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Mohit N Shivdasani - One of the best experts on this subject based on the ideXlab platform.
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EMBC - Electrical Field Shaping Techniques in a Feline Model of Retinal Degeneration
Conference proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and, 2018Co-Authors: Thomas C Spencer, James B Fallon, Carla J Abbott, Penny J Allen, Alice Brandli, Mohit N ShivdasaniAbstract:The majority of preclinical studies investigating multi-electrode field shaping stimulation strategies for retinal prostheses, have been conducted in normally-sighted animals. This study aimed to reassess the effectiveness of two electrical field shaping techniques that have been shown to work in healthy retinae, in a more clinically relevant animal Model of photoreceptor degeneration. Four cats were unilaterally blinded via intravitreal injections of adenosine triphosphate. Cortical responses to traditional monopolar (MP) stimulation, focused multipolar (FMP) stimulation and two-dimensional current steering were recorded. Contrary to our previous work, we found no significant difference between the spread of cortical activation elicited by FMP and MP stimulation, and we were not able to reproduce cortical responses to singleelectrode retinal stimulation using two-dimensional current steering. These findings suggest that while shown to be effective in normally-sighted animals, these techniques may not be readily translatable to patients with retinal degeneration and require further optimization.
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electrical field shaping techniques in a Feline Model of retinal degeneration
International Conference of the IEEE Engineering in Medicine and Biology Society, 2018Co-Authors: Thomas C Spencer, James B Fallon, Carla J Abbott, Penny J Allen, Alice Brandli, Mohit N ShivdasaniAbstract:The majority of preclinical studies investigating multi-electrode field shaping stimulation strategies for retinal prostheses, have been conducted in normally-sighted animals. This study aimed to reassess the effectiveness of two electrical field shaping techniques that have been shown to work in healthy retinae, in a more clinically relevant animal Model of photoreceptor degeneration. Four cats were unilaterally blinded via intravitreal injections of adenosine triphosphate. Cortical responses to traditional monopolar (MP) stimulation, focused multipolar (FMP) stimulation and two-dimensional current steering were recorded. Contrary to our previous work, we found no significant difference between the spread of cortical activation elicited by FMP and MP stimulation, and we were not able to reproduce cortical responses to singleelectrode retinal stimulation using two-dimensional current steering. These findings suggest that while shown to be effective in normally-sighted animals, these techniques may not be readily translatable to patients with retinal degeneration and require further optimization.
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stimulation of a suprachoroidal retinal prosthesis drives cortical responses in a Feline Model of retinal degeneration
Investigative Ophthalmology & Visual Science, 2016Co-Authors: Felix P Aplin, Kirstan A Vessey, Robyn H Guymer, Robert K Shepherd, Erica L Fletcher, Penelope J Allen, Mohit N ShivdasaniAbstract:Purpose: Retinal prostheses have emerged as a promising technology to restore vision in patients with severe photoreceptor degeneration. To better understand how neural degeneration affects the efficacy of electronic implants, we investigated the function of a suprachoroidal retinal implant in a Feline Model. Methods: Unilateral retinal degeneration was induced in four adult Felines by intravitreal injection of adenosine triphosphate (ATP). Twelve weeks post injection, animals received suprachoroidal electrode array implants in each eye, and responses to electrical stimulation were obtained using multiunit recordings from the visual cortex. Histologic measurements of neural and glial changes in the retina at the implant site were correlated with cortical thresholds from individual stimulating electrodes. Results: Adenosine triphosphate-injected eyes displayed changes consistent with mid-to-late stage retinal degeneration and reModeling. A significant increase in electrical charge was required to induce a cortical response from stimulation of the degenerated retina compared to that in the fellow control eye. Spatial and temporal characteristics of the electrically evoked cortical responses were no different between eyes. Individual electrode thresholds varied in both the control and the ATP-injected eyes and were correlated with ganglion cell density. In ATP-injected eyes, cortical threshold was also independently correlated with an increase in the extent of retinal gliosis. Conclusions: These data suggest that even when ganglion cell density remains unaffected, glial changes in the retina following degeneration can influence the efficacy of suprachoroidal electrical stimulation. A better understanding of how glial change impacts retinal prosthesis function may help to further the optimization of retinal implants.
