Maximizing lentiviral vector gene transfer in the CNS
Authors: Sylvain Moser
Nicole Déglon
Maria Rey
Alexia Boizot
Ludiwine Aeby
Mélanie Sipion
Virginie Zimmer
Sara Regio
Morgane Humbel
Mergim Ramosaj
Journal: Gene Therapy (2021)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: Gene transfer; genetic diseases; therapeutic strategies; central nervous system; lentiviral vectors
Affiliations: Lausanne University Hospital (CHUV) and University of Lausanne, Department of Clinical Neurosciences (DNC), Laboratory of Neurotherapies and NeuroModulation, Lausanne, Switzerland., Lausanne University Hospital (CHUV) and University of Lausanne, Neuroscience Research Center (CRN), Laboratory of Cellular and Molecular Neurotherapies (LCMN), Lausanne, Switzerland., Lausanne University Hospital (CHUV) and University of Lausanne, Department of Clinical Neurosciences (DNC), Laboratory of Neurotherapies and NeuroModulation, Lausanne, Switzerland. ., Lausanne University Hospital (CHUV) and University of Lausanne, Neuroscience Research Center (CRN), Laboratory of Cellular and Molecular Neurotherapies (LCMN), Lausanne, Switzerland. ., Laboratory of Neurotherapies and Neuromodulation, Neuroscience reserach Center (CRN), Lausanne Univeristy Hospital (CHUV), Avenue de Beaumont, Pavillon 3, Lausanne, Switzerland. .

Abstract:  Gene transfer is a widely developed technique for studying and treating genetic diseases. However, the development of therapeutic strategies is challenging, due to the cellular and functional complexity of the central nervous system (CNS), its large size and restricted access. We explored two parameters for improving gene transfer efficacy and capacity for the selective targeting of subpopulations of cells with lentiviral vectors (LVs). We first developed a second-generation LV specifically targeting astrocytes for the efficient expression or silencing of genes of interest, and to better study the importance of cell subpopulations in neurological disorders. We then made use of the retrograde transport properties of a chimeric envelope to target brain circuits affected in CNS diseases and achieve a broad distribution. The combination of retrograde transport and specific tropism displayed by this LV provides opportunities for delivering therapeutic genes to specific cell populations and ensuring high levels of transduction in interconnected brain areas following local administration. This new LV and delivery strategy should be of greater therapeutic benefit and opens up new possibilities for the preclinical development of gene therapy for neurodegenerative diseases. 

Retracted: No

PubPeer comments:
 Supplementary Figure 2C and 2D: The lines on these charts are not described by the equations shown. Both have an intercept of around one, but they pass through the origin. I could (sort of) understand why the authors might choose to force the line through the origin (although I don t think that s the correct decision), either way, if an equation and a line are shown on a chart, they should match each other. ![file] , 
 No idea on the method used to fit the line. But the line on the right figure cannot be from OLS. , 
 There was indeed an error during the preparation of the two graphs, the equations and the points are correct, but there was a shift with the lines. We will prepare a corrected version. ,