Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Alerts
  • Advertising
  • Job board
  • Subscribe
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Author's Takes
  • Reviews
    • View all reviews ...
    • Aging (Jul 2022)
    • Next-Generation Sequencing in Medicine (Jun 2022)
    • New Therapeutic Targets in Cardiovascular Diseases (Mar 2022)
    • Immunometabolism (Jan 2022)
    • Circadian Rhythm (Oct 2021)
    • Gut-Brain Axis (Jul 2021)
    • Tumor Microenvironment (Mar 2021)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Commentaries
    • Concise Communication
    • Editorials
    • Viewpoint
    • Top read articles
  • Clinical Medicine
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Author's Takes
  • In-Press Preview
  • Commentaries
  • Concise Communication
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Alerts
  • Advertising
  • Job board
  • Subscribe
  • Contact
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.
View: Text | PDF
Article Genetics

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

  • Text
  • PDF
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

×

Figure 3

Options: View larger image (or click on image) Download as PowerPoint
Retrograde lentivector delivery of SMN at the onset of disease extends s...
Retrograde lentivector delivery of SMN at the onset of disease extends survival and delays the phenotype in SMA mice. (A) Weight measurements of animals treated with lentivector-SMN or lentivector-LacZ. (B) Survival analysis in SMA mice injected at 2 days of age with lentivector-LacZ or lentivector-SMN. Mortality was significantly delayed in mice treated with lentivector-SMN compared with the control LacZ group. (C) Image showing lentivector-mediated expression of SMN in spinal MN at the end stage of disease as monitored using Abs against the HA tag. Arrow indicates gems. (D) Double labeling using HA (green, arrow indicates gems) and CGRP Abs (red) in spinal sections. No HA staining was detected in LacZ-injected mice (E). (F and G) SMN expression in muscles from SMN and LacZ-treated mice, respectively. Arrows in F indicate lentivector-mediated SMN expression. (H) Western blot analysis of ventral spinal cord in LacZ, SMN, and WT animals. Scale bars: 50 μm (C–E), 100 μm (F and G).

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

Sign up for email alerts