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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 2

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Lentivector-mediated restoration of SMN protein expression in vitro. (A)...
Lentivector-mediated restoration of SMN protein expression in vitro. (A) Schematic representation of Lentivector encoding for human SMN gene. CMV, cytomegalovirus; cPPT, central polypurine tract; ΔΔ env, double-deleted envelope leaving only rev response element; WPRE, Woodchuck hepatitis virus posttranscriptional regulation element; SIN, self-inactivating; LTR, long-terminal repeat. (B) Lentivector-mediated expression of SMN in fibroblasts from type I SMA patients. Lentivector-SMN restores SMN expression in gems (arrows). No restoration of gems was observed in fibroblasts incubated with lentivector-LacZ (C). Expression of SMN in human fibroblasts (green) (D) colocalizes with the red immunofluorescence of gemin2 (E), producing yellow staining (F). Arrow indicates colocalization of SMN with gemin2 in gems. Lentivector-LacZ–treated fibroblasts stained with SMN Abs (G) and gemin2 (H). (I) Merged image from G and H. (J) Gem counts in lentivector-SMN–treated and control fibroblast cells. (K) Immunoblot confirming lentivector-mediated SMN expression in human fibroblasts using Abs against SMN. Scale bars: 50 μm (B and C), 100 μm (D–F), 200 μm (G–I).

Copyright © 2022 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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