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safety and efficacy of explanting or replacing suprachoroidal electrode arrays in a Feline Model
Clinical and Experimental Ophthalmology, 2015Co-Authors: Penelope J Allen, Mohit N Shivdasani, Ronald T Leung, David A X Nayagam, Richard A Williams, Cesar Salinasla M RosaAbstract:Background A key requirement for retinal prostheses is the ability for safe removal or replacement. We examined whether suprachoroidal electrode arrays can be removed or replaced after implantation. Methods Suprachoroidal electrode arrays were unilaterally implanted into 13 adult Felines. After 1 month, arrays were surgically explanted (n = 6), replaced (n = 5) or undisturbed (n = 2). The retina was assessed periodically using fundus photography and optical coherence tomography. Three months after the initial implantation, the function of replaced or undisturbed arrays was assessed by measuring the responses of the visual cortex to retinal electrical stimulation. The histopathology of tissues surrounding the implant was examined. Results Array explantation or replacement was successful in all cases. Fundus photography showed localized disruption to the tapetum lucidum near the implant's tip in seven subjects following implantation. Although optical coherence tomography showed localized retinal changes, there were no widespread statistically significant differences in the thickness of the retinal layers or choroid. The distance between the electrodes and retina increased after device replacement but returned to control values within eight weeks (P < 0.03). Staphylomas developed near the scleral wound in five animals after device explantation. Device replacement did not alter the cortical evoked potential threshold. Histopathology showed localized outer nuclear layer thinning, tapetal disruption and pseudo-rosette formation, but the overall retinal morphology was preserved. Conclusions It is feasible to remove or replace conformable medical grade silicone electrode arrays implanted suprachoroidally. The scleral wound requires careful closure to minimize the risk of staphylomas.
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Safety and efficacy of explanting or replacing suprachoroidal electrode arrays in a Feline Model
Clinical and Experimental Ophthalmology, 2014Co-Authors: Ronald T Leung, Penelope J Allen, Mohit N Shivdasani, David A X Nayagam, Richard A Williams, Cesar M. Salinas-la Rosa, Lauren N. Ayton, Meri Basa, Jonathan YeohAbstract:Background A key requirement for retinal prostheses is the ability for safe removal or replacement. We examined whether suprachoroidal electrode arrays can be removed or replaced after implantation. Methods Suprachoroidal electrode arrays were unilaterally implanted into 13 adult Felines. After 1 month, arrays were surgically explanted (n = 6), replaced (n = 5) or undisturbed (n = 2). The retina was assessed periodically using fundus photography and optical coherence tomography. Three months after the initial implantation, the function of replaced or undisturbed arrays was assessed by measuring the responses of the visual cortex to retinal electrical stimulation. The histopathology of tissues surrounding the implant was examined. Results Array explantation or replacement was successful in all cases. Fundus photography showed localized disruption to the tapetum lucidum near the implant's tip in seven subjects following implantation. Although optical coherence tomography showed localized retinal changes, there were no widespread statistically significant differences in the thickness of the retinal layers or choroid. The distance between the electrodes and retina increased after device replacement but returned to control values within eight weeks (P
John J Hopwood - One of the best experts on this subject based on the ideXlab platform.
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advantages of using same species enzyme for replacement therapy in a Feline Model of mucopolysaccharidosis type vi
Journal of Biological Chemistry, 1999Co-Authors: Julie Bielicki, Allison C Crawley, Richard C A Davey, Jodie C Varnai, John J HopwoodAbstract:Abstract In a Feline Model of mucopolysaccharidosis type VI (MPS VI), recombinant FelineN-acetylgalactosamine-4-sulfatase (rf4S) administered at a dose of 1 mg/kg of body weight, altered the clinical course of the disease in two affected cats treated from birth. After 170 days of therapy, both cats were physically indistinguishable from normal cats with the exception of mild corneal clouding. FelineN-acetylgalactosamine-4-sulfatase was effective in reducing urinary glycosaminoglycan levels and lysosomal storage in all cell types examined except for corneal keratocytes and cartilage chondrocytes. In addition, skeletal pathology was nearly normalized as assessed by radiographic evidence and bone morphometric analysis. Comparison of results with a previous study in which recombinant human 4S (rh4S) was used at an equivalent dose and one 5 times higher indicated that rf4S had a more pronounced effect on reducing pathology than the same dose of rh4S, and in some instances such as bone pathology and lysosomal storage in aorta smooth muscle cells, it was as good as, or better than, the higher dose of rh4S. We conclude that in the Feline MPS VI Model the use of native or same species enzyme for enzyme replacement therapy has significant benefits.
