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144 results on '"McCarty, Douglas M."'

7. Integration of adeno-associated virus (AAV) and recombinant AAV vectors

Author

McCarty, Douglas M., Young, Samuel M., Jr., and Samulski, R. Jude

Subjects
Biological sciences
Abstract

The integration of adeno-associated virus (AAV) and the recombinant AAV vectors is studied. Results indicate that AAV integration in any context is inefficient and the episomal genomes could be responsible for the persistence of AAV gene delivery vectors in tissues.

Published
2004

9. Mucopolysaccharidosis IIIB, a lysosomal storage disease, triggers a pathogenic CNS autoimmune response

Author

Popovich Phillip G, Divers Erin, DiRosario Julianne, Killedar Smruti, McCarty Douglas M, and Fu Haiyan

Subjects
Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract Background Recently, using a mouse model of mucopolysaccharidosis (MPS) IIIB, a lysosomal storage disease with severe neurological deterioration, we showed that MPS IIIB neuropathology is accompanied by a robust neuroinflammatory response of unknown consequence. This study was to assess whether MPS IIIB lymphocytes are pathogenic. Methods Lymphocytes from MPS IIIB mice were adoptively transferred to naïve wild-type mice. The recipient animals were then evaluated for signs of disease and inflammation in the central nervous system. Results Our results show for the first time, that lymphocytes isolated from MPS IIIB mice caused a mild paralytic disease when they were injected systemically into naïve wild-type mice. This disease is characterized by mild tail and lower trunk weakness with delayed weight gain. The MPS IIIB lymphocytes also trigger neuroinflammation within the CNS of recipient mice characterized by an increase in transcripts of IL2, IL4, IL5, IL17, TNFα, IFNα and Ifi30, and intraparenchymal lymphocyte infiltration. Conclusions Our data suggest that an autoimmune response directed at CNS components contributes to MPS IIIB neuropathology independent of lysosomal storage pathology. Adoptive transfer of purified T-cells will be needed in future studies to identify specific effector T-cells in MPS IIIB neuroimmune pathogenesis.

Published
2010
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10. Intrathecal long-term gene expression by self-complementary adeno-associated virus type 1 suitable for chronic pain studies in rats

Author

Janssen William GM, McCarty Douglas M, Wang Cheng, Banck Michaela S, Harder Nina M, Storek Benjamin, Morrison John H, Walsh Christopher E, and Beutler Andreas S

Subjects
Pathology, RB1-214
Abstract

Abstract Background Intrathecal (IT) gene transfer is an attractive approach for targeting spinal mechanisms of nociception but the duration of gene expression achieved by reported methods is short (up to two weeks) impairing their utility in the chronic pain setting. The overall goal of this study was to develop IT gene transfer yielding true long-term transgene expression defined as ≥ 3 mo following a single vector administration. We defined "IT" administration as atraumatic injection into the lumbar cerebrospinal fluid (CSF) modeling a lumbar puncture. Our studies focused on recombinant adeno-associated virus (rAAV), one of the most promising vector types for clinical use. Results Conventional single stranded rAAV2 vectors performed poorly after IT delivery in rats. Pseudotyping of rAAV with capsids of serotypes 1, 3, and 5 was tested alone or in combination with a modification of the inverted terminal repeat. The former alters vector tropism and the latter allows packaging of self-complementary rAAV (sc-rAAV) vectors. Combining both types of modification led to the identification of sc-rAAV2/l as a vector that performed superiorly in the IT space. IT delivery of 3 × 10e9 sc-rAAV2/l particles per animal led to stable expression of enhanced green fluorescent protein (EGFP) for ≥ 3 mo detectable by Western blotting, quantitative PCR, and in a blinded study by confocal microscopy. Expression was strongest in the cauda equina and the lower sections of the spinal cord and only minimal in the forebrain. Microscopic examination of the SC fixed in situ with intact nerve roots and meninges revealed strong EGFP fluorescence in the nerve roots. Conclusion sc-rAAVl mediates stable IT transgene expression for ≥ 3 mo. Our findings support the underlying hypothesis that IT target cells for gene transfer lack the machinery for efficient conversion of the single-stranded rAAV genome into double-stranded DNA and favor uptake of serotype 1 vectors over 2. Experiments presented here will provide a rational basis for utilizing IT rAAV gene transfer in basic and translational studies on chronic pain.

Published
2006
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14. Systemic gene transfer of scAAV9.U1a.hSGSH for MPS IIIA: tolerability and preliminary evidence for a biochemical effect

Author

Flanigan, Kevin M., primary, Truxal, Kristen V., additional, McBride, Kim L., additional, McNally, Kelly A., additional, Kunkler, Krista L., additional, Zumberge, Nicholas A., additional, Martin, Lisa, additional, Aylward, Shawn C., additional, Corridore, Marco, additional, McKee, Christopher, additional, Fu, Haiyan, additional, and McCarty, Douglas M., additional

Published
2017
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23. A GLP-compliant toxicology and biodistribution study: systemic delivery of a rAAV9 vector for the treatment of mucopolysaccharidosis IIIB

