Research ArticleSpinal Muscular Atrophy

Systemic Delivery of scAAV9 Expressing SMN Prolongs Survival in a Model of Spinal Muscular Atrophy

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Science Translational Medicine  09 Jun 2010:
Vol. 2, Issue 35, pp. 35ra42
DOI: 10.1126/scitranslmed.3000830

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Enough Protein to Reverse Spinal Muscular Atrophy

A common neuromuscular disease, spinal muscular atrophy (SMA) causes ever-worsening muscle weakness, usually in babies or young children, almost always resulting in early death. The culprit is a defective gene—survival motor neuron (SMN)—that must be inherited from both parents for the child to be affected. A second SMN gene is usually incorrectly spliced and so is nonfunctional. To treat this disease, researchers have set their sights on delivering a replacement SMN to the motor neurons. The hope has been that gene therapy methods could be used to generate enough normal SMN protein to restore neuronal innervation of muscles in the affected children. Valori et al. have now improved on previous attempts to implement such a treatment in mice with an SMN-like disease. Their new gene therapy vector makes enough functional SMN protein to improve the agility of the affected animals and markedly increase their survival.

To find gene therapy methods for SMA that work in animals before trying these treatments in humans, researchers had created mice with the disease. The mouse SMN gene was deleted (mice have only one copy) and replaced with the two human genes—the defective disease-causing form and its poorly spliced sibling. Valori et al. then treated these animals with a gene therapy vector that they had tested in fibroblasts. They coupled a fast, efficient virus (a modified self-complementary adeno-associated virus) to the coding sequence for the SMN protein, optimized for efficient codon usage. A single injection of this vector to new born mice with SMA improved their ability to move and perform physical tests. These mice, which usually die at 2 weeks of age, also showed markedly increased survival times. Subsequent immunohistochemistry showed that the introduced gene was expressed all over the body of the animals but particularly in the lumbar spinal cord, muscle, and liver.

These results bring us one step closer to a successful gene therapy treatment for patients with SMA. The vector used here produces large amounts of replacement SMN protein, a goal that had not been achieved with previous approaches. Another noteworthy feature of this vector is that it increases SMN expression in numerous cell types, not just motor neurons, which may be a clue that the critical defects in SMA may be located in more than one kind of cell.


  • * These authors contributed equally to this work.

  • Citation: C. F. Valori, K. Ning, M. Wyles, R. J. Mead, A. J. Grierson, P. J. Shaw, M. Azzouz, Systemic delivery of scAAV9 expressing SMN prolongs survival in a model of spinal muscular atrophy. Sci. Transl. Med. 2, 35ra42 (2010).

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