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Histomorphometric Analysis of the Tibial Growth Plate in a Feline Model of Mucopolysaccharidosis Type VI
Calcified Tissue International, 1999Co-Authors: J. D. Nuttall, John J Hopwood, Leanne K. Brumfield, Nicola L. Fazzalari, Sharon ByersAbstract:Mucopolysaccharidosis type VI (MPS VI) is a genetically inherited lysosomal storage disorder. Severely affected children exhibit a range of skeletal abnormalities including short stature, facial dysmorphia, and dysostosis multiplex. Naturally occurring and transgenic animal Models of MPS VI are also found which exhibit pathology similar to the human disorder. In this paper we have characterized the formation of trabecular bone from growth plate cartilage in a Feline Model of MPS VI. Tibial trabecular bone was shown to be osteopenic in MPS VI animals with a bone mineral volume (BV/TV) of 4.51% compared with a BV/TV of 15.64% in normal animals. In addition to osteopenia, a rearrangement of trabecular bone architecture was also observed in MPS VI tibiae, with fewer, thinner trabeculae noted; bone formation rate was also decreased. These observations support those previously made in the L5 vertebrae of MPS VI animals. When the sequential formation of growth plate cartilage structural elements, their transition into primary bone spongiosa, and reModeling into secondary bone spongiosa was characterized, no difference between normal and MPS VI could be detected in the number of cartilage septae and their arrangement in the proliferative and hypertrophic regions of the growth plate or trabecular elements in the primary spongiosa. However, a deviation from normal was observed in the resting zone of the growth plate and in the secondary spongiosa of bone. Thus, the osteopenia observed in MPS VI bone appears to arise primarily from a defect in bone production within the metaphysis and diaphysis rather than the creation of an abnormal template in the preceding growth plate cartilage.
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Evaluation of fibroblast-mediated gene therapy in a Feline Model of mucopolysaccharidosis type VI.
Biochimica et Biophysica Acta, 1999Co-Authors: Gouri Yogalingam, Allison C Crawley, John J Hopwood, Donald S. AnsonAbstract:Abstract Fibroblast-mediated ex vivo gene therapy was evaluated in the N -acetylgalactosamine 4-sulfatase (4S) deficient mucopolysaccharidosis type VI (MPS VI) cat. Skin biopsies were obtained at birth from severely affected MPS VI kittens and used to initiate fibroblast outgrowths for retroviral transduction with the 4S cDNA. 4S gene expression in transduced cells was under the transcriptional control of the MoMLV long terminal repeat promoter or the cytomegalovirus (CMV) immediate–early promoter. Characterisation of gene-transduced fibroblasts demonstrated the cells to be over-expressing 4S activity. Twenty-four to forty million autologous, gene-corrected fibroblasts were implanted under the renal capsule of three MPS VI kittens at 8–16 weeks of age. Transient, low levels of 4S activity were detected in peripheral blood leukocytes shortly after implantation but were not detectable within 3–8 weeks’ post-implantation. Long-term biochemical and clinical evaluation of these cats demonstrated identical disease progression to that previously described in untreated, clinically severe MPS VI cats.
