Systemic Antisense Injections Rescue Severe SMA Mice

Treatment of a mouse model of severe spinal muscular atrophy (SMA) with an antisense oligonucleotide results in greater and longer-lasting benefit when given systemically than when given only to the central nervous system, new research shows.

The findings imply that strategies to increase levels of the SMN protein, which is deficient in SMA, have more benefit if given in a way that reaches the entire body (systemically) as opposed to just the brain and spinal fluid; and that SMA is a disease not only of the central nervous system but of other tissues, such as the liver and muscles.

Systemic delivery of the antisense compound ASO-10-27 resulted in a median survival time for treated mice in the highest dosage group that was about 25 times the median survival time for untreated animals (248 days compared to 10 days). By contrast, when the drug was delivered only to the central nervous system, the median survival time was only 1.6 times that of untreated animals (16 days compared to 10 days).

Scientists at Cold Spring Harbor (N.Y.) Laboratory and Isis Pharmaceuticals in Carlsbad, Calif., supported in part by MDA, reported the findings Oct. 6, 2011, in the journal Nature. MDA research grantee Adrian Krainer, a professor at Cold Spring Harbor Laboratory, coordinated the study team.

Systemic ASO injections had marked benefit for survival and function

The new findings confirm an earlier study, published in March 2011, in which a team that included Krainer showed there was significant benefit to injecting an antisense oligonucleotide known as ASO-10-27 directly into the brain and spinal fluid of newborn SMA mice with a severe SMA-like disease.

Antisense oligonucleotides are synthetic molecules that can change RNA splicing, thereby changing the final genetic instructions for proteins. In SMA, antisense oligonucleotides can change the way cells process the RNA from a gene called SMN2 so that full-length, functional SMN protein can be made from this gene. Full-length SMN (“survival of motor neuron”) protein is deficient in SMA.

In the earlier mouse study — in which ASO was delivered only to the central nervous system (brain and spinal cord) — the investigators found that after 16 days, the mice that received ASO-10-27 had spinal cord SMN protein levels that were four to six times higher than those in mice treated with a molecule that didn't alter SMN2 RNA splicing. The ASO-treated mice had more nerve cells in their spinal cords, developed bigger and more structurally sound muscles, had greater strength and lived longer than similar mice that didn't receive the treatment.

In this latest study, Krainer’s team and collaborators compared the life span and functional abilities of a number of severe SMA mouse groups that varied by dosage, timing of administration and route of administration (subcutaneous versus central nervous system) of the antisense compound ASO-10-27. Mice that received the highest dosage of the compound under the skin (subcutaneously) showed a median survival time significantly longer than groups receiving the drug only in the brain and spinal fluid, and 25 times greater than groups that received no treatment.

The timing of the ASO therapy proved to be important. In general, higher doses and earlier treatment were better than lower doses and later treatment. Most of the mice that received subcutaneous doses of the ASO within the first few days of life, with or without brain injections of the ASO, showed no overt signs of motor dysfunction.

A surprising finding was that SMA mice had greatly reduced levels of a circulating hormone called insulin-like growth factor 1 (IGF1), and subcutaneous ASO treatment restored IGF1 to normal levels, suggesting a positive effect of this treatment on liver function, since that’s where IGF1 is made.

Other data showed the ASO, when systemically delivered, also may have had positive effects on the spinal cord, brain, heart, kidneys and skeletal muscles.

Meaning for people with SMA

“It remains to be seen to what extent some of these findings in mice will hold for SMA patients,” Krainer said.

Further laboratory testing, which is being completed, is required before antisense oligonucleotides can be tested in humans.

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