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Neuroanatomy and transgenic technologies

Authors: --- --- --- --- et al.
Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889195138 Year: Pages: 139 DOI: 10.3389/978-2-88919-513-8 Language: English
Publisher: Frontiers Media SA
Subject: Science (General) --- Neurology
Added to DOAB on : 2015-12-03 13:02:24
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Abstract

Neuroanatomists increasingly rely on techniques enabling them to manipulate genes in defined brain cell populations. In particular, engineered transgenes, which encode a variety of fluorescent reporter proteins can be inserted into the genome or delivered into desired brain regions using viral vectors, thereby allowing the labeling of molecularly-defined populations of neurons and/or glial cells. Transgenic technology can also be used to selectively delete genes in targeted neuronal populations or bi-directionally modulate their electrical excitability using optogenetic or chemogenetic techniques. One of the primary advantages of using transgenic reagents is to simplify the identification and tracing of targeted population of brain cells, which can be laborious using traditional techniques in neuroanatomy. In this research topic, we assembled up-to-date reviews and original articles that demonstrate the versatility and power of transgenic tools in advancing our knowledge of the nervous system, with a special emphasis on the application of transgenic technology to neuroanatomical questions.

Immune responses to AAV vectors, from bench to bedside

Authors: --- --- ---
Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889195008 Year: Pages: 95 DOI: 10.3389/978-2-88919-500-8 Language: English
Publisher: Frontiers Media SA
Subject: Allergy and Immunology --- Medicine (General)
Added to DOAB on : 2015-12-03 13:02:24
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The recent wave of clinical studies demonstrating long-term therapeutic efficacy highlights the enormous potential of gene therapy as an approach to the treatment of inherited disorders and cancer. While in recent years lentiviral vectors have dominated the field of ex vivo gene therapy in man, adeno-associated virus (AAV) vectors have become the platform of choice for the in vivo gene delivery, both local and systemic.Despite the achievements in the clinic however, a number of hurdles remain to be overcome in gene therapy, these include availability of scalable vector production systems, potential issues associated with insertional mutagenesis, and concerns related to immunogenicity of gene therapeutics. For AAV vectors, clinical trials showed that immunity directed against the vector could either prevent transduction of a target tissue or limit the duration of therapeutic efficacy. Initial observations in the context of a gene therapy trial for hemophilia spurred over a decade efforts by gene therapists and immunologists to understand the mechanism and identify factors that contribute to AAV’s immunogenicity, including the prevalence of B cell and T cell immunity to wild type AAV in humans and the interaction of AAV vectors with the innate and adaptive immune system. Despite a number of important contributions in particular in the more recent past, our knowledge on the immunology of gene transfer is still rudimental; this is partly due to the fact that the basic understanding of the complex balance between tolerance and immunity to an antigen, key aspect of gene transfer with AAV, keeps evolving rapidly. However, continuing work towards a better definition of the interaction of viral vectors with the immune system has led to significant advances in the knowledge of the factors influencing the outcome of gene transfer, such as the vector dose, the immune privilege of certain tissues, and the induction of tolerance to an antigen. A better understanding of the structure-function relationship of the viral capsid has boosted the development of novel immune-escape vector variants. In addition, novel immunomodulatory strategies were established to prevent or reduce anti-capsid immunity have been developed and are being tested in preclinical models and in clinical trials. Together, these advances are bringing us closer to the goal of achieving safe and sustained therapeutic gene transfer in humans. In this research topic, a collection of Original Research and Review Articles highlights critical aspects of the interaction between gene AAV vectors and the immune system, discussing how these interactions can be either detrimental or constitute an advantage, depending on the context of gene transfer, and providing tools and resources to better understand the issue of immunogenicity of AAV vectors in gene transfer.

Towards Mechanism-based Treatments for Fragile X Syndrome

Authors: ---
ISBN: 9783039215058 / 9783039215065 Year: Pages: 250 DOI: 10.3390/books978-3-03921-506-5 Language: eng
Publisher: MDPI - Multidisciplinary Digital Publishing Institute
Subject: Science (General) --- Biology
Added to DOAB on : 2019-12-09 11:49:15
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Abstract

It has been more than 25 years since the identification of the FMR1 gene and the demonstration of the causative role of CGG-repeat expansion in the disease pathology of fragile X syndrome (FXS), but the underlying mechanisms involved in the expansion mutation and the resulting gene silencing still remain elusive. Our understanding of the pathways impacted by the loss of FMRP function has grown tremendously, and has opened new avenues for targeted treatments for FXS. However, the failure of recent clinical trials that were based on successful preclinical studies using the Fmr1 knockout mouse model has forced the scientific community to revisit clinical trial design and identify objective outcome measures. There has also been a renewed interest in restoring FMR1 gene expression as a possible treatment approach for FXS. This special issue of Brain Sciences highlights the progress that has been made towards understanding the disease mechanisms and how this has informed the development of treatment strategies that are being explored for FXS.

Keywords

fragile X syndrome --- clinical trials --- targeted treatments --- drug development --- fragile X syndrome --- clinical trials --- treatment development --- best practices --- fragile X syndrome --- newborn screening --- early identification --- fragile X syndrome --- X chromosome --- females --- FMR1 --- anxiety --- avoidance --- cognition --- behavior --- brain --- Fragile X --- FMRP --- Fxr2 --- Fmr1 --- fragile X syndrome --- executive function --- working memory --- set-shifting --- cognitive flexibility --- inhibitory control --- attention --- planning --- processing speed --- Fragile X syndrome 1 --- Fragile X-associated Tremor/Ataxia Syndrome 2 --- CRISPR 3 --- Trinucleotide Repeat 4 --- Gene editing --- fragile X syndrome --- FMR1 gene --- voice of the person --- voice of the patient --- characteristics that have the greatest impact --- developmental disorders --- fragile X syndrome --- language development --- automated vocal analysis --- adeno-associated virus --- autism spectrum disorders --- cerebral spinal fluid --- fragile X mental retardation protein --- neurodevelopmental disorders --- viral vector --- fragile X syndrome --- gene reactivation --- RNA:DNA hybrid --- FMRP --- histone methylation --- DNA methylation --- FMR1 --- PRC2 --- fragile X syndrome --- unstable repeat diseases --- epigenetic gene silencing --- DNA methylation --- repeat instability --- pluripotent stem cells --- CGG Repeat Expansion Disease --- DNA instability --- expansion --- contraction --- mismatch repair (MMR) --- base excision repair (BER) --- transcription coupled repair (TCR) --- double-strand break repair (DSBR) --- Non-homologous end-joining (NHEJ) --- mosaicism --- protein synthesis --- Fragile X Syndrome --- biomarker --- iPSC --- fibroblast --- lymphoblast --- fragile X syndrome --- molecular biomarkers --- FMR1 --- FMRP --- intellectual disability --- Fmr1 KO mouse --- ASD --- n/a

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