Author

Meadows, Aaron S, primary, Duncan, F Jason, additional, Camboni, Marybeth, additional, Waligura, Kathryn, additional, Montgomery, Chrystal L, additional, Zaraspe, Kimberly, additional, Naughton, Bartholomew J, additional, Bremer, William G, additional, Shilling, Christopher, additional, Walker, Christopher, additional, Bolon, Brad, additional, Flanigan, Kevin, additional, McBride, Kim L, additional, McCarty, Douglas M, additional, and Fu, Haiyan, additional

Published
2015
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26. 78. An IND-Enabling GLP-Toxicology and Biodistribution Study Assessing Systemic rAAV9-hNAGLU Gene Delivery for Treating MPS IIIB: Genotype- and Sex-Specific Dose-Limiting Acute Liver Toxicity in Male Wild Type C57BL/6 Mice

Author

Fu, Haiyan, primary, Meadows, Aaron S., additional, Jason Duncan, F., additional, Mongomery, Chrystal, additional, Waligura, Kathryn, additional, Camboni, Marybeth, additional, Bremer, William G., additional, Walker, Christopher M., additional, Bolon, Brad, additional, Flanigan, Kevin M., additional, McBride, Kim L., additional, and McCarty, Douglas M., additional

Published
2015
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30. Feasibility and Safety of Systemic rAAV9-hNAGLU Delivery for Treating Mucopolysaccharidosis IIIB: Toxicology, Biodistribution, and Immunological Assessments in Primates

Author

Murrey, Darren A., primary, Naughton, Bartholomew J., additional, Duncan, F. Jason, additional, Meadows, Aaron S., additional, Ware, Tierra A., additional, Campbell, Katie J., additional, Bremer, William G., additional, Walker, Christopher M., additional, Goodchild, Laurie, additional, Bolon, Brad, additional, La Perle, Krista, additional, Flanigan, Kevin M., additional, McBride, Kim L., additional, McCarty, Douglas M., additional, and Fu, Haiyan, additional

Published
2014
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32. Feasibility and Safety of Systemic rAAV9-hNAGLU Delivery for Treating MPS IIIB: Toxicology, Bio-distribution and Immunological Assessments in Primates

Author

Murrey, Darren A, primary, Naughton, Bartholomew J, additional, Duncan, F Jason, additional, Meadows, Aaron S, additional, Ware, Tierra Amber, additional, Campbell, Katie, additional, Bremer, William G, additional, Walker, Christopher, additional, Goodchild, Laurie, additional, Bolon, Brad, additional, La Perle, Krista, additional, Flanigan, Kevin, additional, McBride, Kim L, additional, McCarty, Douglas M, additional, and Fu, Haiyan, additional

Published
2014
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45. Blood Genome-Wide Transcriptional Profiles Reflect Broad Molecular Impairments and Strong Blood-Brain Links in Alzheimer's Disease.

Author

Naughton, Bartholomew J., Duncan, F. Jason, Murrey, Darren A., Meadows, Aaron S., Newsom, David E., Stoicea, Nicoleta, White, Peter, Scharre, Douglas W., Mccarty, Douglas M., and Fu, Haiyan

Subjects
ALZHEIMER'S disease research, BLOOD-brain barrier, RNA analysis, BLOOD testing, NEUROLOGICAL disorders
Abstract

To date, little is known regarding the etiology and disease mechanisms of Alzheimer's disease (AD). There is a general urgency for novel approaches to advance AD research. In this study, we analyzed blood RNA from female patients with advanced AD and matched healthy controls using genome-wide gene expression microarrays. Our data showed significant alterations in 3,944 genes (≥⃒2-fold, FDR ≤1%) in AD whole blood, including 2,932 genes that are involved in broad biological functions. Importantly, we observed abnormal transcripts of numerous tissue-specific genes in AD blood involving virtually all tissues, especially the brain. Of altered genes, 157 are known to be essential in neurological functions, such as neuronal plasticity, synaptic transmission and neurogenesis. More importantly, 205 dysregulated genes in AD blood have been linked to neurological disease, including AD/dementia and Parkinson's disease, and 43 are known to be the causative genes of 42 inherited mental retardation and neurodegenerative diseases. The detected transcriptional abnormalities also support robust inflammation, profound extracellular matrix impairments, broad metabolic dysfunction, aberrant oxidative stress, DNA damage, and cell death. While the mechanisms are currently unclear, this study demonstrates strong blood-brain correlations in AD. The blood transcriptional profiles reflect the complex neuropathological status in AD, including neuropathological changes and broad somatic impairments. The majority of genes altered in AD blood have not previously been linked to AD. We believe that blood genome-wide transcriptional profiling may provide a powerful and minimally invasive tool for the identification of novel targets beyond Aβ and tauopathy for AD research. [ABSTRACT FROM AUTHOR]

Published
2015
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50. Adeno-associated virus serotypes 1 to 5 mediated tumor cell directed gene transfer and improvement of transduction efficiency

Author

Hacker, Ulrich T., primary, Wingenfeld, Lisa, additional, Kofler, David M., additional, Schuhmann, Natascha K., additional, Lutz, Sandra, additional, Herold, Tobias, additional, King, Susan B.S., additional, Gerner, Franz M., additional, Perabo, Luca, additional, Rabinowitz, Joseph, additional, McCarty, Douglas M., additional, Samulski, Richard J., additional, Hallek, Michael, additional, and Büning, Hildegard, additional

Published
2005
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