Lentiviral vectors mediate nonimmunosuppressive rapamycin analog-induced production of secreted therapeutic factors in the brain: regulation at the level of transcription and exocytosis

Human Gene Therapy
Roland VogelJacques Mallet

Abstract

Gene transfer may become a powerful clinical tool for the delivery of secreted therapeutic polypeptides, provided that the in situ production of these peptides can be tightly regulated by the administration of a small inducer molecule. Particularly efficient control may be achieved by simultaneously using two regulation systems that interfere with the biosynthesis of the therapeutic factor at two different levels. Therefore, we have developed a set of two lentiviral vectors containing two regulation systems. These systems are induced by nonimmunosuppressive derivatives of rapamycin ("rapalogs") and allow simultaneous control of expression and of exocytosis of secreted therapeutic polypeptides. The set of vectors was used to produce green fluorescent protein (GFP) and glial cell line-derived neurotrophic factor (GDNF); GFP served as a model factor to demonstrate expression and entry into the exocytotic pathway in transduced cells. The constructs allowed robust in vitro expression and secretion of the polypeptides in the presence of rapalog AP21967. Withdrawal of the inducer resulted in efficient downregulation. In vivo, tightly regulated production of GFP and GDNF was observed after injection of the constructs into the striata o...Continue Reading

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Citations

Jun 29, 2010·Nature Biotechnology·Andrei V KarginovKlaus M Hahn
Jan 25, 2012·Neurology Research International·Jerusha Naidoo, Deborah Young
Dec 21, 2013·Cancer Immunology, Immunotherapy : CII·Joanne Y H LimEdith M Lord
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Feb 26, 2016·Molecular Metabolism·Marion BenazraPhilippe Ravassard
Jul 18, 2019·Frontiers in Pharmacology·Selene IngusciMichele Simonato

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