Global CNS correction in a large brain model of human alpha-mannosidosis by intravascular gene therapy

Abstract Intravascular injection of certain adeno-associated virus vector serotypes can cross the blood–brain barrier to deliver a gene into the CNS. However, gene distribution has been much more limited within the brains of large animals compared to rodents, rendering this approach suboptimal for treatment of the global brain lesions present in most human neurogenetic diseases. The most commonly used serotype in animal and human studies is 9, which also has the property of being transported via axonal pathways to distal neurons. A small number of other serotypes share this property, three of which were tested intravenously in mice compared to 9. Serotype hu.11 transduced fewer cells in the brain than 9, rh8 was similar to 9, but hu.32 mediated substantially greater transduction than the others throughout the mouse brain. To evaluate the potential for therapeutic application of the hu.32 serotype in a gyrencephalic brain of larger mammals, a hu.32 vector expressing the green fluorescent protein reporter gene was evaluated in the cat. Transduction was widely distributed in the cat brain, including in the cerebral cortex, an important target since mental retardation is an important component of many of the human neurogenetic diseases. The therapeutic potential of a hu.32 serotype vector was evaluated in the cat homologue of the human lysosomal storage disease alpha-mannosidosis, which has globally distributed lysosomal storage lesions in the brain. Treated alpha-mannosidosis cats had reduced severity of neurological signs and extended life spans compared to untreated cats. The extent of therapy was dose dependent and intra-arterial injection was more effective than intravenous delivery. Pre-mortem, non-invasive magnetic resonance spectroscopy and diffusion tensor imaging detected differences between the low and high doses, and showed normalization of grey and white matter imaging parameters at the higher dose. The imaging analysis was corroborated by post-mortem histological analysis, which showed reversal of histopathology throughout the brain with the high dose, intra-arterial treatment. The hu.32 serotype would appear to provide a significant advantage for effective treatment of the gyrencephalic brain by systemic adeno-associated virus delivery in human neurological diseases with widespread brain lesions.

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Computational Model of Interstitial Transport in the Rat Brain Using Diffusion Tensor Imaging

ASME 2007 Summer Bioengineering Conference ◽

10.1115/sbc2007-176633 ◽

2007 ◽

Author(s):

Jung Hwan Kim ◽

Thomas H. Mareci ◽

Malisa Sarntinoranont

Keyword(s):

Diffusion Tensor ◽

Therapeutic Potential ◽

Treatment Optimization ◽

Convection Enhanced Delivery ◽

Tissue Properties ◽

Large Molecules ◽

Macromolecular Drugs ◽

Interstitial Transport ◽

Blood Spinal Cord Barrier ◽

The Brain

In spite of the high therapeutic potential of macromolecular drugs, it has proven difficult to apply them to recovery after injury and treatment of cancer, Parkinson’s disease, and other neurodegenerative diseases. One barrier to systemic administration is low capillary permeability, i.e., the blood-brain and blood-spinal cord barrier. To overcome this barrier, convection-enhanced delivery (CED) infuses agents directly into tissue to supplement diffusion and increase the distribution of large molecules in the brain [1,2]. Predictive models of distribution during CED would be useful in treatment optimization and planning. To account for large infusion volumes, such models should incorporate tissue boundaries and anisotropic tissue properties.

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Iba1+/NG2+ Macrophage-Like Cells Expressing a Variety of Neuroprotective Factors Ameliorate Ischemic Damage of the Brain

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2009.233 ◽

2009 ◽

Vol 30 (3) ◽

pp. 603-615 ◽

Cited By ~ 51

Author(s):

Anna Smirkin ◽

Hiroaki Matsumoto ◽

Hisaaki Takahashi ◽

Akihiro Inoue ◽

Masahiko Tagawa ◽

...