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effect of enzyme replacement therapy on bone formation in a Feline Model of mucopolysaccharidosis type vi
Bone, 1997Co-Authors: Sharon Byers, Allison C Crawley, John J Hopwood, J. D. Nuttall, K Smith, Nicola L. FazzalariAbstract:Abstract A range of skeletal abnormalities are evident in mucopolysaccharidosis type VI (MPS VI, Maroteaux-Lamy syndrome) including short stature and dysostosis multiplex, resulting from a deficiency in the lysosomal hydrolase N -acetylgalactosamine-4-sulphatase (4S). In this article, bone pathology was assessed in a Feline Model of MPS VI to evaluate the efficacy of enzyme replacement therapy (ERT) as a treatment modality for this genetic disorder. Osteopenia is clearly evident in MPS VI animals, with bone mineral volume ( BV TV ) falling well below that of normal animals (4.39% vs. 20.11%, respectively). Trabecular bone architecture was also affected in MPS VI with fewer, thinner, and more widely spaced trabeculae apparent. Bone formation rate ( BFR BS ) was also lower in MPS VI animals than controls (0.0011 mm 3 /mm 2 per day vs. 0.008 mm 3 /mm 2 per day, respectively). Vertebral and tibial bone length in MPS VI animals progressively fell behind normal values with increasing age, as did cortical bone thickness. Vertebral body shape was also altered. ERT with recombinant human 4S (rh4S) resulted in a vertebral BV TV of 8.23% in animals treated with an intravenous enzyme dose of 1 mg/kg and a BV TV of 14.33% in animals treated with a dose of 5 mg/kg. BFR BS also increased to 0.0034 mm 3 /mm 2 per day in animals treated with enzyme doses of either 1.0 or 5.0 mg/kg rh4S. All other affected histomorphometric parameters also improved with ERT to a level intermediate between MPS VI untreated animals and normals. However, individual animals treated with 0.2 mg/kg rh4S intravenously or 1.0 mg/kg rh4S administered subcutaneously did not exhibit an improvement over untreated MPS VI animals. Vertebral and tibial bone lengths, tibial cortical bone thickness, and vertebral body shape also responded to ERT, with a trend away from the untreated group. Thus, ERT had a positive effect on bone development in MPS VI animals that was dependent upon the dose of enzyme administered and the route of administration.
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enzyme replacement therapy from birth in a Feline Model of mucopolysaccharidosis type vi
Journal of Clinical Investigation, 1997Co-Authors: Allison C Crawley, Elizabeth L Isaac, Sharon Byers, K H Niedzielski, Richard Davey, John J HopwoodAbstract:We report evidence of a dose responsive effect of enzyme replacement therapy in mucopolysaccharidosis type VI cats from birth, at the clinical, biochemical, and histopathological level. Cats treated with weekly, intravenous recombinant human N-acetylgalactosamine-4-sulfatase at 1 and 5 mg/kg, were heavier, more flexible, had greatly reduced or no spinal cord compression, and had almost normal urinary glycosaminoglycan levels. There was near normalization or complete reversal of lysosomal storage in heart valve, aorta, skin, dura, liver, and brain perivascular cells. No reduction in lysosomal vacuolation was observed in cartilage or cornea; however, articular cartilage was thinner and external ear pinnae were larger in some treated cats. Degenerative joint changes were not obviously delayed in treated cats. Skeletal pathology was reduced, with more normalized bone dimensions and with more uniform bone density and trabecular pattern clearly visible on radiographs by 5 to 6 mo; however, differences between 1 and 5 mg/kg dose rates were not clearly distinguishable. At a dose of 0.2 mg/kg, disease was not significantly altered in the majority of parameters examined. Lysosomal storage was present in all tissues examined in the midterm mucopolysaccharidosis type VI fetus and increased rapidly in extent and severity from birth.
Allison C Crawley - One of the best experts on this subject based on the ideXlab platform.
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advantages of using same species enzyme for replacement therapy in a Feline Model of mucopolysaccharidosis type vi
Journal of Biological Chemistry, 1999Co-Authors: Julie Bielicki, Allison C Crawley, Richard C A Davey, Jodie C Varnai, John J HopwoodAbstract:Abstract In a Feline Model of mucopolysaccharidosis type VI (MPS VI), recombinant FelineN-acetylgalactosamine-4-sulfatase (rf4S) administered at a dose of 1 mg/kg of body weight, altered the clinical course of the disease in two affected cats treated from birth. After 170 days of therapy, both cats were physically indistinguishable from normal cats with the exception of mild corneal clouding. FelineN-acetylgalactosamine-4-sulfatase was effective in reducing urinary glycosaminoglycan levels and lysosomal storage in all cell types examined except for corneal keratocytes and cartilage chondrocytes. In addition, skeletal pathology was nearly normalized as assessed by radiographic evidence and bone morphometric analysis. Comparison of results with a previous study in which recombinant human 4S (rh4S) was used at an equivalent dose and one 5 times higher indicated that rf4S had a more pronounced effect on reducing pathology than the same dose of rh4S, and in some instances such as bone pathology and lysosomal storage in aorta smooth muscle cells, it was as good as, or better than, the higher dose of rh4S. We conclude that in the Feline MPS VI Model the use of native or same species enzyme for enzyme replacement therapy has significant benefits.
