Intravenous delivery of adeno-associated viral gene therapy in feline GM1 gangliosidosis

Brain ◽  
2021 ◽  
Author(s):  
Amanda L Gross ◽  
Heather L Gray-Edwards ◽  
Cassie N Bebout ◽  
Nathan L Ta ◽  
Kayly Nielsen ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Central Nervous System ◽  
Cerebrospinal Fluid ◽  
Nervous System ◽  
Galactosidase Activity ◽  
Gm1 Gangliosidosis ◽  
The Central Nervous System ◽  
Imaging And Spectroscopy ◽  
The Brain

Abstract GM1 gangliosidosis is a fatal neurodegenerative disease caused by a deficiency of lysosomal β-galactosidase. In its most severe form, GM1 gangliosidosis causes death by 4 years of age, and no effective treatments exist. Previous work has shown that injection of the brain parenchyma with an adeno-associated viral vector provides pronounced therapeutic benefit in a feline GM1 model. To develop a less invasive treatment for the brain and increase systemic biodistribution, intravenous injection of AAV9 was evaluated. AAV9 expressing feline β-galactosidase was intravenously administered at 1.5x1013 vector genomes/kilogram body weight to six GM1 cats at approximately 1 month of age. The animals were divided into two cohorts: 1) a long-term group, which was followed to humane endpoint, and 2) a short-term group, which was analyzed 16-weeks post treatment. Clinical assessments included neurological exams, cerebrospinal fluid and urine biomarkers, and 7-Telsa magnetic resonance imaging and spectroscopy. Postmortem analysis included β-galactosidase and virus distribution, histological analysis, and ganglioside content. Untreated GM1 animals survived 8.0 ± 0.6 months while intravenous treatment increased survival to an average of 3.5 years (n = 2) with substantial improvements in quality of life and neurologic function. Neurological abnormalities, which in untreated animals progress to the inability to stand and debilitating neurological disease by 8 months of age, were mild in all treated animals. Cerebrospinal fluid biomarkers were normalized, indicating decreased central nervous system cell damage in the treated animals. Urinary glycosaminoglycans decreased to normal levels in the long-term cohort. Magnetic resonance imaging and spectroscopy showed partial preservation of the brain in treated animals, which was supported by postmortem histological evaluation. β-galactosidase activity was increased throughout the central nervous system, reaching carrier levels in much of the cerebrum and normal levels in the cerebellum, spinal cord and cerebrospinal fluid. Ganglioside accumulation was significantly reduced by treatment. Peripheral tissues such as heart, skeletal muscle, and sciatic nerve also had normal β-galactosidase activity in treated GM1 cats. GM1 histopathology was largely corrected with treatment. There was no evidence of tumorigenesis or toxicity. Restoration of β-galactosidase activity in the central nervous system and peripheral organs by intravenous gene therapy led to profound increases in lifespan and quality of life in GM1 cats. This data supports the promise of intravenous gene therapy as a safe, effective treatment for GM1 gangliosidosis.

Developmental Overview of Central Neuroanatomy

2017 ◽  
Author(s):  
Peggy Mason
Keyword(s):  
Spinal Cord ◽  
Central Nervous System ◽  
Cerebrospinal Fluid ◽  
Nervous System ◽  
Cerebral Cortex ◽  
Neural Tube ◽  
The Central Nervous System ◽  
Dorsal Telencephalon ◽  
Adult Spinal Cord ◽  
The Brain

The central nervous system develops from a proliferating tube of cells and retains a tubular organization in the adult spinal cord and brain, including the forebrain. Failure of the neural tube to close at the front is lethal, whereas failure to close the tube at the back end produces spina bifida, a serious neural tube defect. Swellings in the neural tube develop into the hindbrain, midbrain, diencephalon, and telencephalon. The diencephalon sends an outpouching out of the cranium to form the retina, providing an accessible window onto the brain. The dorsal telencephalon forms the cerebral cortex, which in humans is enormously expanded by growth in every direction. Running through the embryonic neural tube is an internal lumen that becomes the cerebrospinal fluid–containing ventricular system. The effects of damage to the spinal cord and forebrain are compared with respect to impact on self and potential for improvement.

