The protein survival motor neuron (SMN) is missing in children with spinal muscular atrophy. They have an understudy gene—SMN2—but its RNA is misspliced and produces a stunted, useless protein. Scientists have now used simple swatches of nucleic acid to force cells to make the proper SMN2 RNA and protein. Injected into mice, these oligonucleotides alleviated symptoms for a short time and extended lifespan. Researchers at Isis Pharmaceuticals in Carlsbad, California, which is developing the technology, intend to start trials in children later this year. Isis collaborated with a team led by Marco Passini, at the Genzyme Corporation Science Center in Framingham, Massachusetts.

Spinal muscular atrophy (SMA) is caused by a deficiency in the protein survival motor neuron (SMN). SMN is encoded by two genes, SMN1 and SMN2, but SMN2 has a point mutation that results in defective splicing. Mutations in SMN1 result in SMN protein deficiency, but the scientists reasoned that SMN2 could step in if they could just fix the splicing issue.

Isis designed an antisense oligonucleotide to block an intronic splicing silencer sequence. These sequences normally recruit proteins that halt splicing. Quieting the silencer allows the spliceosome to create the correct SMN2 transcript and protein. The treatment has an advantage over splice-modifying small molecule drugs, Passini said, because it specifically targets one gene: “You have a very decreased probability of off-target effects.” Isis is pursuing the antisense technology for conditions ranging from ulcerative colitis to cancer to amyotrophic lateral sclerosis (see ARF related news story). Antisense oligonucleotide technology has been around for decades, but has, for the most part, disappointed in clinical trials. More recently, scientists have become intrigued with using these nucleotides as therapy for disease of missplicing (see review by Pérez et al., 2010) .

Injecting the oligonucleotide into the cerebral lateral ventricle of newborn SMA model mice resulted in a four- to sixfold increase in the number of full-length SMN2 transcripts, and more SMN protein in the spinal cord, compared to SMA mice that received a control oligonucleotide. The treatment boosted the number of motor neurons in the spinal cord, induced larger muscle fibers, and promoted healthier neuromuscular junctions. The treated mice were heavier than the untreated animals, righted themselves more quickly, and gripped objects more strongly, although they were still unhealthier than wild-type mice.

SMA mice normally live for fewer than three weeks, but some of the treated animals lasted for more than five. Ultimately, though, the mice that received the antisense oligonucleotide died suddenly. Passini suspects the oligonucleotide diluted over time. The researchers were only able to inject the treatment up until five days of age; they had trouble finding a way to deliver the oligonucleotide over the long term.

In people, regular infusions would be required, although Isis has not yet worked out the proper dosage schedule. In human trials, the doctors will also need a reliable method to deliver the oligonucleotides. Although there is no nonhuman primate model for SMA, the researchers used cynomolgus monkeys to test delivery. Via intrathecal infusion, they were able to achieve concentrations of the oligonucleotide into the spinal cord that they believe could prove therapeutically effective.

“This study is not only encouraging for the development of an antisense oligonucleotide-based therapy for SMA, but also opens doors for exploring this therapeutic approach in the treatment of other diseases,” wrote Michelle Hastings of the Rosalind Franklin University of Medicine and Science in North Chicago, Illinois, in an e-mail to ARF. Hastings was not involved in the study.—Amber Dance


  1. The work by Passini et al. reports the latest progress in development of antisense oligonucleotides (ASOs) as a therapy for spinal muscular atrophy (SMA). The report marks two important achievements in the aim to bring this potential therapeutic to the clinic. First, a single dose of ASOs can increase survival by more than 50 percent in a mouse model engineered to have a severe form of SMA. Second, the ASOs can be targeted to motor neurons in non-human primates.

    This study is not only encouraging for the development of an ASO-based therapy for SMA, but also opens doors for exploring this therapeutic approach in the treatment of other diseases. An important next step will be to assess the ability of the ASOs to act as a long-term treatment of the disease in mouse models as well as larger animal models of the disease as they become available.

    View all comments by Michelle Hastings

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News Citations

  1. Clinical Trials for ALS: Taking Stock of 2009, Looking to 2010

Paper Citations

  1. . Present and future of antisense therapy for splicing modulation in inherited metabolic disease. J Inherit Metab Dis. 2010 Aug;33(4):397-403. PubMed.

External Citations

  1. Isis Pharmaceuticals

Further Reading


  1. . Antisense correction of SMN2 splicing in the CNS rescues necrosis in a type III SMA mouse model. Genes Dev. 2010 Aug 1;24(15):1634-44. PubMed.
  2. . Bifunctional antisense oligonucleotides provide a trans-acting splicing enhancer that stimulates SMN2 gene expression in patient fibroblasts. Proc Natl Acad Sci U S A. 2003 Apr 1;100(7):4114-9. PubMed.

Primary Papers

  1. . Antisense oligonucleotides delivered to the mouse CNS ameliorate symptoms of severe spinal muscular atrophy. Sci Transl Med. 2011 Mar 2;3(72):72ra18. PubMed.