Keyword(s):

Bone Marrow ◽

Fluorescent Protein ◽

Artery Occlusion ◽

Brain Lesions ◽

Ischemic Lesion ◽

Ischemic Brain ◽

Green Fluorescent ◽

High Level ◽

Cerebral Artery Occlusion ◽

The Brain

In a transient 90-min middle cerebral artery occlusion (MCAO) model of rats, a large ischemic lesion is formed where macrophage-like cells massively accumulate, many of which express a macrophage marker, Iba1, and an oligodendrocyte progenitor cell marker, NG2 chondroitin sulfate proteoglycan (NG2); therefore, the cells were termed BINCs (Brain Iba1+/NG2+Cells). A bone marrow transplantation experiment using green-fluorescent protein-transgenic rats showed that BINCs were derived from bone marrow. 5-Fluorouracil (5FU) injection at 2 days post reperfusion (2 dpr) markedly reduced the number of BINCs at 7 dpr, causing enlargement of necrotic volumes and frequent death of the rats. When isolated BINCs were transplanted into 5FU-aggravated ischemic lesion, the volume of the lesion was much reduced. Quantitative real-time RT-PCR showed that BINCs expressed mRNAs encoding bFGF, BMP2, BMP4, BMP7, GDNF, HGF, IGF-1, PDGF-A, and VEGF. In particular, BINCs expressed IGF-1 mRNA at a very high level. Immunohistochemical staining showed that IGF-1-expressing BINCs were found not only in rat but also human ischemic brain lesions. These results suggest that bone marrow-derived BINCs play a beneficial role in ischemic brain lesions, at least in part, through secretion of neuroprotective factors.

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Circulating Anti-Wild-Type Adeno-Associated Virus Type 2 (AAV2) Antibodies Inhibit Recombinant AAV2 (rAAV2)-Mediated, but Not rAAV5-Mediated, Gene Transfer in the Brain

Journal of Virology ◽

10.1128/jvi.78.12.6344-6359.2004 ◽

2004 ◽

Vol 78 (12) ◽

pp. 6344-6359 ◽

Cited By ~ 156

Author(s):

Carmen S. Peden ◽

Corinna Burger ◽

Nicholas Muzyczka ◽

Ronald J. Mandel

Keyword(s):

Immune Response ◽

Virus Type ◽

Fluorescent Protein ◽

Natural Infection ◽

Cell Counting ◽

Wild Type ◽

Adeno Associated Virus ◽

Live Virus ◽

The Brain

ABSTRACT Epidemiological studies report that 80% of the population maintains antibodies (Ab) to wild-type (wt) adeno-associated virus type 2 (AAV2), with 30% expressing neutralizing Ab (NAb). The blood-brain barrier (BBB) provides limited immune privilege to brain parenchyma, and the immune response to recombinant AAV (rAAV) administration in the brain of a naive animal is minimal. However, central nervous system transduction in preimmunized animals remains unstudied. Vector administration may disrupt the BBB sufficiently to promote an immune response in a previously immunized animal. We tested the hypothesis that intracerebral rAAV administration and readministration would not be affected by the presence of circulating Ab to wt AAV2. Rats peripherally immunized with live wt AAV2 and naive controls were tested with single intrastriatal injections of rAAV2 encoding human glial cell line-derived neurotrophic factor (GDNF) or green fluorescent protein (GFP). Striatal readministration of rAAV2-GDNF was also tested in preimmunized and naive rats. Finally, serotype specificity of the immunization against wt AAV2 was examined by single injections of rAAV5-GFP. Preimmunization resulted in high levels of circulating NAb and prevented transduction by rAAV2 as assessed by striatal GDNF levels. rAAV2-GFP striatal transduction was also prevented by immunization, while rAAV5-GFP-mediated transduction, as assessed by stereological cell counting, was unaffected. Additionally, inflammatory markers were present in those animals that received repeated administrations of rAAV2, including markers of a cell-mediated immune response and cytotoxic damage. A live virus immunization protocol generated the circulating anti-wt-AAV Ab seen in this experiment, while human titers are commonly acquired via natural infection. Regardless, the data show that the presence of high levels of NAb against wt AAV can reduce rAAV-mediated transduction in the brain and should be accounted for in future experiments utilizing this vector.

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Pre- and Intraoperative Tractographic Evaluation of Corticospinal Tract Shift

Neurosurgery ◽

10.1227/neu.0b013e31821a8555 ◽

2011 ◽

Vol 69 (3) ◽

pp. 696-705 ◽

Cited By ~ 32

Author(s):

Andrea Romano ◽

Giancarlo D'Andrea ◽

Luigi Fausto Calabria ◽

Valeria Coppola ◽

Camilla Rossi Espagnet ◽

...