The area postrema plays no role in the pressor action of angiotensin in the rat

1980 ◽  
Vol 239 (1) ◽  
pp. H108-H113 ◽  
Author(s):  
J. R. Haywood ◽  
G. D. Fink ◽  
J. Buggy ◽  
M. I. Phillips ◽  
M. J. Brody
Keyword(s):  
Central Nervous System ◽  
Cerebrospinal Fluid ◽  
Nervous System ◽  
Carotid Arteries ◽  
Area Postrema ◽  
Renal Hypertension ◽  
Conscious Rat ◽  
The Central Nervous System ◽  
Pressor Activity ◽  
The Brain

The area postrema has been shown to have a major role in mediating the pressor effects of peripheral angiotensin in the dog, cat, and rabbit. The purpose of this study was to ascertain the function of the medullary circumventricular structure in the conscious rat. The pressor potency of angiotensin administered into the vertebral and carotid arteries was compared with intra-aortic infusions of angiotensin. Although no difference in pressor activity of angiotensin could be detected between intraaortic and intravertebral administration, greater sensitivity was observed during intracarotid infusion. No difference in the course of one-kidney renal hypertension was observed between sham-lesioned rats and animals with an area postrema lesion. In addition, lesioned and sham-lesioned animals showed equivalent responses to graded doses of angiotensin administered either intravenously or into the lateral ventricle. It was concluded that in the rat the area postrema plays no role in mediating the central nervous system actions of angiotensin whether the peptide reaches the brain via the blood or the cerebrospinal fluid.

scholarly journals Infectious Progression of Canine Distemper Virus from Circulating Cerebrospinal Fluid into the Central Nervous System

2016 ◽  
Vol 90 (20) ◽  
pp. 9285-9292 ◽  
Author(s):  
Akiko Takenaka ◽  
Hiroki Sato ◽  
Fusako Ikeda ◽  
Misako Yoneda ◽  
Chieko Kai
Keyword(s):  
Central Nervous System ◽  
Cerebrospinal Fluid ◽  
Nervous System ◽  
Hippocampal Formation ◽  
Target Cells ◽  
Canine Distemper ◽  
P Gene ◽  
The Central Nervous System ◽  
The Brain ◽  
Parental Mouse

ABSTRACTIn the current study, we generated recombinant chimeric canine distemper viruses (CDVs) by replacing the hemagglutinin (H) and/or phosphoprotein (P) gene in an avirulent strain expressing enhanced green fluorescent protein (EGFP) with those of a mouse-adapted neurovirulent strain. Anin vitroexperimental infection indicated that the chimeric CDVs possessing the H gene derived from the mouse-adapted CDV acquired infectivity for neural cells. These cells lack the CDV receptors that have been identified to date (SLAM and nectin-4), indicating that the H protein defines infectivity in various cell lines. The recombinant viruses were administered intracerebrally to 1-week-old mice. Fatal neurological signs of disease were observed only with a recombinant CDV that possessed both the H and P genes of the mouse-adapted strain, similar to the parental mouse-adapted strain, suggesting that both genes are important to drive virulence of CDV in mice. Using this recombinant CDV, we traced the intracerebral propagation of CDV by detecting EGFP. Widespread infection was observed in the cerebral hemispheres and brainstems of the infected mice. In addition, EGFP fluorescence in the brain slices demonstrated a sequential infectious progression in the central nervous system: CDV primarily infected the neuroependymal cells lining the ventricular wall and the neurons of the hippocampus and cortex adjacent to the ventricle, and it then progressed to an extensive infection of the brain surface, followed by the parenchyma and cortex. In the hippocampal formation, CDV spread in a unidirectional retrograde pattern along neuronal processes in the hippocampal formation from the CA1 region to the CA3 region and the dentate gyrus. Our mouse model demonstrated that the main target cells of CDV are neurons in the acute phase and that the virus spreads via neuronal transmission pathways in the hippocampal formation.IMPORTANCECDV is the etiological agent of distemper in dogs and other carnivores, and in many respects, the pathogenesis of CDV infection in animals resembles that of measles virus infection in humans. We successfully generated a recombinant CDV containing the H and P genes from a mouse-adapted neurovirulent strain and expressing EGFP. The recombinant CDV exhibited severe neurovirulence with high mortality, comparable to the parental mouse-adapted strain. The mouse-infectious model could become a useful tool for analyzing CDV infection of the central nervous system subsequent to passing through the blood-cerebrospinal fluid barrier and infectious progression in the target cells in acute disease.

