title: αCAR IGF-1 vector targeting of motor neurons ameliorates disease progression in ALS mice.
abstract: OBJECTIVE
  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 theαCAR-targeted vector to investigate the in vivo neuroprotective effects of lentivirally expressedIGF-1for inducing neuronal survival and ameliorating the neuropathology and behavioral phenotypes of the SOD1G93Amouse model of ALS.
  
  
  METHODS
  We produced cell factories ofIGF-1expressing lentiviral vectors (LVs) bearingαCAR 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 eitherαCARIGF-1or VSVGIGF-1LVs into key muscles of SOD1G93Amice prior to disease onset at day 28. Motor performance, coordination and gait analysis were assessed weekly.
  
  
  RESULTS
  We observed substantial therapeutic efficacy only with theαCARIGF-1LV pretreatment with up to 50% extension of survival compared to controls.αCARIGF-1LV-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 thatαCARIGF-1LV treatment delays disease onset by increasing MN survival compared with age-matched controls. Intrastriatal injection ofαCAReGFPLV in rats leads to transduction of neurons and glia locally and neurons in olfactory bulb distally.
  
  
  CONCLUSIONS
  Our data are indicative of the efficacy of theαCARIGF-1LV in this model and support its candidacy for early noninvasive neuroprotective therapy in ALS.
authors.affiliation: Gene Therapy Centre for Neuroinflammation & Neurodegeneration Division of Brain Sciences Faculty of Medicine Imperial College London Hammersmith Hospital Campus London W12 0NN UK.
authors.forename: Ioanna
authors.initials: I
authors.lastname: Eleftheriadou
authors.affiliation: Gene Therapy Centre for Neuroinflammation & Neurodegeneration Division of Brain Sciences Faculty of Medicine Imperial College London Hammersmith Hospital Campus London W12 0NN UK.
authors.forename: Ioannis
authors.initials: I
authors.lastname: Manolaras
authors.affiliation: Metabolic Signaling Group MRC Clinical Sciences Centre Imperial College London Hammersmith Hospital Campus London W12 0NN UK.
authors.forename: Elaine E
authors.initials: EE
authors.lastname: Irvine
authors.affiliation: Gene Therapy Centre for Neuroinflammation & Neurodegeneration Division of Brain Sciences Faculty of Medicine Imperial College London Hammersmith Hospital Campus London W12 0NN UK.
authors.forename: Michael
authors.initials: M
authors.lastname: Dieringer
authors.affiliation: Gene Therapy Centre for Neuroinflammation & Neurodegeneration Division of Brain Sciences Faculty of Medicine Imperial College London Hammersmith Hospital Campus London W12 0NN UK.
authors.forename: Antonio
authors.initials: A
authors.lastname: Trabalza
authors.affiliation: Gene Therapy Centre for Neuroinflammation & Neurodegeneration Division of Brain Sciences Faculty of Medicine Imperial College London Hammersmith Hospital Campus London W12 0NN UK.
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Mazarakis