Keyword(s):

Corticospinal Tract ◽

Diffusion Tensor ◽

Tumor Resection ◽

Brain Lesions ◽

Peritumoral Edema ◽

Brain Shift ◽

Neuronavigation System ◽

Dural Opening ◽

Glioma Resection ◽

The Brain

Abstract BACKGROUND: Magnetic resonance with diffusion tensor image (DTI) may be able to estimate trajectories compatible with subcortical tracts close to brain lesions. A limit of DTI is brain shifting (movement of the brain after dural opening and tumor resection). OBJECTIVE: To calculate the brain shift of trajectories compatible with the corticospinal tract (CST) in patients undergoing glioma resection and predict the shift directions of CST. METHODS: DTI was acquired in 20 patients and carried out through 12 noncollinear directions. Dedicated software “merged” all sequences acquired with tractographic processing and the whole dataset was sent to the neuronavigation system. Preoperative, after dural opening (in 11) and tumor resection (in all) DTI acquisitions were performed to evaluate CST shifting. The extent of shifting was considered as the maximum distance between the preoperative and intraoperative contours of the trajectories. RESULTS: An outward shift of CST was observed in 8 patients and an inward shift in 10 patients during surgery. In the remaining 2 patients, no intraoperative displacement was detected. Only peritumoral edema showed a statistically significant correlation with the amount of shift. In those patients in which DTI was acquired after dural opening as well (11 patients), an outward shifting of CST was evident in that phase. CONCLUSION: The use of intraoperative DTI demonstrated brain shifting of the CST. DTI evaluation of white matter tracts can be used during surgical procedures only if updated with intraoperative acquisitions.

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Systemic Delivery of Tyrosine-Mutant AAV Vectors Results in Robust Transduction of Neurons in Adult Mice

BioMed Research International ◽

10.1155/2013/974819 ◽

2013 ◽

Vol 2013 ◽

pp. 1-8 ◽

Cited By ~ 31

Author(s):

Asako Iida ◽

Naomi Takino ◽

Hitomi Miyauchi ◽

Kuniko Shimazaki ◽

Shin-ichi Muramatsu

Keyword(s):

Transgene Expression ◽

Neurological Diseases ◽

Systemic Delivery ◽

Adeno Associated Virus ◽

Gene Therapies ◽

Adult Mice ◽

The Central Nervous System ◽

Foreign Dna ◽

The Brain ◽

Limited Usefulness

Recombinant adeno-associated virus (AAV) vectors are powerful tools for both basic neuroscience experiments and clinical gene therapies for neurological diseases. Intravascularly administered self-complementary AAV9 vectors can cross the blood-brain barrier. However, AAV9 vectors are of limited usefulness because they mainly transduce astrocytes in adult animal brains and have restrictions on foreign DNA package sizes. In this study, we show that intracardiac injections of tyrosine-mutant pseudotype AAV9/3 vectors resulted in extensive and widespread transgene expression in the brains and spinal cords of adult mice. Furthermore, the usage of neuron-specific promoters achieved selective transduction of neurons. These results suggest that tyrosine-mutant AAV9/3 vectors may be effective vehicles for delivery of therapeutic genes, including miRNAs, into the brain and for treating diseases that affect broad areas of the central nervous system.

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Brain Imaging

10.1093/med/9780190850128.003.0005 ◽

2018 ◽

Author(s):

Jack M. Gorman

Keyword(s):

Magnetic Resonance Imaging ◽

Magnetic Resonance ◽

Brain Imaging ◽

Diffusion Tensor ◽

Brain Structures ◽

The Body ◽

Resonance Spectroscopy ◽

Resonance Imaging ◽

Axial Tomography ◽

The Brain

The blood–brain barrier vigorously limits what can get into and out of the brain, making our ability to understand brain function much more difficult than with any other organ in the body. The modern era of brain imaging began about a half-century ago with the introduction of computed axial tomography (CAT) and magnetic resonance imaging (MRI). Although CAT scanning shows brain structure in great detail and revolutionized the precision of medical diagnosis, including of brain disorders, it has had relatively little impact on psychiatry because most psychiatric illnesses do not involve visible abnormalities of the size, shape, or volume of brain structures. Similarly, although we have gained some insights from structural MRI, it primarily shows us the anatomy of the brain. Three other variants of MRI, however, have been extremely useful in studying psychiatric issues: functional magnetic resonance imaging, diffusion tensor imaging, and magnetic resonance spectroscopy.

