VEGF delivery with retrogradely transported lentivector prolongs survival in a mouse ALS model

• Published in: Nature Vol. 429; no. 6990; pp. 413 - 417
• Main Authors: Azzouz, Mimoun, Mazarakis, Nicholas D, Ralph, G. Scott, Storkebaum, Erik, Walmsley, Lucy E, Mitrophanous, Kyriacos A, Kingsman, Susan M, Carmeliet, Peter
• Format: Journal Article
• Language: English
• Published: London Nature Publishing 27.05.2004; Nature Publishing Group
• Subjects: Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - genetics; Amyotrophic Lateral Sclerosis - pathology; Amyotrophic Lateral Sclerosis - therapy; Animals; Axonal Transport; Biological and medical sciences; Brain Stem - pathology; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Disease Models, Animal; Disease Progression; Gene Expression; Genes; Genetic Therapy - methods; Genetic Vectors - administration & dosage; Genetic Vectors - genetics; Humans; Infectious Anemia Virus, Equine - genetics; Injections, Intramuscular; Lentivirus; Life expectancy; Medical sciences; Medical treatment; Mice; Mice, Transgenic; Motor Neurons - metabolism; Motor Neurons - pathology; Muscles; Neurology; Point Mutation - genetics; Spinal Cord - pathology; Superoxide Dismutase - genetics; Superoxide Dismutase - metabolism; Superoxide Dismutase-1; Survival Rate; Time Factors; Transgenes - genetics; Vascular Endothelial Growth Factor A - adverse effects; Vascular Endothelial Growth Factor A - genetics; Vascular Endothelial Growth Factor A - metabolism; Vascular Endothelial Growth Factor A - therapeutic use; Nervous system diseases; Rodentia; Amyotrophic lateral sclerosis; Experimental study; Vertebrata; Chemotherapy; Mammalia; Vascular endothelium growth factor; Treatment; Mouse; Animal; Central nervous system disease; Degenerative disease; Spinal cord disease
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature02544

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 (SOD1G93A) (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.