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Evaluation of fibroblast-mediated gene therapy in a Feline Model of mucopolysaccharidosis type VI.
Biochimica et Biophysica Acta, 1999Co-Authors: Gouri Yogalingam, Allison C Crawley, John J Hopwood, Donald S. AnsonAbstract:Abstract Fibroblast-mediated ex vivo gene therapy was evaluated in the N -acetylgalactosamine 4-sulfatase (4S) deficient mucopolysaccharidosis type VI (MPS VI) cat. Skin biopsies were obtained at birth from severely affected MPS VI kittens and used to initiate fibroblast outgrowths for retroviral transduction with the 4S cDNA. 4S gene expression in transduced cells was under the transcriptional control of the MoMLV long terminal repeat promoter or the cytomegalovirus (CMV) immediate–early promoter. Characterisation of gene-transduced fibroblasts demonstrated the cells to be over-expressing 4S activity. Twenty-four to forty million autologous, gene-corrected fibroblasts were implanted under the renal capsule of three MPS VI kittens at 8–16 weeks of age. Transient, low levels of 4S activity were detected in peripheral blood leukocytes shortly after implantation but were not detectable within 3–8 weeks’ post-implantation. Long-term biochemical and clinical evaluation of these cats demonstrated identical disease progression to that previously described in untreated, clinically severe MPS VI cats.
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effect of enzyme replacement therapy on bone formation in a Feline Model of mucopolysaccharidosis type vi
Bone, 1997Co-Authors: Sharon Byers, Allison C Crawley, John J Hopwood, J. D. Nuttall, K Smith, Nicola L. FazzalariAbstract:Abstract A range of skeletal abnormalities are evident in mucopolysaccharidosis type VI (MPS VI, Maroteaux-Lamy syndrome) including short stature and dysostosis multiplex, resulting from a deficiency in the lysosomal hydrolase N -acetylgalactosamine-4-sulphatase (4S). In this article, bone pathology was assessed in a Feline Model of MPS VI to evaluate the efficacy of enzyme replacement therapy (ERT) as a treatment modality for this genetic disorder. Osteopenia is clearly evident in MPS VI animals, with bone mineral volume ( BV TV ) falling well below that of normal animals (4.39% vs. 20.11%, respectively). Trabecular bone architecture was also affected in MPS VI with fewer, thinner, and more widely spaced trabeculae apparent. Bone formation rate ( BFR BS ) was also lower in MPS VI animals than controls (0.0011 mm 3 /mm 2 per day vs. 0.008 mm 3 /mm 2 per day, respectively). Vertebral and tibial bone length in MPS VI animals progressively fell behind normal values with increasing age, as did cortical bone thickness. Vertebral body shape was also altered. ERT with recombinant human 4S (rh4S) resulted in a vertebral BV TV of 8.23% in animals treated with an intravenous enzyme dose of 1 mg/kg and a BV TV of 14.33% in animals treated with a dose of 5 mg/kg. BFR BS also increased to 0.0034 mm 3 /mm 2 per day in animals treated with enzyme doses of either 1.0 or 5.0 mg/kg rh4S. All other affected histomorphometric parameters also improved with ERT to a level intermediate between MPS VI untreated animals and normals. However, individual animals treated with 0.2 mg/kg rh4S intravenously or 1.0 mg/kg rh4S administered subcutaneously did not exhibit an improvement over untreated MPS VI animals. Vertebral and tibial bone lengths, tibial cortical bone thickness, and vertebral body shape also responded to ERT, with a trend away from the untreated group. Thus, ERT had a positive effect on bone development in MPS VI animals that was dependent upon the dose of enzyme administered and the route of administration.
