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Lentivector-mediated SMN replacement in a mouse model of spinal muscular atrophy
Mimoun Azzouz, … , Arthur H.M. Burghes, Nicholas D. Mazarakis
Mimoun Azzouz, … , Arthur H.M. Burghes, Nicholas D. Mazarakis
Published December 15, 2004
Citation Information: J Clin Invest. 2004;114(12):1726-1731. https://doi.org/10.1172/JCI22922.
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Article Genetics

Lentivector-mediated SMN replacement in a mouse model of spinal muscular atrophy

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Abstract

Spinal muscular atrophy (SMA) is a frequent recessive autosomal disorder. It is caused by mutations or deletion of the telomeric copy of the survival motor neuron (SMN) gene, leading to depletion in SMN protein levels. The treatment rationale for SMA is to halt or delay the degeneration of motor neurons, but to date there are no effective drug treatments for this disease. We have previously demonstrated that pseudotyping of the nonprimate equine infectious anemia virus (using the lentivector gene transfer system) with the glycoprotein of the Evelyn-Rokitnicki-Abelseth strain of the rabies virus confers retrograde axonal transport on these vectors. Here, we report that lentivector expressing human SMN was successfully used to restore SMN protein levels in SMA type 1 fibroblasts. Multiple single injections of a lentiviral vector expressing SMN in various muscles of SMA mice restored SMN to motor neurons, reduced motor neuron death, and increased the life expectancy by an average of 3 and 5 days (20% and 38%) compared with LacZ and untreated animals, respectively. Further extension of survival by SMN expression constructs will likely require a knowledge of when and/or where high levels of SMN are needed.

Authors

Mimoun Azzouz, Thanh Le, G. Scott Ralph, Lucy Walmsley, Umrao R. Monani, Debbie C.P. Lee, Fraser Wilkes, Kyriacos A. Mitrophanous, Susan M. Kingsman, Arthur H.M. Burghes, Nicholas D. Mazarakis

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Figure 1

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EIAV-based lentivector-mediated gene transfer in vivo. Transverse sectio...
EIAV-based lentivector-mediated gene transfer in vivo. Transverse sections of lumbar spinal cord (A), brain stem (B and C), and muscle (D) showing transduction of both muscle and MNs after injection of 30 μl rabies G pseudotyped lentivector-LacZ vector in the gastrocnemius (A) and facial muscles (B and C) of postnatal P2 FVB mice. (E) Cell counts of total transduced MNs in the lumbar spinal cord, facial nucleus, and motor trigeminal nucleus (MTN) after intramuscular injections of lentivector-LacZ into 2-day-old SMA mice. Data are means ± SEM. Expression of β-gal (green) (F) colocalizes with the immunofluorescence of CGRP (red) in spinal MNs, producing yellow staining (G). Scale bars: 400 μm (A and B), 200 μm (C and D), 100 μm (F and G).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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