CNS-targeted gene therapy improves survival and motor function in a mouse model of spinal muscular atrophy
Marco A. Passini, … , Lamya S. Shihabuddin, Seng H. Cheng
Marco A. Passini, … , Lamya S. Shihabuddin, Seng H. Cheng
Published March 15, 2010
Citation Information: J Clin Invest. 2010;120(4):1253-1264. https://doi.org/10.1172/JCI41615.
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Research Article Neuroscience

CNS-targeted gene therapy improves survival and motor function in a mouse model of spinal muscular atrophy

Abstract

Spinal muscular atrophy (SMA) is a neuromuscular disease caused by a deficiency of survival motor neuron (SMN) due to mutations in the SMN1 gene. In this study, an adeno-associated virus (AAV) vector expressing human SMN (AAV8-hSMN) was injected at birth into the CNS of mice modeling SMA. Western blot analysis showed that these injections resulted in widespread expression of SMN throughout the spinal cord, and this translated into robust improvement in skeletal muscle physiology, including increased myofiber size and improved neuromuscular junction architecture. Treated mice also displayed substantial improvements on behavioral tests of muscle strength, coordination, and locomotion, indicating that the neuromuscular junction was functional. Treatment with AAV8-hSMN increased the median life span of mice with SMA-like disease to 50 days compared with 15 days for untreated controls. Moreover, injecting mice with SMA-like disease with a human SMN–expressing self-complementary AAV vector — a vector that leads to earlier onset of gene expression compared with standard AAV vectors — led to improved efficacy of gene therapy, including a substantial extension in median survival to 157 days. These data indicate that CNS-directed, AAV-mediated SMN augmentation is highly efficacious in addressing both neuronal and muscular pathologies in a severe mouse model of SMA.

Authors

Marco A. Passini, Jie Bu, Eric M. Roskelley, Amy M. Richards, S. Pablo Sardi, Catherine R. O’Riordan, Katherine W. Klinger, Lamya S. Shihabuddin, Seng H. Cheng

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Figure 8

scAAV8-hSMN expression increased motor neuron counts and improved the NMJ in SMA mice.

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scAAV8-hSMN expression increased motor neuron counts and improved the NM...
Shown is the percentage of mChAT immunopositive cells that colocalized with hSMN expression in the thoracic-lumbar region at 16 days after injection (A). Shown are the average numbers of mChAT immunopositive cells in the lumbar (B), thoracic (C), and cervical (D) segments and the average percentages of collapsed NMJs in the quadriceps (E) and intercostal (F) muscles at 16, 58–66, and 214–269 days. As a reference for panels E and F, 75%–90% of NMJ in the quadriceps and intercostal muscles of untreated SMA mice contained an aberrant collapsed structure at 16 days (see Figure 4F). SMA (n = 8 at 16 days), AAV, AAV8-hSMN (n = 8 at 16 days; n = 5 at 58–66 days); scAAV (n = 5 at each time point); WT (n = 8 at 16 days; n = 5 each at 58–66 and 216–269 days). Data represent the mean ± SEM. Statistical comparisons were performed with 1-way ANOVA and Bonferroni’s multiple post hoc tests at 16 days (B–F). The unpaired 2-tailed Student’s t tests compared (a) the 2 vectors to each other at 16 days (A) and 58–66 days (B–D); (b) the relative number of ChAT cells in the 58- to 66-day and 214- to 269-day groups with scAAV8-hSMN treatment (B–D); (c) the relative number of abnormal NMJs between the age-matched untreated WT and scAAV8-hSMN–treated SMA mice at 214–269 days (E and F). *P < 0.05; **P < 0.01; ***P < 0.001.