VEGF delivery with retrogradely transported lentivector prolongs survival in a mouse ALS model.
Amyotrophic lateral sclerosis (ALS) causes adult-onset, progressive motor neuron degeneration in the brain and spinal cord, resulting in paralysis and death three to five years after onset in most patients. ALS is still incurable, in part because its complex aetiology remains insufficiently understood. Recent reports have indicated that reduced levels of vascular endothelial growth factor (VEGF), which is essential in angiogenesis and has also been implicated in neuroprotection, predispose mice and humans to ALS. However, the therapeutic potential of VEGF for the treatment of ALS has not previously been assessed. Here we report that a single injection of a VEGF-expressing lentiviral vector into various muscles delayed onset and slowed progression of ALS in mice engineered to overexpress the gene coding for the mutated G93A form of the superoxide dismutase-1 (SOD1(G93A)) (refs 7-10), even when treatment was only initiated at the onset of paralysis. VEGF treatment increased the life expectancy of ALS mice by 30 per cent without causing toxic side effects, thereby achieving one of the most effective therapies reported in the field so far.
Azzouz
Mimoun
M
Oxford BioMedica plc, The Oxford Science Park, Medawar Centre, Oxford OX4 4GA, UK. m.azzouz@oxfordbiomedica.co.uk
Ralph
G Scott
GS
Storkebaum
Erik
E
Walmsley
Lucy E
LE
Mitrophanous
Kyriacos A
KA
Kingsman
Susan M
SM
Carmeliet
Peter
P
Mazarakis
Nicholas D
ND
D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D000818:Animals; D001370:Axonal Transport; D001933:Brain Stem / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D006801:Humans; D004860:Infectious Anemia Virus, Equine / Q000235:genetics*; D007273:Injections, Intramuscular; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology; D017354:Point Mutation / Q000235:genetics; D013116:Spinal Cord / Q000473:pathology; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D015996:Survival Rate; D013997:Time Factors; D019076:Transgenes / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000009:adverse effects / Q000235:genetics* / Q000378:metabolism / Q000627:therapeutic use*
C000606290:SOD1 protein, human; D042461:Vascular Endothelial Growth Factor A; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1