Brandon L. Brunson
Auburn University
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Featured researches published by Brandon L. Brunson.
Molecular Therapy | 2013
Allison M. Bradbury; J Nicholas Cochran; Victoria J. McCurdy; A. Johnson; Brandon L. Brunson; Heather L. Gray-Edwards; Stanley G. LeRoy; Misako Hwang; Ashley N. Randle; Laura S Jackson; Nancy E. Morrison; Rena C. Baek; Thomas N. Seyfried; Seng H. Cheng; Nancy R. Cox; Henry J. Baker; M. Begoña Cachón-González; Timothy M. Cox; Miguel Sena-Esteves; Douglas R. Martin
Salutary responses to adeno-associated viral (AAV) gene therapy have been reported in the mouse model of Sandhoff disease (SD), a neurodegenerative lysosomal storage disease caused by deficiency of β-N-acetylhexosaminidase (Hex). While untreated mice reach the humane endpoint by 4.1 months of age, mice treated by a single intracranial injection of vectors expressing human hexosaminidase may live a normal life span of 2 years. When treated with the same therapeutic vectors used in mice, two cats with SD lived to 7.0 and 8.2 months of age, compared with an untreated life span of 4.5 ± 0.5 months (n = 11). Because a pronounced humoral immune response to both the AAV1 vectors and human hexosaminidase was documented, feline cDNAs for the hexosaminidase α- and β-subunits were cloned into AAVrh8 vectors. Cats treated with vectors expressing feline hexosaminidase produced enzymatic activity >75-fold normal at the brain injection site with little evidence of an immune infiltrate. Affected cats treated with feline-specific vectors by bilateral injection of the thalamus lived to 10.4 ± 3.7 months of age (n = 3), or 2.3 times as long as untreated cats. These studies support the therapeutic potential of AAV vectors for SD and underscore the importance of species-specific cDNAs for translational research.
Metabolism-clinical and Experimental | 2008
Eric P. Plaisance; Peter W. Grandjean; Brandon L. Brunson; Robert L. Judd
Niacin has recently been shown to increase serum total concentrations of the adipocyte-derived protein adiponectin. Adiponectin possesses important vascular anti-inflammatory and metabolic properties that have been attributed to the active high-molecular weight (HMW) complex of the protein. Our purpose was to examine the influence of extended-release niacin on the distribution of HMW and low-molecular weight (LMW) adiponectin complexes. Fifteen men with the metabolic syndrome were treated for 6 weeks with extended-release niacin. Serum total adiponectin concentrations increased by 46% after the niacin intervention (P < .05). High-molecular weight adiponectin accounted for 63% of the increase in total adiponectin, which was reflected by a shift in the HMW/LMW adiponectin ratio from 0.69 to 0.86 (+25%) (P < .05). Serum insulin concentrations increased by 20% after the niacin intervention despite an increase in HMW adiponectin concentrations (P < .05). These results suggest that the increase in total adiponectin concentrations observed with extended-release niacin is primarily due to an increase in the active HMW complex. Therefore, at least part of the cardioprotective benefits of niacin may be attributed to a shift in the HMW/LMW adiponectin ratio in obese men with the metabolic syndrome.