scholarly journals Aino Virus Antigen in Brain Lesions of a Naturally Aborted Bovine Fetus

1998 ◽  
Vol 35 (5) ◽  
pp. 409-411 ◽  
Author(s):  
Y. Noda ◽  
Y. Uchinuno ◽  
H. Shirakawa ◽  
S. Nagasue ◽  
N. Nagano ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Cerebrospinal Fluid ◽  
Nervous System ◽  
Brain Lesion ◽  
Neutralizing Antibody ◽  
Virus Antigen ◽  
Brain Lesions ◽  
Significant Feature ◽  
The Central Nervous System ◽  
The Brain

A bovine fetus aborted at 187 days of gestation was serologically and immunohistopathologically examined. Serum and cerebrospinal fluid samples had high titers of virus-neutralizing antibody for Aino virus. A severe necrotizing encephalopathy was noted. Aino virus antigen was demonstrated in neuroglial cells within the brain lesion. The destruction of developing neuronal cells appeared to be a significant feature of the pathogenesis of lesions due to Aino virus infection in the central nervous system.

scholarly journals Modern aspects of neuropathogenesis and neurological manifestations of COVID-19

2021 ◽  
Vol 17 (2) ◽  
pp. 6-15
Author(s):  
L.A. Dziak ◽  
O.S. Tsurkalenko ◽  
K.V. Chekha ◽  
V.M. Suk
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Psychiatric Symptoms ◽  
Clinical Manifestations ◽  
The Body ◽  
Altered Level ◽  
Wide Range ◽  
The Central Nervous System ◽  
The Brain

Coronavirus infection is a systemic pathology resulting in impairment of the nervous system. The involvement of the central nervous system in COVID-19 is diverse by clinical manifestations and main mechanisms. The mechanisms of interrelations between SARS-CoV-2 and the nervous system include a direct virus-induced lesion of the central nervous system, inflammatory-mediated impairment, thrombus burden, and impairment caused by hypoxia and homeostasis. Due to the multi-factor mechanisms (viral, immune, hypoxic, hypercoagulation), the SARS-CoV-2 infection can cause a wide range of neurological disorders involving both the central and peripheral nervous system and end organs. Dizziness, headache, altered level of consciousness, acute cerebrovascular diseases, hypogeusia, hyposmia, peripheral neuropathies, sleep disorders, delirium, neuralgia, myalgia are the most common signs. The structural and functional changes in various organs and systems and many neurological symptoms are determined to persist after COVID-19. Regardless of the numerous clinical reports about the neurological and psychiatric symptoms of COVID-19 as before it is difficult to determine if they are associated with the direct or indirect impact of viral infection or they are secondary to hypoxia, sepsis, cytokine reaction, and multiple organ failure. Penetrated the brain, COVID-19 can impact the other organs and systems and the body in general. Given the mechanisms of impairment, the survivors after COVID-19 with the infection penetrated the brain are more susceptible to more serious diseases such as Parkinson’s disease, cognitive decline, multiple sclerosis, and other autoimmune diseases. Given the multi-factor pathogenesis of COVID-19 resulting in long-term persistence of the clinical symptoms due to impaired neuroplasticity and neurogenesis followed by cholinergic deficiency, the usage of Neuroxon® 1000 mg a day with twice-day dosing for 30 days. Also, a long-term follow-up and control over the COVID-19 patients are recommended for the prophylaxis, timely determination, and correction of long-term complications.

A Nonlinear Biphasic Hyperelastic Model for Acute Hydrocephalus

2008 ◽  
Author(s):  
Joshua H. Smith ◽  
Jose Jaime García
Keyword(s):  
Central Nervous System ◽  
Cerebrospinal Fluid ◽  
Nervous System ◽  
Ventricular Pressure ◽  
Csf Flow ◽  
Acute Hydrocephalus ◽  
The Central Nervous System ◽  
Hyperelastic Model ◽  
The Brain ◽  
Significant Increment

The cerebrospinal fluid present in the central nervous system plays an important role in the physiological activities and protection of the brain. Disruptions of CSF flow lead to different forms of a disease known as hydrocephalus, characterized by a significant increment of the ventricular space. In acute hydrocephalus the Sylvius aqueduct is blocked and ventricular pressure is greatly increased.

