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αCAR IGF-1 vector targeting of motor neurons ameliorates disease progression in ALS mice

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Title: αCAR IGF-1 vector targeting of motor neurons ameliorates disease progression in ALS mice
Author(s): Eleftheriadou, I
Manolaras, I
Irvine, EE
Dieringer, M
Trabalza, A
Mazarakis, ND
Item Type: Journal Article
Abstract: Objective: We have previously described the generation of coxsackievirus and adenovirus receptor (aCAR)-targeted vector, and shown that intramuscular delivery in mouse leg muscles resulted in specific retrograde transduction of lumbar-motor neurons (MNs). Here, we utilized the aCAR-targeted vector to investigate the in vivo neuroprotective effects of lentivirally expressed IGF-1 for inducing neuronal survival and ameliorating the neuropathology and behavioral phenotypes of the SOD1G93A mouse model of ALS. Methods: We produced cell factories of IGF-1 expressing lentiviral vectors (LVs) bearing aCAR or Vesicular Stomatitis Virus glycoprotein (VSV-G) on their surface so as to compare neuroprotection from MN transduced versus muscle transduced cells. We performed intramuscular delivery of either aCAR IGF-1 or VSVG IGF-1 LVs into key muscles of SOD1G93A mice prior to disease onset at day 28. Motor performance, coordination and gait analysis were assessed weekly. Results: We observed substantial therapeutic efficacy only with the aCAR IGF-1 LV pretreatment with up to 50% extension of survival compared to controls. aCAR IGF-1 LV-treated animals retained muscle tone and had better motor performance during their prolonged survival. Histological analysis of spinal cord samples at end-stage further confirmed that aCAR IGF-1 LV treatment delays disease onset by increasing MN survival compared with age-matched controls. Intrastriatal injection of aCAR eGFP LV in rats leads to transduction of neurons and glia locally and neurons in olfactory bulb distally. Interpretation: Our data are indicative of the efficacy of the aCAR IGF-1 LV in this model and support its candidacy for early noninvasive neuroprotective therapy in ALS.
Publication Date: 7-Sep-2016
Date of Acceptance: 28-Jun-2016
URI: http://hdl.handle.net/10044/1/40502
DOI: http://dx.doi.org/10.1002/acn3.335
ISSN: 2328-9503
Publisher: Wiley
Start Page: 752
End Page: 768
Journal / Book Title: Annals of Clinical and Translational Neurology
Volume: 3
Issue: 10
Copyright Statement: This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
Sponsor/Funder: Commission of the European Communities
Commission of the European Communities
Funder's Grant Number: Agreement no 233147
620253
Publication Status: Published
Appears in Collections:Department of Medicine
Faculty of Medicine



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