Science Translational Medicine | 2014
Victoria J. McCurdy; A. Johnson; Heather L. Gray-Edwards; Ashley N. Randle; Brandon L. Brunson; Nancy E. Morrison; Nouha Salibi; Jacob A. Johnson; Misako Hwang; Ronald J. Beyers; Stanley G. LeRoy; Stacy Maitland; Thomas S. Denney; Nancy R. Cox; Henry J. Baker; Miguel Sena-Esteves; Douglas R. Martin
In a feline model of lysosomal storage disease, intracranial gene therapy achieved therapeutic efficacy in the CNS and increased long-term survival. Gene Therapy for a Lysosomal Storage Disease GM1 gangliosidosis results from defects in the lysosomal enzyme β-galactosidase (β-gal) and subsequent accumulation of GM1 ganglioside, which causes neurodegeneration and premature death. Although no effective treatment exists, encouraging gene therapy data from the GM1 mouse model warranted an evaluation of the feasibility for human clinical application in a large animal model. In a new study, McCurdy et al. injected an adeno-associated viral vector encoding feline β-gal bilaterally into two brain targets (thalamus and deep cerebellar nuclei) of cats with GM1 gangliosidosis. Sixteen weeks after injection, β-gal activity and GM1 storage were normalized throughout the central nervous system of the animals, with accompanying increases in enzyme activity in cerebrospinal fluid and liver. In long-term studies, the mean survival of 12 treated cats with GM1 gangliosidosis was >38 months, compared to 8 months for untreated cats. A minority of cats that progressed to the humane endpoint had low β-gal activity in the spinal cord, yet still lived >2.5 times longer than untreated animals. Most of the treated GM1 cats demonstrated subtle or no gait abnormalities, and magnetic resonance imaging showed normalization of brain architecture up to at least 32 months of age. Long-term correction of the disease phenotype in cats with GM1 gangliosidosis suggests that gene therapy may be useful for treating the human disorder. Progressive debilitating neurological defects characterize feline GM1 gangliosidosis, a lysosomal storage disease caused by deficiency of lysosomal β-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 GM1 gangliosidosis. Gene therapy normalized β-galactosidase activity and storage throughout the brain and spinal cord. The mean survival of 12 treated GM1 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 GM1 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.
Gene Therapy | 2015
Victoria J. McCurdy; Hannah E. Rockwell; Julian R. Arthur; Allison M. Bradbury; A. Johnson; Ashley N. Randle; Brandon L. Brunson; Misako Hwang; Heather L. Gray-Edwards; Nancy E. Morrison; Jacob A. Johnson; Henry J. Baker; Nancy R. Cox; Thomas N. Seyfried; Miguel Sena-Esteves; Douglas R. Martin
Sandhoff disease (SD) is caused by deficiency of N-acetyl-β-hexosaminidase (Hex) resulting in pathological accumulation of GM2 ganglioside in lysosomes of the central nervous system (CNS) and progressive neurodegeneration. Currently, there is no treatment for SD, which often results in death by the age of five years. Adeno-associated virus (AAV) gene therapy achieved global CNS Hex restoration and widespread normalization of storage in the SD mouse model. Using a similar treatment approach, we sought to translate the outcome in mice to the feline SD model as an important step toward human clinical trials. Sixteen weeks after four intracranial injections of AAVrh8 vectors, Hex activity was restored to above normal levels throughout the entire CNS and in cerebrospinal fluid, despite a humoral immune response to the vector. In accordance with significant normalization of a secondary lysosomal biomarker, ganglioside storage was substantially improved, but not completely cleared. At the study endpoint, 5-month-old AAV-treated SD cats had preserved neurological function and gait compared with untreated animals (humane endpoint, 4.4±0.6 months) demonstrating clinical benefit from AAV treatment. Translation of widespread biochemical disease correction from the mouse to the feline SD model provides optimism for treatment of the larger human CNS with minimal modification of approach.
