scholarly journals Intrastriatal gene delivery of GDNF persistently attenuates methamphetamine self-administration and relapse in mice

2013 ◽  
Vol 16 (7) ◽  
pp. 1559-1567 ◽  
Author(s):  
Yijin Yan ◽  
Yoshiaki Miyamoto ◽  
Atsumi Nitta ◽  
Shin-ichi Muramatsu ◽  
Keiya Ozawa ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Drug Abuse ◽  
Locomotor Activity ◽  
Gene Transfer ◽  
Mouse Models ◽  
Clinical Settings ◽  
Self Administration ◽  
Adeno Associated Virus ◽  
Gdnf Gene ◽  
The Brain

Abstract Relapse of drug abuse after abstinence is a major challenge to the treatment of addicts. In our well-established mouse models of methamphetamine (Meth) self-administration and reinstatement, bilateral microinjection of adeno-associated virus vectors expressing GDNF (AAV-Gdnf) into the striatum significantly reduced Meth self-administration, without affecting locomotor activity. Moreover, the intrastriatal AAV-Gdnf attenuated cue-induced reinstatement of Meth-seeking behaviour in a sustainable manner. In addition, this manipulation showed that Meth-primed reinstatement of Meth-seeking behaviour was reduced. These findings suggest that the AAV vector-mediated Gdnf gene transfer into the striatum is an effective and sustainable approach to attenuate Meth self-administration and Meth-associated cue-induced relapsing behaviour and that the AAV-mediated Gdnf gene transfer in the brain may be a valuable gene therapy against drug dependence and protracted relapse in clinical settings.

scholarly journals Hemophilia gene therapy comes of age

2017 ◽  
Vol 1 (26) ◽  
pp. 2591-2599 ◽  
Author(s):  
Lindsey A. George
Keyword(s):  
Clinical Trial ◽  
Gene Therapy ◽  
Gene Transfer ◽  
Factor Ix ◽  
Large Animal Model ◽  
Large Animal ◽  
Adeno Associated Virus ◽  
Target Disease ◽  
American Society ◽  
Clinical Trial Results

Abstract Concurrent with the development of recombinant factor replacement products, the characterization of the F9 and F8 genes over 3 decades ago allowed for the development of recombinant factor products and made the hemophilias a target disease for gene transfer. The progress of hemophilia gene therapy has been announced in 3 American Society of Hematology scientific plenary sessions, including the first “cure” in a large animal model of hemophilia B in 1998, first in human sustained vector-derived factor IX activity in 2011, and our clinical trial results reporting sustained vector-derived factor IX activity well into the mild or normal range in 2016. This progression to clinically meaningful success combined with numerous ongoing recombinant adeno-associated virus (rAAV)–mediated hemophilia gene transfer clinical trials suggest that the goal of gene therapy to alter the paradigm of hemophilia care may soon be realized. Although several novel therapeutics have recently emerged for hemophilia, gene therapy is unique in its potential for a one-time disease-altering, or even curative, treatment. This review will focus on the prior progress and current clinical trial investigation of rAAV-mediated gene transfer for hemophilia A and B.

scholarly journals Sterile Abscess in the Myocardium after Direct Intramyocardial Injection Related to Gene Therapy in a Swine Model

2011 ◽  
Vol 2011 ◽  
pp. 1-2 ◽  
Author(s):  
Kiyotake Ishikawa ◽  
Dennis Ladage ◽  
Lisa Tilemann ◽  
Yoshiaki Kawase ◽  
Roger J. Hajjar
Keyword(s):  
Gene Therapy ◽  
Gene Transfer ◽  
Viral Vectors ◽  
Swine Model ◽  
Clinical Settings ◽  
Intramyocardial Injection ◽  
New Therapy ◽  
Sterile Abscess ◽  
Efficient Gene ◽  
Cardiac Gene

Cardiac gene therapy is one of the most promising approaches to cure patients with cardiac dysfunctions. Many ways of efficient gene transfer using viral vectors are tested, and some of them are already used in clinical settings. However, it is always important to be keenly alert to the possible complications when a new therapy is introduced. We present a case of myocardial sterile abscess in a swine model associated with a direct myocardial injection.

scholarly journals Adeno-associated virus-mediated aspartoacylase gene transfer to the brain of knockout mouse for canavan disease

