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

An adeno-associated virus vector expressing the survival motor neuron protein rescues mice with spinal muscular atrophy. 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. Spinal muscular atrophy is one of the most common genetic causes of death in childhood, and there is currently no effective treatment. The disease is caused by mutations in the survival motor neuron gene. Gene therapy aimed at restoring the protein encoded by this gene is a rational therapeutic approach to ameliorate the disease phenotype. We previously reported that intramuscular delivery of a lentiviral vector expressing survival motor neuron increased the life expectancy of transgenic mice with spinal muscular atrophy. The marginal efficacy of this therapeutic approach, however, prompted us to explore different strategies for gene therapy delivery to motor neurons to achieve a more clinically relevant effect. Here, we report that a single injection of self-complementary adeno-associated virus serotype 9 expressing green fluorescent protein or of a codon-optimized version of the survival motor neuron protein into the facial vein 1 day after birth in mice carrying a defective survival motor neuron gene led to widespread gene transfer. Furthermore, this gene therapy resulted in a substantial extension of life span in these animals. These data demonstrate a significant increase in survival in a mouse model of spinal muscular atrophy and provide evidence for effective therapy.