Acute Disseminated Encephalomyelitis

2017 ◽  
Author(s):  
Benjamin M. Greenberg ◽  
Allen Desena
Keyword(s):  
Spinal Cord ◽  
Central Nervous System ◽  
Nervous System ◽  
Supportive Care ◽  
Acute Disseminated Encephalomyelitis ◽  
Autoimmune Response ◽  
Inflammatory Disorder ◽  
The Central Nervous System ◽  
The Brain

Acute disseminated encephalomyelitis (ADEM) is a rare inflammatory disorder of the central nervous system (CNS) that can be fatal or lead to long-term disability. Various triggers have been identified in children and adults, which presumably cause an autoimmune response targeting myelin. The resulting inflammation causes demyelination and edema of the brain, spinal cord, and optic nerves. Depending on which portion of the CNS is affected, patients will experience a variety of symptoms including weakness, numbness, ataxia, encephalopathy, and seizures. Treatment is currently focused on reducing the amount of inflammation and supportive care.

The role of metabolites and the role of histo-hematological barriers in the regulation of body functions. (End)

1937 ◽  
Vol 33 (5) ◽  
pp. 523-532
Author(s):  
L. S. Stern
Keyword(s):  
Central Nervous System ◽  
Cerebrospinal Fluid ◽  
Nervous System ◽  
General Circulation ◽  
Physiological State ◽  
The State ◽  
The Central Nervous System ◽  
The Brain ◽  
Physiological Systems

Evaluation of the results obtained in the study of the effect of cerebrospinal fluid on various physiological systems is complicated by the fact that the composition of the cerebrospinal fluid depends to a large extent on the state of the blood-brain barrier, and thus reflects not only a certain physiological state of the central nervous system. There is no doubt that the metabolic products of the brain, secreted into the cerebrospinal fluid, exert their effect not only on the activity of various parts of the brain and on the coordination of their functions, but due to the rapid transition of these substances from the cerebrospinal fluid into the general circulation, they also affect as a humoral a factor on the function of other physiological systems, as it was revealed in a number of experiments carried out in recent years in our laboratories. For example, it turned out that under various influences (direct irritation of the central nervous system in experimental epilepsy, irritation of the sensory nerves associated with severe pain, traumatic shock, toxemic or chemical shock, as well as starvation, prolonged insomnia, etc.) - substances appear in the cerebrospinal fluid that affect the state and activity of the cardiovascular system, the tone of smooth muscles, the excitability of the central nervous system, etc. These are the results of the work of our employees: Zeitlin, Weiss, Harles, Voskresensky, Gromakovskaya , Bazarova, Gotsman, Komarova and others. Work in this direction continues at the present time.

scholarly journals Streptococcus pneumoniae Causes Experimental Meningitis following Intranasal and Otitis Media Infections via a Nonhematogenous Route

2001 ◽  
Vol 69 (12) ◽  
pp. 7318-7325 ◽  
Author(s):  
Andrea Marra ◽  
Daniel Brigham
Keyword(s):  
Central Nervous System ◽  
Cerebrospinal Fluid ◽  
Nervous System ◽  
Streptococcus Pneumoniae ◽  
Otitis Media ◽  
Intranasal Inoculation ◽  
The Central Nervous System ◽  
Human Infections ◽  
The Brain ◽  
Do So

ABSTRACT Using two different animal models of Streptococcus pneumoniae infection, we have demonstrated that this organism is able to spread to the central nervous system and cause meningitis by bypassing the bloodstream. Following respiratory tract infection induced via intranasal inoculation, bacteria were rapidly found in the bloodstream and brains in the majority of infected mice. A similar pattern of dissemination occurred following otitis media infection via transbullar injection of gerbils. However, a small percentage of animals infected by either route showed no bacteria in the blood and yet did have significant numbers of bacteria in brain tissue. Subsequent experiments using a galU mutant of S. pneumoniae, which is impaired in its ability to disseminate to the bloodstream following infection, showed that this organism is able to spread to the brain and cerebrospinal fluid. These results demonstrate that, unlike many bacterial pathogens that cause meningitis, S. pneumoniae is able to do so independent of bloodstream involvement upon different routes of infection. This may address the difficulty in treating human infections caused by this organism.

Sign in / Sign up

Export Citation Format

Share Document