V. Batrakova"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0061852.t001", "stats"=>{"downloads"=>0, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Effect_of_catalase_transfected_macrophages_on_inflammation_and_neurodegeneration_in_mice_with_PD_model_a_/686764", "title"=>"Effect of catalase-transfected macrophages on inflammation and neurodegeneration in mice with PD model<sup>a</sup>.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2013-04-19 01:52:44"}
  • {"files"=>["https://ndownloader.figshare.com/files/1029944"], "description"=>"<p>Raw 264.7 macrophages were incubated with 2 µg/ml GFP (<b>A, C</b>) or catalase (<b>B, D</b>) <i>p</i>DNA and 300 µl/ml Gene PORTER 3000 transfection agent for 4 hours, washed, and cultured in complete media for various times. Levels of the encoded protein and percentage of transfected macrophages were assessed by FACS (<b>A</b>), and the expressed protein (green) was visualized by confocal microscopy on day 4 (<b>C</b>), and day 21 (<b>D</b>). Up to 40% of cells expressed GFP (<b>A</b>) with the maximum at day 4 (<b>A, C</b>) and sustained expression for at least 21 days (<b>D</b>). For the release studies, macrophages grown on 24-well plates were transfected with: GFP <i>p</i>DNA (<b>B</b>, black squares) or catalase <i>p</i>DNA (<b>B</b>, white squares), then cells were washed, cultured for different times, and amount of the expressed protein was assessed by fluorescence (GFP) or catalytic activity (catalase). In consistence with the transfection levels, maximum of the encoded protein was detected in the culture media at day 4 with sustained levels up to three weeks. Levels of fluorescence and enzymatic activity in non-transfected macrophages are shown by arrow on corresponding axes and dashed lines. Statistical significance of GFP expression levels in macrophages, and GFP or catalase released from macrophages compared to untreated cell levels is shown by asterisk (*<i>p</i><0.05; **<i>p</i><0.005) was calculated by one-way ANOVA. Errors are mean ± SEM, <i>N</i> = 4. The bar: 20 µm.</p>", "links"=>[], "tags"=>["biotechnology", "immunology", "Immune cells", "Model organisms", "Animal models", "mouse", "Molecular cell biology", "Cellular types", "neuroscience", "Bioengineering", "Clinical research design", "Animal models of disease", "Drugs and devices", "neurology", "Neurodegenerative diseases", "Parkinson disease", "macrophages", "gfp", "catalase", "prolonged", "encoded"], "article_id"=>686735, "categories"=>["Medicine", "Engineering", "Biological Sciences"], "users"=>["Matthew J. Haney", "Yuling Zhao", "Emily B. Harrison", "Vivek Mahajan", "Shaheen Ahmed", "Zhijian He", "Poornima Suresh", "Shawn D. Hingtgen", "Natalia L. Klyachko", "R. Lee Mosley", "Howard E. Gendelman", "Alexander V. Kabanov", "Elena V. Batrakova"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0061852.g001", "stats"=>{"downloads"=>1, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Transfection_of_macrophages_with_GFP_or_catalase_p_DNA_and_prolonged_release_of_the_encoded_protein_/686735", "title"=>"Transfection of macrophages with GFP or catalase <i>p</i>DNA and prolonged release of the encoded protein.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-04-19 01:52:15"}
  • {"files"=>["https://ndownloader.figshare.com/files/1029988", "https://ndownloader.figshare.com/files/1029994", "https://ndownloader.figshare.com/files/1029998"], "description"=>"<div><p>The ability to precisely upregulate genes in inflamed brain holds great therapeutic promise. Here we report a novel class of vectors, genetically modified macrophages that carry reporter and therapeutic genes to neural cells. Systemic administration of macrophages transfected <i>ex vivo</i> with a plasmid DNA (<i>p</i>DNA) encoding a potent antioxidant enzyme, catalase, produced month-long expression levels of catalase in the brain resulting in three-fold reductions in inflammation and