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Effects of early low-level lead exposure on human brain structure, organization and functions

Journal of Developmental Origins of Health and Disease ◽

10.1017/s2040174410000486 ◽

2010 ◽

Vol 2 (1) ◽

pp. 17-24 ◽

Cited By ~ 5

Author(s):

K. M. Cecil

Keyword(s):

Magnetic Resonance Imaging ◽

Magnetic Resonance ◽

Lead Exposure ◽

Brain Structure ◽

Diffusion Tensor ◽

Adult Brain ◽

Resonance Spectroscopy ◽

Resonance Imaging ◽

Environmental Lead ◽

The Brain

Advanced neuroimaging techniques offer unique insights into how childhood lead exposure impacts the brain. Volumetric magnetic resonance imaging affords anatomical information about the size of global, regional and subcomponent structures within the brain. Diffusion tensor imaging provides information about white matter architecture by quantitatively describing how water molecules diffuse within it. Proton magnetic resonance spectroscopy generates quantitative measures of neuronal, axonal and glial elements via concentration levels of select metabolites. Functional magnetic resonance imaging infers neuronal activity associated with a given task performed. Employing these techniques in the study of the Cincinnati Lead Study, a relatively homogeneous birth cohort longitudinally monitored for over 30 years, one can non-invasively and quantitatively explore how childhood lead exposure is associated with adult brain structure, organization and function. These studies yield important findings how environmental lead exposure impacts human health.

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Proton magnetic resonance spectroscopy: clinical applications in patients with brain lesions

Sao Paulo Medical Journal ◽

10.1590/s1516-31802003000600008 ◽

2003 ◽

Vol 121 (6) ◽

pp. 254-259 ◽

Cited By ~ 10

Author(s):

Sérgio Luiz Ramin ◽

Waldir Antonio Tognola ◽

Antonio Ronaldo Spotti

Keyword(s):

Amino Acids ◽

Magnetic Resonance ◽

Magnetic Resonance Spectroscopy ◽

Proton Magnetic Resonance ◽

Proton Magnetic Resonance Spectroscopy ◽

Clinical Applications ◽

Brain Lesions ◽

Resonance Spectroscopy ◽

Proton Spectroscopy ◽

The Brain

CONTEXT: Proton spectroscopy has been recognized as a safe and noninvasive diagnostic method that, coupled with magnetic resonance imaging techniques, allows for the correlation of anatomical and physiological changes in the metabolic and biochemical processes occurring within previously-determined volumes in the brain. There are two methods of proton magnetic resonance spectroscopy: single voxel and chemical shift imaging OBJECTIVE: The present work focused on the clinical applications of proton magnetic resonance spectroscopy in patients with brain lesions. CONCLUSIONS: In vivo proton spectroscopy allows the detection of certain metabolites in brain tissue, such as N-acetyl aspartate, creatine, choline, myoinositol, amino acids and lipids, among others. N-acetyl aspartate is a neuronal marker and, as such, its concentration will decrease in the presence of aggression to the brain. Choline increase is the main indicator of neoplastic diseases. Myoinositol is raised in patients with Alzheimer's disease. Amino acids are encountered in brain abscesses. The presence of lipids is related to necrotic processes.

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Roles of TRP Channels in Neurological Diseases

Oxidative Medicine and Cellular Longevity ◽

10.1155/2020/7289194 ◽

2020 ◽

Vol 2020 ◽

pp. 1-13

Author(s):

Rui Wang ◽

Sheng Tu ◽

Jianmin Zhang ◽

Anwen Shao

Keyword(s):

Transient Receptor Potential ◽

Trp Channels ◽

Therapeutic Potential ◽

Neurological Diseases ◽

Receptor Potential ◽

Physiological Processes ◽

Neuroprotective Strategies ◽

Transient Receptor ◽

Physical And Chemical ◽

The Brain

Transient receptor potential (TRP) proteins consist of a superfamily of cation channels that have been involved in diverse physiological processes in the brain as well as in the pathogenesis of neurological disease. TRP channels are widely expressed in the brain, including neurons and glial cells, as well as in the cerebral vascular endothelium and smooth muscle. Members of this channel superfamily show a wide variety of mechanisms ranging from ligand binding to voltage, physical, and chemical stimuli, implying the promising therapeutic potential of TRP in neurological diseases. In this review, we focus on the physiological functions of TRP channels in the brain and the pathological roles in neurological disorders to explore future potential neuroprotective strategies.

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