CNS-targeted gene therapy improves survival and motor function in a mouse model of spinal muscular atrophy
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
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
View: Text | PDF
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

×

Figure 3

The myofiber cross-section area was increased with AAV8-hSMN treatment.

Options: View larger image (or click on image) Download as PowerPoint
The myofiber cross-section area was increased with AAV8-hSMN treatment. ...
Stacked graphs of the quadriceps, gastrocnemius, and intercostal muscles from 16 days (first row) and 58–66 days (second row) showed that the relative distribution of myofiber sizes was similar between the AAV8-hSMN–treated SMA mice and the untreated WT controls (A). Furthermore, the number of myofibers with a cross-section area of less than 100 μm2 was significantly reduced with AAV8-hSMN treatment (A). The overall mean of the myofiber cross-section area was higher with treatment compared with untreated SMA at 16 days (B). In addition, at 58–66 days, the average myofiber size in treated SMA mice approached WT levels, particularly in the gastrocnemius and intercostal muscles (B). SMA (n = 8 at 16 days); AAV (n = 8 at 16 days; n = 5 at 58–66 days); WT (n = 8 at 16 days; n = 5 at 58–66 days). Values represent the mean ± SEM. Statistical comparisons were performed with 1-way ANOVA and Bonferroni’s multiple post hoc tests at 16 days (A and B) and with unpaired 2-tailed Student’s t tests at 58–66 days (B). *P < 0.05; ***P < 0.001.