scholarly journals Safety profile of the transcription factor EB (TFEB)-based gene therapy through intracranial injection in mice

2020 ◽  
Vol 11 (1) ◽  
pp. 241-250
Author(s):  
Zhenyu Li ◽  
Guangqian Ding ◽  
Yudi Wang ◽  
Zelong Zheng ◽  
Jianping Lv
Keyword(s):  
Gene Therapy ◽  
Transcription Factor ◽  
Neurodegenerative Diseases ◽  
Brain Tissue ◽  
Inflammatory Responses ◽  
Tissue Samples ◽  
Protein Levels ◽  
Virus Serotype ◽  
Transcription Factor Eb ◽  
The Brain

AbstractTranscription factor EB (TFEB)-based gene therapy is a promising therapeutic strategy in treating neurodegenerative diseases by promoting autophagy/lysosome-mediated degradation and clearance of misfolded proteins that contribute to the pathogenesis of these diseases. However, recent findings have shown that TFEB has proinflammatory properties, raising the safety concerns about its clinical application. To investigate whether TFEB induces significant inflammatory responses in the brain, male C57BL/6 mice were injected with phosphate-buffered saline (PBS), adeno-associated virus serotype 8 (AAV8) vectors overexpressing mouse TFEB (pAAV8-CMV-mTFEB), or AAV8 vectors expressing green fluorescent proteins (GFPs) in the barrel cortex. The brain tissue samples were collected at 2 months after injection. Western blotting and immunofluorescence staining showed that mTFEB protein levels were significantly increased in the brain tissue samples of mice injected with mTFEB-overexpressing vectors compared with those injected with PBS or GFP-overexpressing vectors. pAAV8-CMV-mTFEB injection resulted in significant elevations in the mRNA and protein levels of lysosomal biogenesis indicators in the brain tissue samples. No significant changes were observed in the expressions of GFAP, Iba1, and proinflammation mediators in the pAAV8-CMV-mTFEB-injected brain compared with those in the control groups. Collectively, our results suggest that AAV8 successfully mediates mTFEB overexpression in the mouse brain without inducing apparent local inflammation, supporting the safety of TFEB-based gene therapy in treating neurodegenerative diseases.

Adenovirus in the brain: recent advances of gene therapy for neurodegenerative diseases

1998 ◽  
Vol 55 (4) ◽  
pp. 333-341 ◽  
Author(s):  
M. Barkats ◽  
A. Bilang-Bleuel ◽  
M.H. Buc-Caron ◽  
M.N. Castel-Barthe ◽  
O. Corti ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Neurodegenerative Diseases ◽  
Recent Advances ◽  
The Brain

scholarly journals Scatterometry Measurements With Scattered Light Imaging Enable New Insights Into the Nerve Fiber Architecture of the Brain

2021 ◽  
Vol 15 ◽  
Author(s):  
Miriam Menzel ◽  
Marouan Ritzkowski ◽  
Jan A. Reuter ◽  
David Gräßel ◽  
Katrin Amunts ◽  
...  
Keyword(s):  
Human Brain ◽  
Nerve Fiber ◽  
Brain Tissue ◽  
Scattered Light ◽  
Polar Angle ◽  
Nerve Fibers ◽  
Fiber Architecture ◽  
Whole Brain ◽  
Tissue Samples ◽  
The Brain

The correct reconstruction of individual (crossing) nerve fibers is a prerequisite when constructing a detailed network model of the brain. The recently developed technique Scattered Light Imaging (SLI) allows the reconstruction of crossing nerve fiber pathways in whole brain tissue samples with micrometer resolution: the individual fiber orientations are determined by illuminating unstained histological brain sections from different directions, measuring the transmitted scattered light under normal incidence, and studying the light intensity profiles of each pixel in the resulting image series. So far, SLI measurements were performed with a fixed polar angle of illumination and a small number of illumination directions, providing only an estimate of the nerve fiber directions and limited information about the underlying tissue structure. Here, we use a display with individually controllable light-emitting diodes to measure the full distribution of scattered light behind the sample (scattering pattern) for each image pixel at once, enabling scatterometry measurements of whole brain tissue samples. We compare our results to coherent Fourier scatterometry (raster-scanning the sample with a non-focused laser beam) and previous SLI measurements with fixed polar angle of illumination, using sections from a vervet monkey brain and human optic tracts. Finally, we present SLI scatterometry measurements of a human brain section with 3 μm in-plane resolution, demonstrating that the technique is a powerful approach to gain new insights into the nerve fiber architecture of the human brain.

