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      Humanization of the blood–brain barrier transporter ABCB1 in mice disrupts genomic locus — lessons from three unsuccessful approaches


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          ATP-binding cassette (ABC) transporters are of major importance for the restricted access of toxins and drugs to the human body. At the body's barrier tissues like the blood–brain barrier, these transporters are highly represented. Especially, ABCB1 (P-glycoprotein) has been a priority target of pharmaceutical research, for instance, to aid chemotherapy of cancers, therapy resistant epilepsy, and lately even neurodegenerative diseases. To improve translational research, the humanization of mouse genes has become a popular tool although, like recently seen for Abcb1, not all approaches were successful. Here, we report the characterization of another unsuccessful commercially available ABCB1 humanized mouse strain. In vivo assessment of transporter activity using positron emission tomography imaging revealed a severe reduction of ABCB1 function in the brain of these mice. Analyses of brain mRNA and protein expression showed that the murine Abcb1a gene is still expressed in homozygous humanized animals while expression of the human gene is minimal. Promoter region analyses underpinned that the introduced human gene might dysregulate normal expression and provided insights into the regulation of both transcription and translation of Abcb1a. We conclude that insertion of the human coding DNA sequence (CDS) into exon 3 instead of exon 2 most probably represents a more promising strategy for Abcb1a humanization.

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          Membrane transporters in drug development.

          Membrane transporters can be major determinants of the pharmacokinetic, safety and efficacy profiles of drugs. This presents several key questions for drug development, including which transporters are clinically important in drug absorption and disposition, and which in vitro methods are suitable for studying drug interactions with these transporters. In addition, what criteria should trigger follow-up clinical studies, and which clinical studies should be conducted if needed. In this article, we provide the recommendations of the International Transporter Consortium on these issues, and present decision trees that are intended to help guide clinical studies on the currently recognized most important drug transporter interactions. The recommendations are generally intended to support clinical development and filing of a new drug application. Overall, it is advised that the timing of transporter investigations should be driven by efficacy, safety and clinical trial enrolment questions (for example, exclusion and inclusion criteria), as well as a need for further understanding of the absorption, distribution, metabolism and excretion properties of the drug molecule, and information required for drug labelling.
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            AMIDE: a free software tool for multimodality medical image analysis.

            Amide's a Medical Image Data Examiner (AMIDE) has been developed as a user-friendly, open-source software tool for displaying and analyzing multimodality volumetric medical images. Central to the package's abilities to simultaneously display multiple data sets (e.g., PET, CT, MRI) and regions of interest is the on-demand data reslicing implemented within the program. Data sets can be freely shifted, rotated, viewed, and analyzed with the program automatically handling interpolation as needed from the original data. Validation has been performed by comparing the output of AMIDE with that of several existing software packages. AMIDE runs on UNIX, Macintosh OS X, and Microsoft Windows platforms, and it is freely available with source code under the terms of the GNU General Public License.
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              Drug resistance in brain diseases and the role of drug efflux transporters.

              Resistance to drug treatment is an important hurdle in the therapy of many brain disorders, including brain cancer, epilepsy, schizophrenia, depression and infection of the brain with HIV. Consequently, there is a pressing need to develop new and more effective treatment strategies. Mechanisms of resistance that operate in cancer and infectious diseases might also be relevant in drug-resistant brain disorders. In particular, drug efflux transporters that are expressed at the blood-brain barrier limit the ability of many drugs to access the brain. There is increasing evidence that drug efflux transporters have an important role in drug-resistant brain disorders, and this information should allow more efficacious treatment strategies to be developed.

                Author and article information

                European Journal of Microbiology and Immunology
                Akadémiai Kiadó
                September 2018
                : 8
                : 3
                : 78-86
                [ 1 ]Translational Neurodegeneration Research and Neuropathology Lab, Department of Neuro-/Pathology, University of Oslo and Oslo University Hospital , Oslo, Norway
                [ 2 ]Center for Health and Bioresources, AIT Austrian Institute of Technology GmbH , Seibersdorf, Austria
                [ 3 ]Inserm UMR-S 1144, Faculté de Pharmacie, Université Paris Descartes , Paris, France
                [ 4 ]Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine , Hannover, Germany
                [ 5 ]Department of Clinical Pharmacology, Medical University of Vienna , Vienna, Austria
                [ 6 ]Department of Biomedical Imaging and Image-guided Therapy, Division of Nuclear Medicine, Medical University of Vienna , Vienna, Austria
                [ 7 ] Center for Systems Neuroscience , Hannover, Germany
                [ 8 ]LIED, University of Lübeck , Lübeck, Germany
                [ 9 ] Department of Bioorganic Chemistry, Leibniz-Institute of Plant Biochemistry , Halle, Germany
                [ 10 ]Department of Pharmacology, University of Latvia , Riga, Latvia
                Author notes

                Corresponding author: Department for Neuro/Patologi, Oslo Universitetssykehus HF, Rikshospitalet, A2.M051, Postboks 4950 Nydalen, 0424 Oslo, Norway; markuskrohn@ 123456gmail.com ; +4723071478; +4723071410.

                [ † ]

                These authors shared last authorship.

                © 2018 The Author(s)

                This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License ( https://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted use, distribution, and reproduction in any medium for non-commercial purposes, provided the original author and source are credited, a link to the CC License is provided, and changes - if any - are indicated.

                : 17 April 2018
                : 16 May 2018
                Page count
                Pages: 9
                Original Research Paper

                Medicine,Immunology,Health & Social care,Microbiology & Virology,Infectious disease & Microbiology
                humanization,ABCB1,P-gp,ABC transporter,PET imaging,mouse models


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