Eleftheriadou, IIEleftheriadouManolaras, IIManolarasIrvine, EEIrvineMazarakis, NDNDMazarakis2016-11-182016-09-072016-11-182015-10-01Human Gene Therapy, 2015, 26 (10), pp.A14-A151043-0342http://hdl.handle.net/10044/1/42577Objective We have previously described the generation of coxsackievirus and adenovirus receptor (αCAR)-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 αCAR-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 αCAR 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 αCAR 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 αCAR IGF-1 LV pretreatment with up to 50% extension of survival compared to controls. αCAR 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 αCAR IGF-1 LV treatment delays disease onset by increasing MN survival compared with age-matched controls. Intrastriatal injection of αCAR 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 αCAR IGF-1 LV in this model and support its candidacy for early noninvasive neuroprotective therapy in ALS.© 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 License (https://creativecommons.org/licenses/by-nc-nd/4.0/), 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.Science & TechnologyLife Sciences & BiomedicineBiotechnology & Applied MicrobiologyGenetics & HeredityMedicine, Research & ExperimentalResearch & Experimental MedicineBiotechnology1004 Medical Biotechnology1103 Clinical SciencesJournal Articlehttps://www.dx.doi.org/10.1002/acn3.335Agreement no 233147