A team of research scientists has found that mice with a disease resembling a severe form of spinal muscular atrophy (SMA) that were treated with a gene-modifying molecule produced more of a needed protein throughout their spinal cords; developed bigger, stronger muscles; and survived longer than expected.
Adrian Krainer at Cold Spring Harbor (N.Y.) Laboratory, with colleagues at Harvard Medical School in Boston, Isis Pharmaceuticals in Carlsbad, Calif., and Genzyme Corp., in Framingham, Mass., published the new findings March 2, 2011, in the journal Science Translational Medicine.
The study corroborates results from an earlier study that tested the same molecule and antisense oligonucleotide treatment in mice with a disease resembling a mild form of SMA. (See Antisense Treatment Restores Full-Length SMN in SMA Mice.)
MDA funded Krainer for the initial study; he noted that the current findings are "a direct extension of the work previously funded by MDA."
About the findings
SMA is caused by a flawed or missing SMN1 gene, which leads to insufficient production of SMN protein. (SMN stands for "survival of motor neurons.")
A nearly identical gene, SMN2, also is located on chromosome 5. Most of the time, protein-building procedures that involve “splicing”cause the instructions carried by the SMN2 gene to leave out a critical stretch of genetic code known as exon 7. The exclusion of exon 7 leads to shortened, unstable and nonfunctional SMN protein. (See SMA Research: The Curious Case of a Backup Gene.)
In this experiment, investigators treated newborn SMA mice with an antisense oligonucleotide molecule called ASO-10-27. It is one of a class of molecules designed to target genetic instructions at the RNA stage, which bridges the genetic instructions carried in DNA and the protein-building process inside cells.
The molecule was infused directly into the brains and spinal fluid of newborn research mice, where it coaxed cells to include exon 7. After 16 days, the investigators found four- to six-times higher levels of full-length SMN protein throughout the spinal cords of treated mice as compared with similar mice treated with a molecule that didn't alter SMN2 splicing.
The increase in SMN protein production in turn led to an increase in the size and strength of muscle fibers in the mice treated with ASO-10-27, as well as improved muscle performance and better coordination. The treated mice also exhibited increased levels of spinal cord motor neurons and more properly structured neuromuscular junctions (the place where muscle meets nerve).
Taking it one step further, the researchers also demonstrated that injecting ASO-10-27 into the spinal fluid of cynomolgus monkeys resulted in therapeutic levels of the oligonucleotide in primate spinal tissue.
Meaning for people with SMA
A number of different strategies currently are under investigation for SMA. (See In Focus: Spinal Muscular Atrophy.)
The ASO-10-27 antisense molecule appears particularly beneficial, allowing SMA-affected mice to make a significant amount of SMN protein, and ameliorating the symptoms of the disease. The molecule, like all other experimental therapies, will need to undergo extensive laboratory testing before it can be tested in humans.
Toxicology tests on the molecule still need to be completed in a nonhuman primate, Krainer said, "after which we certainly hope it will make it to human clinical trials."