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

Abstract

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 patients1. 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 neuroprotection2,3,4, predispose mice and humans to ALS5,6. 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.

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Figure 1: EIAV vector-mediated gene transfer in vitro and in vivo.
Figure 2: Effects of EIAV vector delivery of VEGF.
Figure 3: VEGF gene therapy protects spinal and brainstem motor neurons in SOD1G93A transgenic mice.
Figure 4: The effects of VEGF gene therapy five weeks after intramuscular injections of viral vectors.

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Acknowledgements

We thank H. Mehmet and A. Kingsman for critical review of the manuscript. SOD1G93A transgenic mice were a gift from P. Shaw. Oxford BioMedica supported this work.

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Correspondence to Mimoun Azzouz or Nicholas D. Mazarakis.

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Some authors in this paper hold shares at Oxford Biomedica (Ltd).

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EIAV-VEGF gene therapy in SOD1G93A mice induce minimal immune response (PPT 651 kb)

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Azzouz, M., Ralph, G., Storkebaum, E. et al. VEGF delivery with retrogradely transported lentivector prolongs survival in a mouse ALS model. Nature 429, 413–417 (2004). https://doi.org/10.1038/nature02544

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