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enzyme replacement therapy from birth in a Feline Model of mucopolysaccharidosis type vi
Journal of Clinical Investigation, 1997Co-Authors: Allison C Crawley, Elizabeth L Isaac, Sharon Byers, K H Niedzielski, Richard Davey, John J HopwoodAbstract:We report evidence of a dose responsive effect of enzyme replacement therapy in mucopolysaccharidosis type VI cats from birth, at the clinical, biochemical, and histopathological level. Cats treated with weekly, intravenous recombinant human N-acetylgalactosamine-4-sulfatase at 1 and 5 mg/kg, were heavier, more flexible, had greatly reduced or no spinal cord compression, and had almost normal urinary glycosaminoglycan levels. There was near normalization or complete reversal of lysosomal storage in heart valve, aorta, skin, dura, liver, and brain perivascular cells. No reduction in lysosomal vacuolation was observed in cartilage or cornea; however, articular cartilage was thinner and external ear pinnae were larger in some treated cats. Degenerative joint changes were not obviously delayed in treated cats. Skeletal pathology was reduced, with more normalized bone dimensions and with more uniform bone density and trabecular pattern clearly visible on radiographs by 5 to 6 mo; however, differences between 1 and 5 mg/kg dose rates were not clearly distinguishable. At a dose of 0.2 mg/kg, disease was not significantly altered in the majority of parameters examined. Lysosomal storage was present in all tissues examined in the midterm mucopolysaccharidosis type VI fetus and increased rapidly in extent and severity from birth.
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enzyme replacement therapy in a Feline Model of maroteaux lamy syndrome
Journal of Clinical Investigation, 1996Co-Authors: Allison C Crawley, Doug A Brooks, Vivienne Muller, Birgit Petersen, Elizabeth L Isaac, Julie Bielicki, Barbara King, Christine D Boulter, Alison J Moore, Nick L FazzalariAbstract:We report studies that suggest enzyme replacement therapy will result in a significant reduction in disease progression and tissue pathology in patients with Maroteaux-Lamy syndrome (Mucopolysaccharidosis type VI, MPS VI). A Feline Model for MPS VI was used to evaluate tissue distribution and clinical efficacy of three forms of recombinant human N-acetylgalactosamine-4-sulfatase (rh4S, EC 3.1.6.1). Intravenously administered rh4S was rapidly cleared from circulation. The majority of rh4S was distributed to liver, but was also detected in most other tissues. Tissue half-life was approximately 2-4 d. Three MPS VI cats given regular intravenous infusions of rh4S for up to 20 mo showed variable reduction of storage vacuoles in Kupffer cells and connective tissues, however cartilage chondrocytes remained vacuolated. Vertebral bone mineral volume was improved in two MPS VI cats in which therapy was initiated before skeletal maturity, and increased bone volume appeared to correlate with earlier age of onset of therapy. One cat showed greater mobility in response to therapy.
Jan Bauer - One of the best experts on this subject based on the ideXlab platform.
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selective limbic blood brain barrier breakdown in a Feline Model of limbic encephalitis with lgi1 antibodies
Frontiers in Immunology, 2017Co-Authors: Anna R Troscher, Andrea Klang, Maria French, Lucia Quemadagarrido, S Kneissl, Christian G Bien, Akos Pakozdy, Jan BauerAbstract:Human leucine-rich glioma-inactivated protein 1 encephalitis (LGI1) is an autoimmune limbic encephalitis in which serum and cerebrospinal fluid contain antibodies targeting LGI1, a protein of the voltage gated potassium channel (VGKC) complex. Recently, we showed that a Feline Model of limbic encephalitis with LGI1 antibodies, called Feline complex partial seizures with orofacial involvement (FEPSO), is highly comparable to human LGI1 encephalitis. In human LGI1 encephalitis, neuropathological investigations are difficult because very little material is available. Taking advantage of this natural animal Model to study pathological mechanisms will therefore contribute to a better understanding of its human counterpart. Here, we present a brain-wide histopathological analysis of FEPSO. We discovered that blood-brain-barrier leakage was present not only in all regions of the hippocampus but also in other limbic structures such as the subiculum, amygdala and piriform lobe. However, in other regions, such as the cerebellum, no leakage was observed. In addition, this brain-region specific immunoglobulin leakage was associated with the breakdown of endothelial tight junctions. Brain areas affected by blood-brain-barrier dysfunction also revealed immunoglobulin and complement deposition as well as neuronal cell death. These neuropathological findings were supported by magnetic resonance imaging (MRI) showing signal and volume increase in the amygdala and the piriform lobe. Importantly, we could show that blood-brain-barrier disturbance in LGI1 encephalitis does not depend on T cell infiltrates, which were present brain-wide. This finding points towards another, so far unknown, mechanism of opening the blood-brain barrier. The limbic predilection sites of immunoglobulin antibody leakage into the brain may explain why most patients with LGI1 antibodies have a limbic phenotype even though LGI1, the target protein, is ubiquitously distributed across the central nervous system.