Experimental Neurology | 2015
Allison M. Bradbury; Heather L. Gray-Edwards; Jamie L. Shirley; Victoria J. McCurdy; Alexandria Colaco; Ashley N. Randle; Pete W. Christopherson; Allison E Church Bird; A. Johnson; Diane U. Wilson; Judith A. Hudson; Nicholas L. De Pompa; Donald C. Sorjonen; Brandon L. Brunson; Mylvaganam Jeyakumar; Frances M. Platt; Henry J. Baker; Nancy R. Cox; Miguel Sena-Esteves; Douglas R. Martin
The GM2 gangliosidoses, Tay-Sachs disease (TSD) and Sandhoff disease (SD), are progressive neurodegenerative disorders that are caused by a mutation in the enzyme β-N-acetylhexosaminidase (Hex). Due to the recent emergence of novel experimental treatments, biomarker development has become particularly relevant in GM2 gangliosidosis as an objective means to measure therapeutic efficacy. Here we describe blood, cerebrospinal fluid (CSF), magnetic resonance imaging (MRI), and electrodiagnostic methods for evaluating disease progression in the feline SD model and application of these approaches to assess AAV-mediated gene therapy. SD cats were treated by intracranial injections of the thalami combined with either the deep cerebellar nuclei or a single lateral ventricle using AAVrh8 vectors encoding feline Hex. Significantly altered in untreated SD cats, blood and CSF based biomarkers were largely normalized after AAV gene therapy. Also reduced after treatment were expansion of the lysosomal compartment in peripheral blood mononuclear cells and elevated activity of secondary lysosomal enzymes. MRI changes characteristic of the gangliosidoses were documented in SD cats and normalized after AAV gene therapy. The minimally invasive biomarkers reported herein should be useful to assess disease progression of untreated SD patients and those in future clinical trials.
Molecular Genetics and Metabolism | 2015
Heather L. Gray-Edwards; Brandon L. Brunson; Merrilee Holland; Adrien-Maxence Hespel; Allison M. Bradbury; Victoria J. McCurdy; Patricia M. Beadlescomb; Ashley N. Randle; Nouha Salibi; Thomas S. Denney; Ronald J. Beyers; A. Johnson; Meredith L. Voyles; Ronald D. Montgomery; Diane U. Wilson; Judith A. Hudson; Nancy R. Cox; Henry J. Baker; Miguel Sena-Esteves; Douglas R. Martin
Sandhoff disease (SD) is a fatal neurodegenerative disease caused by a mutation in the enzyme β-N-acetylhexosaminidase. Children with infantile onset SD develop seizures, loss of motor tone and swallowing problems, eventually reaching a vegetative state with death typically by 4years of age. Other symptoms include vertebral gibbus and cardiac abnormalities strikingly similar to those of the mucopolysaccharidoses. Isolated fibroblasts from SD patients have impaired catabolism of glycosaminoglycans (GAGs). To evaluate mucopolysaccharidosis-like features of the feline SD model, we utilized radiography, MRI, echocardiography, histopathology and GAG quantification of both central nervous system and peripheral tissues/fluids. The feline SD model exhibits cardiac valvular and structural abnormalities, skeletal changes and spinal cord compression that are consistent with accumulation of GAGs, but are much less prominent than the severe neurologic disease that defines the humane endpoint (4.5±0.5months). Sixteen weeks after intracranial AAV gene therapy, GAG storage was cleared in the SD cat cerebral cortex and liver, but not in the heart, lung, skeletal muscle, kidney, spleen, pancreas, small intestine, skin, or urine. GAG storage worsens with time and therefore may become a significant source of pathology in humans whose lives are substantially lengthened by gene therapy or other novel treatments for the primary, neurologic disease.