2003 ◽  
Vol 7 (5) ◽  
pp. 580-587 ◽  
Author(s):  
Reuben Matalon ◽  
Sankar Surendran ◽  
Peter L Rady ◽  
Michael J Quast ◽  
Gerald A Campbell ◽  
...  
Keyword(s):  
Gene Transfer ◽  
Knockout Mouse ◽  
Canavan Disease ◽  
Adeno Associated Virus ◽  
The Brain

Adeno-Associated Viral Vectors for Gene Transfer and Gene Therapy

1999 ◽  
Vol 380 (6) ◽  
Author(s):  
H. Büeler
Keyword(s):  
Gene Expression ◽  
Gene Therapy ◽  
Gene Transfer ◽  
Gene Delivery ◽  
Viral Vectors ◽  
Delivery Systems ◽  
Adeno Associated Virus ◽  
Viral Genes ◽  
Virus Recombinant

AbstractAdeno-associated virus (AAV) is a defective, non-pathogenic human parvovirus that depends for growth on coinfection with a helper adenovirus or herpes virus. Recombinant adeno-associated viruses (rAAVs) have attracted considerable interest as vectors for gene therapy. In contrast to other gene delivery systems, rAAVs lack all viral genes and show long-term gene expression

scholarly journals Adeno Associated Virus 9–Based Gene Therapy Delivers a Functional Monocarboxylate Transporter 8, Improving Thyroid Hormone Availability to the Brain of Mct8-Deficient Mice

Thyroid ◽  
2016 ◽  
Vol 26 (9) ◽  
pp. 1311-1319 ◽  
Author(s):  
Hideyuki Iwayama ◽  
Xiao-Hui Liao ◽  
Lyndsey Braun ◽  
Soledad Bárez-López ◽  
Brian Kaspar ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Thyroid Hormone ◽  
Monocarboxylate Transporter ◽  
Adeno Associated Virus ◽  
The Brain ◽  
Deficient Mice

Multiple obstacles to gene therapy in the brain

1995 ◽  
Vol 18 (1) ◽  
pp. 67-68
Author(s):  
David Avram Sanders
Keyword(s):  
Gene Therapy ◽  
Animal Model ◽  
Gene Transfer ◽  
Human Brain ◽  
Viral Vector ◽  
Mode Of Delivery ◽  
The Brain ◽  
Multiple Obstacles

AbstractNeuwelt et al. have proposed gene-transfer experiments utilizing an animal model that offers many important advantages for investigating the feasibility of gene therapy in the human brain. A variety of tissues concerning the viral vector and mode of delivery of the corrective genes need to be resolved, however, before such therapy is scientifically supportable.

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 Evaluation of AAV-DJ vector for retinal gene therapy

PeerJ ◽  
2019 ◽  
Vol 7 ◽  
pp. e6317 ◽  
Author(s):  
Yusaku Katada ◽  
Kenta Kobayashi ◽  
Kazuo Tsubota ◽  
Toshihide Kurihara
Keyword(s):  
Gene Therapy ◽  
Gene Transfer ◽  
Cell Types ◽  
Egfp Expression ◽  
Adeno Associated Virus ◽  
Photoreceptor Layer ◽  
Mueller Cells ◽  
Efficient Gene ◽  
Clinical Gene Therapy ◽  
Preclinical And Clinical Studies

Purpose The most common virus vector used in gene therapy research for ophthalmologic diseases is the adeno-associated virus (AAV) vector, which has been used successfully in a number of preclinical and clinical studies. It is important to evaluate novel AAV vectors in animal models for application of clinical gene therapy. The AAV-DJ (type 2/type 8/type 9 chimera) was engineered from shuffling eight different wild-type native viruses. In this study, we investigated the efficiency of gene transfer by AAV-DJ injections into the retina. Methods One microliter of AAV-2-CAGGS-EGFP or AAV-DJ-CAGGS-EGFP vector at a titer of 1.4 × 10e12 vg/ml was injected intravitreally or subretinally in each eye of C57BL/6 mice. We evaluated the transduction characteristics of AAV-2 and -DJ vectors using fluorescence microscopy and electroretinography. Results The results confirmed that AAV-DJ could deeply transfer gene to photoreceptor layer with intravitreal injection and has an efficient gene transfer to various cell types especially the Mueller cells in the retina. Retinal function was not affected by AAV-DJ infection or ectopic EGFP expression. Conclusions The AAV-DJ vector efficiently induces the reporter gene in both the inner and outer murine retina without functional toxicity. These data indicated that the AAV-DJ vector is a useful tool for the gene therapy research targeting retinal disorders.

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.

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