Design of a Novel Gene Therapy Construct to Achieve Sustained Brain-Derived Neurotrophic Factor Signaling in Neurons

Human Gene Therapy
Andrew OsborneKeith R G Martin

Abstract

Brain-derived neurotrophic factor (BDNF) acting through the tropomyosin-related receptor-B (TrkB) is an important signaling system for the maintenance and survival of neurons. Gene therapy using either recombinant adeno-associated virus (AAV) or lentiviral vectors can provide sustained delivery of BDNF to tissues where reduced BDNF signaling is hypothesized to contribute to disease pathophysiology. However, elevation in BDNF at target sites has been shown to lead to a downregulation of TrkB receptors, thereby reducing the effect of chronic BDNF delivery over time. A novel gene sequence has been designed coding both the ligand (BDNF) and the TrkB receptor in a single transgene separated by a short viral-2A sequence. The single transgene is efficiently processed intracellularly in vitro and in vivo to yield the two mature proteins, which are then independently transported to their final cellular locations: TrkB receptors to the cell surface, and BDNF contained within secretory vesicles. To accommodate the coding sequences of both BDNF and TrkB receptors within the narrow confines of the AAV vectors (4.7 kb pairs), the coding region for the pro-domain of BDNF was removed and the signal peptide sequence modified to improve producti...Continue Reading

References

May 19, 1995·The Journal of Biological Chemistry·J V Heymach, E M Shooter
Nov 1, 1994·European Journal of Biochemistry·R KolbeckY A Barde
Mar 1, 1996·Brain Research. Molecular Brain Research·J F Poduslo, G L Curran
Jul 2, 1999·Journal of Molecular Biology·M H UltschA M de Vos
Apr 5, 2003·Annual Review of Biochemistry·Eric J Huang, Louis F Reichardt
May 29, 2003·Current Drug Targets. CNS and Neurological Disorders·Scott J Pollack, Sarah J Harper
Jan 1, 2004·Progress in Brain Research·Jannifer J GentryBruce D Carter
Mar 17, 2004·Molecular and Cellular Biology·Chunxiao Wu, James C Alwine
Dec 25, 2004·The Journal of Gene Medicine·Lei ZhangA James Mixson
Jun 3, 2005·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Henry K TengBarbara L Hempstead
Jul 1, 2005·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Zhe-Yu ChenFrancis S Lee
Feb 21, 2006·The European Journal of Neuroscience·Silvia GinésJordi Alberch
Sep 29, 2006·Developmental Biology·Brian A TurnerBarbara L Hempstead
Jan 22, 2008·Nature Neuroscience·Tomoya MatsumotoYves-Alain Barde
Apr 21, 2011·The Journal of Clinical Investigation·Maxime CazorlaDidier Rognan
Mar 14, 2012·The Journal of Cell Biology·Sandra DieniYves-Alain Barde
Mar 30, 2012·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·João R GomesCarlos B Duarte
Apr 17, 2012·Trends in Neurosciences·Carlos F Ibáñez, Anastasia Simi
Apr 19, 2013·Molecular Medicine Reports·Yu LiuXueliang Xu
Sep 26, 2013·Oncology Reports·Jing XiongXin-Fu Zhou
May 25, 2016·Journal of Neurochemistry·Catia C ProencaFrancis S Lee
Jun 2, 2016·Parkinsonism & Related Disorders·Yu WangXiang Yang Zhang
Sep 30, 2016·Nature·Stephen C HarwardJames O McNamara

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Citations

Aug 8, 2018·International Journal of Molecular Sciences·Еlena V MitroshinaMaria V Vedunova
Jun 4, 2018·Human Molecular Genetics·Simon CoulyFlorence Maschat
Sep 3, 2019·Current Eye Research·Tasneem Z Khatib, Keith R Martin
Sep 6, 2019·International Journal of Molecular Sciences·Marie ClaesLieve Moons
Sep 3, 2020·International Journal of Molecular Sciences·Anna Wójcik-GryciukMałgorzata Skup
Jul 25, 2018·Journal of Alzheimer's Disease : JAD·Sudhanshu P RaikwarAsgar Zaheer
Nov 3, 2020·BioDrugs : Clinical Immunotherapeutics, Biopharmaceuticals and Gene Therapy·Paula I Fuller-CarterLivia S Carvalho
Jan 28, 2021·Genes·Michael James GilhooleyPatrick Yu Wai Man
Jan 8, 2021·Stem Cell Reviews and Reports·Sanjucta AdakBithiah Grace Jaganathan
Dec 4, 2020·Current Ophthalmology Reports·Lauren K WarehamDavid J Calkins
Sep 7, 2020·Progress in Retinal and Eye Research·Uday B KompellaMadhoosudan A Patil
Dec 2, 2021·Stem Cells and Development·Olga V StepanovaVladimir P Chekhonin

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Methods Mentioned

BETA
Assay
enzyme-linked immunosorbent assay
protein assay
dissection
confocal microscopy
protein folding
transfection

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