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.