An oligonucleotide designed to tamp down an enzyme that causes amyotrophic lateral sclerosis seems safe, as reported in the May Lancet Neurology. The Phase 1 clinical trial results, covered by Alzforum in December at the International Symposium on ALS/MND (see ARF related news story), represent an accomplishment for the antisense RNA therapy as well as the delivery method. Scientists infused the antisense oligonucleotides into the cerebrospinal fluid because the compounds fail to cross the blood-brain barrier (see ARF related news story). This treatment, known as SOD1Rx, suppresses all versions of superoxide dismutase 1 (SOD1), which is mutated in about 2 percent of people with ALS. Toxic aggregates of the protein have also been reported in sporadic cases of the disease (see ARF related news story).

“The safety profile was great,” said first author Timothy Miller of Washington University in St. Louis, Missouri, who led the study with senior author Merit Cudkowicz of Massachusetts General Hospital in Boston. Twenty-one participants, all SOD1 mutation carriers, tolerated single intrathecal infusions of SOD1Rx or placebo. The main side effects were pain and headache, likely due to the lumbar puncture rather than the drug itself. In addition, the oligonucleotide concentration in participants’ cerebrospinal fluid (CSF) increased after treatment and was then quickly cleared, consistent with predictions based on studies of monkeys.

The researchers had no expectation that their treatment, provided at low doses for a short time, would modify SOD1 levels. They did analyze SOD1 concentrations in the CSF but observed no change. The team also examined SOD1 levels in the spinal cord of one trial participant who died of ALS a few months after the infusion. Compared to other tissue samples from people with the disease, his SOD1 levels were on the low end of the normal range. In addition, some of the SOD1Rx was detectable in that person’s spinal cord. “This supports the idea that the oligos are long-lived in people,” Miller said.

Antisense therapies have been a long time in coming. SOD1Rx maker Isis Pharmaceuticals of Carlsbad, California, obtained U.S. regulatory approval in January of this year to market a different oligonucleotide, Kynamro®, for an inherited cholesterol disorder. Kynamro marks the first antisense drug approved for systemic treatment. Another Isis compound, fomivirsen, was approved in 1998 for injection into the eye. It treated eye infections associated with AIDS, but was discontinued in 2004 because it was unprofitable.

Part of Isis’ success stems from chemically modifying oligonucleotides to make them last longer in the body and bind more tightly to their target RNAs. SOD1Rx, like Kynamro, includes 2’-O-methoxyethyl sugars on its backbone. This modification typifies Isis’ second generation of oligonucleotide chemistry, but the company has developed other options. For SOD1 antisense, they plan to make it more potent before starting further safety trials, probably with higher doses and longer treatment times. Researchers are also considering antisense treatment for another genetic form of ALS caused by expansions in the C9ORF72 gene (see ARF related news story).—Amber Dance


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News Citations

  1. Chicago—ALS Protein SOD1 Painted as Disease Template
  2. Cut to the Chase: Therapies Go Directly to Central Nervous System
  3. Research Brief: SOD1 in Sporadic ALS Suggests Common Pathway
  4. Chicago—RNA Inclusions Offer Therapeutic Target in ALS

External Citations

  1. Phase 1 clinical trial

Further Reading


  1. . SOD1 in Cerebral Spinal Fluid as a Pharmacodynamic Marker for Antisense Oligonucleotide Therapy. Arch Neurol. 2012 Nov 12;:1-7. PubMed.
  2. . Antisense makes sense for amyotrophic lateral sclerosis. Lancet Neurol. 2013 May;12(5):416-7. PubMed.
  3. . Antisense oligonucleotide therapy for neurodegenerative disease. J Clin Invest. 2006 Aug;116(8):2290-6. PubMed.

Primary Papers

  1. . An antisense oligonucleotide against SOD1 delivered intrathecally for patients with SOD1 familial amyotrophic lateral sclerosis: a phase 1, randomised, first-in-man study. Lancet Neurol. 2013 May;12(5):435-42. Epub 2013 Mar 29 PubMed.