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 7

Comparison of AAV vector tropism in the lumbar spinal cord.

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Comparison of AAV vector tropism in the lumbar spinal cord. Human SMN im...
Human SMN immunostaining was performed on frozen tissue sections from untreated SMA (A and D), AAV8-hSMN–treated SMA (B, D, and F), and scAAV8-hSMN–treated SMA (C–E, and G) mice at 16 days (A–D, F, and G) and 157 days (E) after injection. A diffuse hSMN immunostaining pattern consistent with glial cell morphology was observed at 16 days with AAV8-hSMN (B and D). Doubling immunolabeling (yellow) of hSMN (red) and mGFAP (green) confirmed that a subset of the AAV8-hSMN–transduced cells were astrocytes (D). In contrast, scAAV8 treatment resulted in hSMN expression only in distinct cell bodies with neuronal morphology (C), which did not colocalize with GFAP (D). Double immunolabeling (yellow) of hSMN (red) and the motor neuron marker mChAT (green) confirmed that a subset of cells transduced by scAAV8-hSMN (E and G) and AAV8-hSMN (F) were motor neurons. hSMN expression (red) was also observed in the interneuronal cell layers of the spinal cord with both viral vectors, as exemplified by scAAV8-hSMN at 157 days (E). Scale bars: 100 microns (A–C); 200 microns (D and E).