complete neuroprotection in mouse models of Parkinson's disease (PD). This resulted in significant improvements in motor functions in PD mice. Mechanistic studies revealed that transfected macrophages secreted extracellular vesicles, exosomes, packed with catalase genetic material, <i>p</i>DNA and mRNA, active catalase, and NF-κb, a transcription factor involved in the encoded gene expression. Exosomes efficiently transfer their contents to contiguous neurons resulting in <i>de novo</i> protein synthesis in target cells. Thus, genetically modified macrophages serve as a highly efficient system for reproduction, packaging, and targeted gene and drug delivery to treat inflammatory and neurodegenerative disorders.</p></div>", "links"=>[], "tags"=>["biotechnology", "immunology", "Immune cells", "Model organisms", "Animal models", "mouse", "Molecular cell biology", "Cellular types", "neuroscience", "Bioengineering", "Clinical research design", "Animal models of disease", "Drugs and devices", "neurology", "Neurodegenerative diseases", "Parkinson disease", "transfection", "inflamed", "therapeutic", "neurodegenerative"], "article_id"=>686768, "categories"=>["Medicine", "Engineering", "Biological Sciences"], "users"=>["Matthew J. Haney", "Yuling Zhao", "Emily B. Harrison", "Vivek Mahajan", "Shaheen Ahmed", "Zhijian He", "Poornima Suresh", "Shawn D. Hingtgen", "Natalia L. Klyachko", "R. Lee Mosley", "Howard E. Gendelman", "Alexander V. Kabanov", "Elena V. Batrakova"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0061852.s001", "https://dx.doi.org/10.1371/journal.pone.0061852.s002", "https://dx.doi.org/10.1371/journal.pone.0061852.s003"], "stats"=>{"downloads"=>12, "page_views"=>10, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Specific_Transfection_of_Inflamed_Brain_by_Macrophages_A_New_Therapeutic_Strategy_for_Neurodegenerative_Diseases_/686768", "title"=>"Specific Transfection of Inflamed Brain by Macrophages: A New Therapeutic Strategy for Neurodegenerative Diseases", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2013-04-19 01:52:48"}
  • {"files"=>["https://ndownloader.figshare.com/files/1029952"], "description"=>"<p>Balb/C mice were <i>i.c.</i> injected into substantia nigra pars compacta, <i>SNpc</i> with 6-OHDA (<b>A</b>), or with PBS (<b>B</b>). Twenty one days after injections, mice were <i>i.v.</i> injected with luciferase-transfected macrophages. IVIS representative images from <i>N</i> = 4 mice per group demonstrate prolonged expression of luciferase in the brain (<b>A</b>), which peaked at days 3–5 after adoptive cell transfer. Stable luciferase expression levels were attained over a month, suggesting that along with the delivered luciferase, recorded luminescence may originate from the transfected brain tissues. In contrast, low, if any, luminescence was detected in the healthy animals (<b>B</b>). <b>I</b>: whole body images, <b>II</b>: images of mouse head for corresponding time. <b>C</b>: Sections of midbrain (both hemispheres), spleen, lymph nodes and liver of Balb/C mice <i>i.c.</i> injected with LPS into <i>SNpc</i>, and then <i>i.v.</i> injected GFP-transfected macrophages (24 hour following intoxication). Brain sections obtained after 24 hours after transfer (left column) show GFP-expressing macrophages in the ipsilateral hemisphere, spleen, lymph node. No fluorescence was detected in the liver, as well as in the contralateral brain hemisphere. Notably, substantial fluorescence throughout the whole brain was demonstrated five days after macrophages administration (right column) suggesting that genetically-modified macrophages transfected ipsilateral brain tissues with inflammation. The bar: 20 µm.