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α CAR IGF‐1 vector targeting of motor neurons ameliorates disease progression in ALS mice

OBJECTIVE: We have previously described the generation of coxsackievirus and adenovirus receptor (α CAR)‐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 α CAR‐targeted vector...

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Autores principales: Eleftheriadou, Ioanna, Manolaras, Ioannis, Irvine, Elaine E., Dieringer, Michael, Trabalza, Antonio, Mazarakis, Nicholas D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5048386/
https://www.ncbi.nlm.nih.gov/pubmed/27752511
http://dx.doi.org/10.1002/acn3.335
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author Eleftheriadou, Ioanna
Manolaras, Ioannis
Irvine, Elaine E.
Dieringer, Michael
Trabalza, Antonio
Mazarakis, Nicholas D.
author_facet Eleftheriadou, Ioanna
Manolaras, Ioannis
Irvine, Elaine E.
Dieringer, Michael
Trabalza, Antonio
Mazarakis, Nicholas D.
author_sort Eleftheriadou, Ioanna
collection PubMed
description OBJECTIVE: We have previously described the generation of coxsackievirus and adenovirus receptor (α CAR)‐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 α CAR‐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 SOD1(G93A) mouse model of ALS. METHODS: We produced cell factories of IGF‐1 expressing lentiviral vectors (LVs) bearing α CAR 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 α CAR IGF‐1 or VSVG IGF‐1 LVs into key muscles of SOD1(G93A) 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 α CAR IGF‐1 LV pretreatment with up to 50% extension of survival compared to controls. α CAR 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 α CAR IGF‐1 LV treatment delays disease onset by increasing MN survival compared with age‐matched controls. Intrastriatal injection of α CAR 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 α CAR IGF‐1 LV in this model and support its candidacy for early noninvasive neuroprotective therapy in ALS.
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spelling pubmed-50483862016-10-17 α CAR IGF‐1 vector targeting of motor neurons ameliorates disease progression in ALS mice Eleftheriadou, Ioanna Manolaras, Ioannis Irvine, Elaine E. Dieringer, Michael Trabalza, Antonio Mazarakis, Nicholas D. Ann Clin Transl Neurol Research Articles OBJECTIVE: We have previously described the generation of coxsackievirus and adenovirus receptor (α CAR)‐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 α CAR‐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 SOD1(G93A) mouse model of ALS. METHODS: We produced cell factories of IGF‐1 expressing lentiviral vectors (LVs) bearing α CAR 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 α CAR IGF‐1 or VSVG IGF‐1 LVs into key muscles of SOD1(G93A) 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 α CAR IGF‐1 LV pretreatment with up to 50% extension of survival compared to controls. α CAR 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 α CAR IGF‐1 LV treatment delays disease onset by increasing MN survival compared with age‐matched controls. Intrastriatal injection of α CAR 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 α CAR IGF‐1 LV in this model and support its candidacy for early noninvasive neuroprotective therapy in ALS. John Wiley and Sons Inc. 2016-09-07 /pmc/articles/PMC5048386/ /pubmed/27752511 http://dx.doi.org/10.1002/acn3.335 Text en © 2016 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association. This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs (http://creativecommons.org/licenses/by-nc-nd/4.0/) 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.
spellingShingle Research Articles
Eleftheriadou, Ioanna
Manolaras, Ioannis
Irvine, Elaine E.
Dieringer, Michael
Trabalza, Antonio
Mazarakis, Nicholas D.
α CAR IGF‐1 vector targeting of motor neurons ameliorates disease progression in ALS mice
title α CAR IGF‐1 vector targeting of motor neurons ameliorates disease progression in ALS mice
title_full α CAR IGF‐1 vector targeting of motor neurons ameliorates disease progression in ALS mice
title_fullStr α CAR IGF‐1 vector targeting of motor neurons ameliorates disease progression in ALS mice
title_full_unstemmed α CAR IGF‐1 vector targeting of motor neurons ameliorates disease progression in ALS mice
title_short α CAR IGF‐1 vector targeting of motor neurons ameliorates disease progression in ALS mice
title_sort α car igf‐1 vector targeting of motor neurons ameliorates disease progression in als mice
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5048386/
https://www.ncbi.nlm.nih.gov/pubmed/27752511
http://dx.doi.org/10.1002/acn3.335
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