The predominant therapeutic strategy for treating SMA has focused on using what's already there in the genome. Take the SMN2 gene and make it work better, the reasoning goes. But another tactic involves putting back what's missing. The SMN2 gene doesn't work all that well anyway. Why not re-introduce fully functioning copies of SMN1 instead?

That's the approach being pursued by Brian Kaspar and his colleagues at the Nationwide Children's Hospital in Columbus, Ohio. “We're putting back exactly the target that one needs,” Kaspar says. Using an adeno-associated virus as a vector, Kaspar's group has successfully introduced extra copies of the sequence for the human SMN protein into mouse models of SMA. Not only did this extend the animals' lifespans from a matter of weeks to months and sometimes years, but it also restored motor function to near-normal levels (Nat. Biotechnol. 28, 271–274, 2010).

“Gene delivery studies have demonstrated some of the most remarkable survival spans,” Kaspar says. Similar preclinical results with comparable gene therapy products have also been reported by scientists at Genzyme, a Massachusetts-based subsidiary of the French drug giant Sanofi, and at Généthon, a nonprofit organization funded by the French Muscular Dystrophy Association (J. Clin. Invest. 120, 1253–1264, 2010; Hum. Mol. Genet. 20, 681–693, 2011).

Deliver the goods: Injection of the Ohio group's gene therapy construct results in gene expression (green) within dorsal root ganglia and motor neurons (red) in the spinal cords of SMA mice. Credit: Nat. Biotechnol. 28, 271–274 (2010).

With an eye to the clinic, Kaspar and his colleagues have also administered their viral construct to newborns from two larger animal species: pigs and cynomulgus macaque monkeys. The researchers showed that both blood- and brain-targeted injections led to successful viral uptake, with the introduced gene being expressed throughout the central nervous systems of these young animals with few adverse effects (Mol. Ther. 19, 1971–1980, 2011).

Now the Ohio team is working on generating the toxicology and pharmacokinetic data necessary for a full regulatory application. Led by Jerry Mendell, director of the Center for Gene Therapy at Nationwide Children's Hospital, the researchers intend to start clinical trials involving infants with type I SMA within the next year. “We think we have a very convincing argument,” says Mendell, “and we'll have good safety data that we'll be able to move into a clinical trial in the zero- to six-month-old children.”