scholarly journals Neurodegenerative disorders and sterile inflammation: lessons from a Drosophila model

2019 ◽  
Vol 166 (3) ◽  
pp. 213-221 ◽  
Author(s):  
Firzan Nainu ◽  
Emil Salim ◽  
Rangga Meidianto Asri ◽  
Aki Hori ◽  
Takayuki Kuraishi
Keyword(s):  
Neurodegenerative Diseases ◽  
Inflammatory Responses ◽  
Biological Significance ◽  
Sterile Inflammation ◽  
Medical Interventions ◽  
Drosophila Model ◽  
Progressive Neurodegeneration ◽  
Molecular Patterns ◽  
The Brain ◽  
Lateral Sclerosis

Abstract Central nervous system (CNS)-related disorders, including neurodegenerative diseases, are common but difficult to treat. As effective medical interventions are limited, those diseases will likely continue adversely affecting people’s health. There is evidence that the hyperactivation of innate immunity is a hallmark of most neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis and polyglutamine diseases. In mammalian and fly CNS, the presence of noninfectious ligands, including danger-associated molecular patterns, is recognized by (micro)glial cells, inducing the expression of proinflammatory cytokines. Such inflammation may contribute to the onset and progression of neurodegenerative states. Studies using fruit flies have shed light on the types of signals, receptors and cells responsible for inducing the inflammation that leads to neurodegeneration. Researchers are using fly models to assess the mechanisms of sterile inflammation in the brain and its link to progressive neurodegeneration. Given the similarity of its physiological system and biochemical function to those of mammals, especially in activating and regulating innate immune signalling, Drosophila can be a versatile model system for studying the mechanisms and biological significance of sterile inflammatory responses in the pathogenesis of neurodegenerative diseases. Such knowledge would greatly facilitate the quest for a novel effective treatment for neurodegenerative diseases.

scholarly journals The Effect of Gender on Brain Tissue Changes Induced by Renal Ischemia-Reperfusion Injury in Adult Rats

2019 ◽  
Vol 8 (2) ◽  
pp. 113-118
Author(s):  
Fakhri Armin ◽  
Fariba Azarkish ◽  
Ali Atash Ab Parvar ◽  
Aghdas Dehghani
Keyword(s):  
Brain Tissue ◽  
Inflammatory Responses ◽  
Ischemia Reperfusion ◽  
Left Kidney ◽  
Renal Ischemia ◽  
Female Rats ◽  
Male Rats ◽  
Adult Rats ◽  
Sensitive Organ ◽  
The Brain

Background: Renal ischemia-reperfusion (RIR) is a common clinical injury that affects the function of other remote organs such as the brain by initiating a cascade of complex and wide-ranging inflammatory responses. RIR also follows a different course in men and women. Since there is little information on the effect of RIR on the brain as a sensitive organ in both males and females, the present research was performed to investigate the effect of gender on RIR-induced brain tissue alterations in adult rats. Materials and Methods: In this study, 28 Wistar rats (14 female and 14 male rats) weighing 200 ± 20 g were divided into the following groups: 1- male sham (MS), 2- female sham (FS), 3- male ischemia (MI) with 3-hour reperfusion (ISC3hr), and 4- Female ischemia (FI) with 3-hour reperfusion (ISC3hr). Bilateral renal ischemia was induced for 45 minutes and blood samples were taken after reperfusion for the measurements of serum blood urea nitrogen (BUN), creatinine (Cr), malondialdehyde (MDA), and nitrite levels. The left kidney was removed for evaluation of MDA and tissue nitrite levels. Right kidney and brain tissue underwent histological examination. Results: Serum BUN level increased in both genders. Serum nitrite level was significantly different between both genders, meaning that it was increased in the female rats as compared to male ones. Overall brain tissue damage was significantly increased in males compared to females. Conclusion: RIR has an effect on the function and tissue of kidney and brain in both genders. Female rats are more susceptible to the nitric oxide system than the male ones. This study showed that male brain tissue was more susceptible to RIR. Therefore, gender is one of the important factors that should be considered in clinical treatments.

