More expansive gene transfer to the rat CNS: AAV PHP.EB vector dose-response and comparison to AAV PHP.B

Gene Therapy
Robert D DaytonRonald L Klein

Abstract

Engineered recombinant adeno-associated virus (AAV) vectors have advanced the transduction of neurons in the CNS on an expansive, wide-scale basis since the papers first using AAV9 for this purpose. Wide-scale CNS expression is relevant to gene therapy as well as indispensable for basic studies such as disease modeling. For example, the wide-scale gene transfer approach could expedite hypothesis testing in vivo relative to the generation of germ-line transgenic mice for all of the genes of interest. Wide-scale gene transfer is more efficient in neonates than in adults, so improving gene transfer efficiency in adults is an important goal. Here we characterized the relatively novel AAV PHP.EB vector for expansive gene transfer in the CNS of adult rats at three doses. The dose-response data were consistent; expression levels can be controlled in a reproducible manner in the rat from moderate to robust levels. Within the CNS, the AAV PHP.EB-derived expression was neuron-selective to neuron-specific, while outside the CNS, organs such as the liver and heart were transduced by the parenteral gene delivery. Though we demonstrated graded expression levels, only the high dose, 1.2 × 1014 vector genomes/kg, yielded efficient expression i...Continue Reading

References

Aug 23, 2002·Proceedings of the National Academy of Sciences of the United States of America·Guang-Ping GaoJames M Wilson
Dec 6, 2005·Molecular Therapy : the Journal of the American Society of Gene Therapy·Ronald L KleinRichard M Zweig
Jan 18, 2006·Molecular Therapy : the Journal of the American Society of Gene Therapy·Cassia N Cearley, John H Wolfe
Oct 24, 2007·Molecular Therapy : the Journal of the American Society of Gene Therapy·Ronald L KleinPhillip P Henning
Dec 23, 2008·Nature Biotechnology·Kevin D FoustBrian K Kaspar
Apr 16, 2009·Molecular Therapy : the Journal of the American Society of Gene Therapy·Sandra DuqueMartine Barkats
Sep 30, 2010·Molecular Therapy : the Journal of the American Society of Gene Therapy·David B WangRonald L Klein
Apr 24, 2012·Expert Opinion on Biological Therapy·Robert D DaytonRonald L Klein
May 22, 2013·Molecular Therapy : the Journal of the American Society of Gene Therapy·Robert D DaytonRonald L Klein
Jun 27, 2013·PloS One·Georg von JonquieresMatthias Klugmann
Nov 2, 2014·Molecular Therapy : the Journal of the American Society of Gene Therapy·Kathrin MeyerBrian K Kaspar
Oct 9, 2015·Molecular Therapy. Methods & Clinical Development·Kasey L JacksonRonald L Klein
Feb 2, 2016·Nature Biotechnology·Benjamin E DevermanViviana Gradinaru
Mar 5, 2016·Frontiers in Molecular Neuroscience·Georg von JonquieresMatthias Klugmann
Feb 13, 2018·Molecular Therapy : the Journal of the American Society of Gene Therapy·Juliette HordeauxJames M Wilson

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Citations

Mar 1, 2019·British Journal of Pharmacology·Lars M IttnerYazi D Ke
May 1, 2019·Diseases·Kenneth Lundstrom
Sep 29, 2020·Neural Regeneration Research·Gilad Levy, Boaz Barak
Nov 18, 2020·Metabolic Brain Disease·Dan LiuYong Diao
Mar 2, 2021·Molecular Therapy : the Journal of the American Society of Gene Therapy·Kyung-Won ParkJoanna L Jankowsky
Mar 20, 2021·Molecular Therapy. Methods & Clinical Development·Dan XiaoGuang-Xian Zhang
Jul 3, 2021·International Journal of Molecular Sciences·Ana Fajardo-SerranoJosé Luis Lanciego
May 6, 2020·Molecular Therapy. Methods & Clinical Development·Carola J MaturanaEsteban A Engel
Sep 14, 2021·Frontiers in Neurology·Dylan J FinneranMarcia N Gordon
Oct 12, 2021·Frontiers in Neuroscience·Jonathan M Fischell, Paul S Fishman

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Clinical Trials Mentioned

NCT02122952

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