</p>", "links"=>[], "tags"=>["biotechnology", "immunology", "Immune cells", "Model organisms", "Animal models", "mouse", "Molecular cell biology", "Cellular types", "neuroscience", "Bioengineering", "Clinical research design", "Animal models of disease", "Drugs and devices", "neurology", "Neurodegenerative diseases", "Parkinson disease", "tissues", "genetically-modified", "macrophages", "murine"], "article_id"=>686743, "categories"=>["Medicine", "Engineering", "Biological Sciences"], "users"=>["Matthew J. Haney", "Yuling Zhao", "Emily B. Harrison", "Vivek Mahajan", "Shaheen Ahmed", "Zhijian He", "Poornima Suresh", "Shawn D. Hingtgen", "Natalia L. Klyachko", "R. Lee Mosley", "Howard E. Gendelman", "Alexander V. Kabanov", "Elena V. Batrakova"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0061852.g002", "stats"=>{"downloads"=>0, "page_views"=>10, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Transfection_of_brain_tissues_by_genetically_modified_macrophages_in_murine_models_of_PD_/686743", "title"=>"Transfection of brain tissues by genetically-modified macrophages in murine models of PD.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-04-19 01:52:23"}
  • {"files"=>["https://ndownloader.figshare.com/files/1029957"], "description"=>"<p><b>A</b>: LPS-induced encephalitis in BALB/C mice were injected <i>i.v.</i> with catalase-transfected macrophages (red curve), or PBS (blue curve). IVIS images over 40 days were taken ten minutes after intraperitoneal (<i>i.p.</i>) injection of a XenoLight RediJect probe for inflammation. The chemiluminescent signal was quantified and presented as radiance ratios of treated animal after 24 hours after LPS injection and at various times thereafter. Genetically-modified macrophages caused prolonged decreases of neuroinflammation in LPS-intoxicated mice. IVIS representative images at day 30 are shown. (<b>B</b>) and (<b>C</b>): BALB/c mice were <i>i.c.</i> injected with 6-OHDA. Forty eight hours later animals were <i>i.v.</i> injected with catalase-transfected macrophages, and 21 days later they were sacrificed, and mid-brain slides were stained for expression of <b>B</b>: CD11b, a marker for activated microglia or <b>C</b>: TH, a marker for dopaminergic neurons. Whereas 6-OHDA treatment caused significant microglia activation and neuronal loss, administration of catalase-transfected macrophages dramatically decreased oxidative stress, and increased neuronal survival. Administration of empty-vector transfected macrophages did not affect microglia activation, or number of dopaminergic neurons in in mice with brain inflammation. Statistical significance (shown by asterisk: <i>p</i><0.05) was assessed by a standard t-test compared to mice with <i>i.c.</i> LPS injections followed by <i>i.v.</i> PBS injections (healthy controls). Values are means ± SEM (<i>N</i> = 4).</p>", "links"=>[], "tags"=>["biotechnology", "immunology", "Immune cells", "Model organisms", "Animal models", "mouse", "Molecular cell biology", "Cellular types", "neuroscience", "Bioengineering", "Clinical research design", "Animal models of disease", "Drugs and devices", "neurology", "Neurodegenerative diseases", "Parkinson disease", "neuroprotective", "catalase-transfected", "macrophages", "pd", "murine"], "article_id"=>686748, "categories"=>["Medicine", "Engineering", "Biological Sciences"], "users"=>["Matthew J. Haney", "Yuling Zhao", "Emily B. Harrison", "Vivek Mahajan", "Shaheen Ahmed", "Zhijian He", "Poornima Suresh", "Shawn D. Hingtgen", "Natalia L. Klyachko", "R. Lee Mosley", "Howard E. Gendelman", "Alexander V. Kabanov", "Elena V. Batrakova"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0061852.g003", "stats"=>{"downloads"=>0, "page_views"=>11, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Anti_inflammatory_and_neuroprotective_effects_of_catalase_transfected_macrophages_in_PD_murine_models_/686748", "title"=>"Anti-inflammatory and neuroprotective effects of catalase-transfected macrophages in PD murine models.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-04-19 01:52:28"}

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Relative Metric

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