scholarly journals Whole brain delivery of an instability-proneMecp2transgene improves behavioral and molecular pathological defects in mouse models of Rett syndrome

2019 ◽  
Author(s):  
Mirko Luoni ◽  
Serena Giannelli ◽  
Marzia Indrigo ◽  
Antonio Niro ◽  
Luca Massimino ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Gene Transfer ◽  
Rett Syndrome ◽  
Protein Translation ◽  
Mutant Mice ◽  
Severe Toxicity ◽  
Male And Female ◽  
Protein Levels ◽  
Mecp2 Protein ◽  
The Brain

AbstractRett syndrome (RTT) is an incurable neurodevelopmental disorder caused by mutations in the gene encoding for methyl-CpG binding-protein 2 (MeCP2). Gene therapy for this disease presents inherent hurdles sinceMECP2is expressed throughout the brain and its duplication leads to severe neurological conditions as well. However, the recent introduction of AAV-PHP.eB, an engineered capsid with an unprecedented efficiency in crossing the blood-brain barrier upon intravenous injection, has provided an invaluable vehicle for gene transfer in the mouse nervous system. Herein, we use AAV-PHP.eB to deliver an instability-proneMecp2(iMecp2) transgene cassette which, increasing RNA destabilization and inefficient protein translation of the viralMecp2transgene, limits supraphysiological Mecp2 protein levels in transduced neural tissues. Intravenous injections of the PHP.eB-iMecp2virus in symptomatic male and femaleMecp2mutant mice significantly ameliorated the disease progression with improved locomotor activity, coordination, lifespan and normalization of altered gene expression and mTOR signaling. Remarkably, PHP.eB-iMecp2administration did not result in severe toxicity effects either in femaleMecp2mutant or in wild-type animals. In contrast, we observed a strong immune response to the transgene in treated maleMecp2mutant mice that was overcome by immunosuppression. Overall, PHP.eB-mediated delivery of theiMecp2cassette provided widespread and efficient gene transfer maintaining physiological Mecp2 protein levels in the brain. This combination defines a novel viral system with significant therapeutic efficacy and increased safety which can contribute to overcome the hurdles that are delaying clinical applications of gene therapy for RTT.One Sentence SummaryGlobal brain transduction of the instability-proneMecp2transgene by systemic AAV-PHP.eB administration is both safe and effective in protecting male and femaleMecp2mutant mice from the RTT disease phenotype.

scholarly journals VIROLOGICAL AND SEROLOGICAL DIAGNOSIS OF RABIES IN BATS FROM AN URBAN AREA IN THE BRAZILIAN AMAZON

2015 ◽  
Vol 57 (6) ◽  
pp. 497-503 ◽  
Author(s):  
Rubens Souza de OLIVEIRA ◽  
Lanna Jamile Corrêa da COSTA ◽  
Fernanda Atanaena Gonçalves de ANDRADE ◽  
Wilson UIEDA ◽  
Luzia Fátima Alves MARTORELLI ◽  
...  
Keyword(s):  
Brain Tissue ◽  
Urban Area ◽  
Amazon Basin ◽  
Common Species ◽  
Urban Context ◽  
Serum Samples ◽  
Tissue Samples ◽  
Dry Seasons ◽  
The Brain ◽  
Wet And Dry Seasons