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Selective Limbic Blood–Brain Barrier Breakdown in a Feline Model of Limbic Encephalitis with LGI1 Antibodies
Frontiers in Immunology, 2017Co-Authors: Anna R Troscher, Andrea Klang, Maria French, S Kneissl, Christian G Bien, Akos Pakozdy, Lucía Quemada-garrido, Jan BauerAbstract:Human leucine-rich glioma-inactivated protein 1 encephalitis (LGI1) is an autoimmune limbic encephalitis in which serum and cerebrospinal fluid contain antibodies targeting LGI1, a protein of the voltage gated potassium channel (VGKC) complex. Recently, we showed that a Feline Model of limbic encephalitis with LGI1 antibodies, called Feline complex partial seizures with orofacial involvement (FEPSO), is highly comparable to human LGI1 encephalitis. In human LGI1 encephalitis, neuropathological investigations are difficult because very little material is available. Taking advantage of this natural animal Model to study pathological mechanisms will therefore contribute to a better understanding of its human counterpart. Here, we present a brain-wide histopathological analysis of FEPSO. We discovered that blood-brain-barrier leakage was present not only in all regions of the hippocampus but also in other limbic structures such as the subiculum, amygdala and piriform lobe. However, in other regions, such as the cerebellum, no leakage was observed. In addition, this brain-region specific immunoglobulin leakage was associated with the breakdown of endothelial tight junctions. Brain areas affected by blood-brain-barrier dysfunction also revealed immunoglobulin and complement deposition as well as neuronal cell death. These neuropathological findings were supported by magnetic resonance imaging (MRI) showing signal and volume increase in the amygdala and the piriform lobe. Importantly, we could show that blood-brain-barrier disturbance in LGI1 encephalitis does not depend on T cell infiltrates, which were present brain-wide. This finding points towards another, so far unknown, mechanism of opening the blood-brain barrier. The limbic predilection sites of immunoglobulin antibody leakage into the brain may explain why most patients with LGI1 antibodies have a limbic phenotype even though LGI1, the target protein, is ubiquitously distributed across the central nervous system.
Victoria J. Mccurdy - One of the best experts on this subject based on the ideXlab platform.
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widespread correction of central nervous system disease after intracranial gene therapy in a Feline Model of sandhoff disease
Gene Therapy, 2015Co-Authors: Victoria J. Mccurdy, Aime K. Johnson, Ashley N. Randle, Brandon L. Brunson, Misako Hwang, Hannah E Rockwell, Julian R Arthur, Allison M Bradbury, Heather L GrayedwardsAbstract:Widespread correction of central nervous system disease after intracranial gene therapy in a Feline Model of Sandhoff disease
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Sustained normalization of neurological disease after intracranial gene therapy in a Feline Model
Science Translational Medicine, 2014Co-Authors: Victoria J. Mccurdy, Aime K. Johnson, Heather L. Gray-edwards, Ashley N. Randle, Brandon L. Brunson, Nouha Salibi, Jacob A. Johnson, Misako Hwang, Nancy E Morrison, Ronald J. BeyersAbstract:Progressive debilitating neurological defects characterize Feline G M1 gangliosidosis, a lysosomal storage disease caused by deficiency of lysosomal b-galactosidase. No effective therapy exists for affected children, who often die before age 5 years. An adeno-associated viral vector carrying the therapeutic gene was injected bilaterally into two brain targets (thalamus and deep cerebellar nuclei) of a Feline Model of G M1 gangliosidosis. Gene therapy nor-malized b-galactosidase activity and storage throughout the brain and spinal cord. The mean survival of 12 treated G M1 animals was >38 months, compared to 8 months for untreated animals. Seven of the eight treated animals remaining alive demonstrated normalization of disease, with abrogation of many symptoms including gait deficits and postural imbalance. Sustained correction of the G M1 gangliosidosis disease phenotype after limited intracranial targeting by gene therapy in a large animal Model suggests that this approach may be useful for treating the human version of this lysosomal storage disorder.