Neuroscience | 2017
Allison M. Bradbury; Tiffany Peterson; Amanda L. Gross; Stephen Z. Wells; Victoria J. McCurdy; Karen G. Wolfe; John C. Dennis; Brandon L. Brunson; Heather L. Gray-Edwards; Ashley N. Randle; A. Johnson; Edward E. Morrison; Nancy R. Cox; Henry J. Baker; Miguel Sena-Esteves; Douglas R. Martin
Sandhoff disease (SD) is a lysosomal storage disorder characterized by the absence of hydrolytic enzyme β-N-acetylhexosaminidase (Hex), which results in storage of GM2 ganglioside in neurons and unremitting neurodegeneration. Neuron loss initially affects fine motor skills, but rapidly progresses to loss of all body faculties, a vegetative state, and death by five years of age in humans. A well-established feline model of SD allows characterization of the disease in a large animal model and provides a means to test the safety and efficacy of therapeutic interventions before initiating clinical trials. In this study, we demonstrate a robust central nervous system (CNS) inflammatory response in feline SD, primarily marked by expansion and activation of the microglial cell population. Quantification of major histocompatibility complex II (MHC-II) labeling revealed significant up-regulation throughout the CNS with areas rich in white matter most severely affected. Expression of the leukocyte chemokine macrophage inflammatory protein-1 alpha (MIP-1α) was also up-regulated in the brain. SD cats were treated with intracranial delivery of adeno-associated viral (AAV) vectors expressing feline Hex, with a study endpoint 16weeks post treatment. AAV-mediated gene delivery repressed the expansion and activation of microglia and normalized MHC-II and MIP-1α levels. These data reiterate the profound inflammatory response in SD and show that neuroinflammation is abrogated after AAV-mediated restoration of enzymatic activity.
Molecular Therapy | 2016
Amanda L. Gross; Heather L. Gray-Edwards; Bryan Murdock; Amanda R. Taylor; Brandon L. Brunson; Ashley N. Randle; Lorelei Stocia; Sophia Todessa; Jaclyn Lata; Miguel Sena-Esteves; Douglas R. Martin
GM1 gangliosidosis, a hereditary lysosomal storage disease caused by a deficiency of lysosomal β-galactosidase, is characterized by rapidly progressing and fatal neurologic disease. The most common form of GM1 affects children and is fatal by approximately 4 years of age. Currently, there is no effective treatment for GM1 gangliosidosis beyond palliative or supportive care. There are several naturally occurring models of GM1 gangliosidosis, including a well-characterized feline model that closely reproduces human disease progression and facilitates testing of experimental therapies for clinical application. Adeno-associated viral (AAV) therapy has proven effective in GM1 cats, with a greater than 6 fold increase in lifespan after thalamic and deep cerebellar nuclei injections. Prior to initiation of human clinical trials, CSF delivery was evaluated to circumvent the risk of cerebellar parenchymal injection and to improve cortical biodistribution. AAVrh10 was delivered at a total dose of 1e12 vector genomes/kg body weight via 3 routes: cisterna magna (CM), bilateral intracerebroventricular (ICV), or lumbar cistern (LC). Cats were followed for 4 weeks post injection, after which biodistribution of enzyme and vector were assessed. After LC injection, enzyme was limited to the spinal cord, where it reached a maximum of 0.7 fold normal. As expected, the highest vector concentration was limited to the lumbar spinal cord. This indicates limited cranial flow of vector from the lumbar cistern of injected cats, minimizing the efficacy of lumbar delivery. Delivery by the CM led to 0.4 fold - 1.5 fold normal levels of enzyme activity in the spinal cord and up to 2.1 fold the cerebellum and thalamic regions. Following CM injection, vector distributed well to the caudal region of the cerebrum, all of the cerebellum, and throughout the spinal cord. Enzyme activity after ICV injections showed increases from 0.2 fold - 0.8 fold normal in the spinal cord and 0.1 fold - 0.5 fold in the brain. ICV injections led to vector distribution throughout the cerebrum as well as the spinal cord. CSF delivery via cisterna magna, ICV, or lumbar injection is substantially less invasive than cerebellar injection. Based on the results presented here, CM or ICV injection may prove beneficial in clinical trials. Additionally, combining cisterna magna and ICV injection of vector could further enhance therapeutic effect.View Large Image | Download PowerPoint Slide
Biochemical and Biophysical Research Communications | 2006
Deepa Bedi; Kristen J. Clarke; John C. Dennis; Qiao Zhong; Brandon L. Brunson; Edward E. Morrison; Robert L. Judd
American Journal of Veterinary Research | 2007
Brandon L. Brunson; Qiao Zhong; Kristen J. Clarke; Deepa Bedi; Tim D. Braden; Edzard van Santen; Robert L. Judd