The outbreaks of rabies in humans transmitted by Desmodus rotundus in 2004 and 2005, in the northeast of the Brazilian State of Para, eastern Amazon basin, made this a priority area for studies on this zoonosis. Given this, the present study provides data on this phenomenon in an urban context, in order to assess the possible circulation of the classic rabies virus (RABV) among bat species in Capanema, a town in the Amazon basin. Bats were collected, in 2011, with mist nets during the wet and dry seasons. Samples of brain tissue and blood were collected for virological and serological survey, respectively. None of the 153 brain tissue samples analyzed tested positive for RABV infection, but 50.34% (95% CI: 45.67-55.01%) of the serum samples analyzed were seropositive. Artibeus planirostris was the most common species, with a high percentage of seropositive individuals (52.46%, 95% CI: 52.31 52.60%). Statistically, equal proportions of seropositive results were obtained in the rainy and dry seasons (c2 = 0.057, d.f. = 1, p = 0.88). Significantly higher proportions of males (55.96%, 95% CI: 48.96-62.96%) and adults (52.37%, 95% CI: 47.35-57.39%) were seropositive. While none of the brain tissue samples tested positive for infection, the high proportion of seropositive specimens indicates that RABV may be widespread in this urban area.

Reduced Immunogenicity of Intraparenchymal Delivery of Adeno-Associated Virus Serotype 2 Vectors: Brief Overview

2021 ◽  
Vol 21 ◽  
Author(s):  
Wuh-Liang Hwu ◽  
Shin-Ichi Muramatsu ◽  
Bruria Gidoni-Ben-Zeev
Keyword(s):  
Gene Therapy ◽  
Immune Response ◽  
Clinical Trial Data ◽  
Trial Data ◽  
Acid Decarboxylase ◽  
Adeno Associated Virus ◽  
Amino Acid Decarboxylase ◽  
Virus Serotype ◽  
The Brain ◽  
Decarboxylase Deficiency

: Preexisting immunity to adeno-associated virus (AAV) poses a concern in AAV vector–mediated gene therapy. Localized administration of low doses of carefully chosen AAV serotypes can mitigate the risk of an immune response. This article will illustrate the low risk of immune response to AAV serotype 2 vector–mediated gene therapy to the brain with support from clinical trial data in aromatic L-amino acid decarboxylase deficiency and Parkinson disease.

scholarly journals PET and the multitracer concept in the study of neurodegenerative diseases

2015 ◽  
Vol 9 (4) ◽  
pp. 343-349 ◽  
Author(s):  
Henry Engler ◽  
Andres Damian ◽  
Cecilia Bentancourt
Keyword(s):  
Positron Emission Tomography ◽  
Molecular Imaging ◽  
Neurodegenerative Diseases ◽  
Brain Tissue ◽  
Neurodegenerative Disorders ◽  
Clinical Symptoms ◽  
Emission Tomography ◽  
Positron Emission ◽  
The Brain

ABSTRACT The complexity of the pathological reactions of the brain to an aggression caused by an internal or external noxa represents a challenge for molecular imaging. Positron emission tomography (PET) can indicate in vivo,anatomopathological changes involved in the development of different clinical symptoms in patients with neurodegenerative disorders. PET and the multitracer concept can provide information from different systems in the brain tissue building an image of the whole disease. We present here the combination of 18F-flourodeoxyglucose (FDG) and N-[11C-methyl]-L-deuterodeprenyl (DED), FDG and N-[11C-methyl] 2-(4'-methylaminophenyl)-6-hydroxybenzothiazole (PIB), PIB and L-[11C]-3'4-Dihydrophenylalanine (DOPA) and finally PIB and [15O]H2O.

Design and Evaluation of Advanced Smart Needles for Brain Biopsy

2017 ◽  
Author(s):  
Mohammad Sahlabadi ◽  
Seyedvahid Khodaei ◽  
Parsaoran Hutapea
Keyword(s):  
Brain Tissue ◽  
Needle Biopsy ◽  
Brain Biopsy ◽  
Lateral Movement ◽  
Open Biopsy ◽  
Tissue Samples ◽  
Tissue Cutting ◽  
Nitinol Wire ◽  
The Brain ◽  
Stereotactic Core

Biopsy involves removing a piece of tissues for further medical examination. Brain biopsy is generally performed using different techniques, such as open biopsy, stereotactic core biopsy, and needle biopsy. Open biopsy is the most common and the most invasive form of the brain biopsy. During the procedure, a piece of the skull is removed and the brain is exposed. Stereotactic core and needle biopsies are minimally invasive. In these procedures, a hole is usually drilled into the skull and a needle is inserted through the hole to extract the tissue. Brain biopsy has its risks and complications due to the vulnerability of the brain tissue. Although using needle or stereotactic biopsies reduce the risks, brain biopsy may cause swelling or bleeding in the brain, and in some cases, can result in infection, stroke, seizure or even coma. A needle biopsy with conventional needles involves pulling or pushing the cutting stylet inside the needle hollow body (cannula). The manual pulling and pushing procedure induces lateral movement of the needle, which increases the damage in brain tissue. The goal here is to completely remove the needle harmful lateral movement. In this work, design of smart biopsy needles is proposed and demonstrated by incorporating nitinol wires and springs to control the lateral movement of the cutting stylet. The first design comprises of two parts. The first part of the needle is a 360° tissue cutting stylet, and the second part is the cannula. The cutting stylet can slide inside the cannula and a nitinol wire is embedded at the end of the stylet and the end of the cannula. As the electric current is applied on the nitinol wire, it shrinks and pulls the cutting stylet. The second design is almost similar to the first design, but it has a 180° tissue cutting stylet with a similar actuating mechanism. The last design uses a nitinol torsion spring that is attached to the cutting stylet. It cuts tissue samples by activating the nitinol spring to rotate the cutting stylet.

scholarly journals Analysis of the Biomarkers for Neurodegenerative Diseases in Aged Progranulin Deficient Mice

2022 ◽  
Vol 23 (2) ◽  
pp. 629
Author(s):  
Xiangli Zhao ◽  
Sadaf Hasan ◽  
Benjamin Liou ◽  
Yi Lin ◽  
Ying Sun ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Neurodegenerative Disease ◽  
Brain Tissue ◽  
Clinical Settings ◽  
Progressive Degeneration ◽  
Disease Modifying Therapies ◽  
Β Amyloid ◽  
And Function ◽  
The Brain ◽  
Deficient Mice

Neurodegenerative diseases are debilitating impairments that affect millions of people worldwide and are characterized by progressive degeneration of structure and function of the central or peripheral nervous system. Effective biomarkers for neurodegenerative diseases can be used to improve the diagnostic workup in the clinic as well as facilitate the development of effective disease-modifying therapies. Progranulin (PGRN) has been reported to be involved in various neurodegenerative disorders. Hence, in the current study we systematically compared the inflammation and accumulation of typical neurodegenerative disease markers in the brain tissue between PGRN knockout (PGRN KO) and wildtype (WT) mice. We found that PGRN deficiency led to significant neuron loss as well as activation of microglia and astrocytes in aged mice. Several characteristic neurodegenerative markers, including α-synuclein, TAR DNA-binding protein 43 (TDP-43), Tau, and β-amyloid, were all accumulated in the brain of PGRN-deficient mice as compared to WT mice. Moreover, higher aggregation of lipofuscin was observed in the brain tissue of PGRN-deficient mice compared with WT mice. In addition, the autophagy was also defective in the brain of PGRN-deficient mice, indicated by the abnormal expression level of autophagy marker LC3-II. Collectively, comprehensive assays support the idea that PGRN plays an important role during the development of neurodegenerative disease, indicating that PGRN might be a useful biomarker for neurodegenerative diseases in clinical settings.

Sign in / Sign up

Export Citation Format

Share Document