A mouse model of adult-onset spinal muscular atrophy, developed with MDA support, suggests a treatment now in testing for early-onset disease may benefit adults
Scientists supported in part by MDA have developed a new research mouse model with a disorder that mimics the adult-onset form of chromosome 5-related spinal muscular atrophy (SMA), a genetic disease of spinal nerve cells that control muscle activity (motor neurons).
Previously developed SMA mouse models have helped scientists study the more severe and intermediate forms of the disease, in which onset can occur in newborns, infants or older children.
The researchers say the new mouse is the first to exhibit disease-related symptoms similar to those experienced by people who develop the disease only after they've reached adulthood. Like people with adult-onset SMA, the newly developed adult-onset SMA mice have gait abnormalities and reduced strength that begin in adulthood (about 2 months of age for the mouse).
This type of mouse model for a human disease — or, in this case, a specific form of the disease — increases understanding of the disorder and enables researchers to screen potential treatments before trying them in humans.
Former MDA grantee Adrian Krainer at Cold Spring Harbor Laboratory (CSHL) in Cold Spring Harbor, N.Y., led the research team. MDA supported Kentaro Sahashi, previously at CSHL and now at Nagoya University Graduate School of Medicine in Japan, for his work on this project.
The team published its findings online Sept. 9, 2013, in EMBO Molecular Medicine. Read the full report, for free: Pathological Impact of SMN2 Mis-Splicing in Adult SMA Mice.
SMN protein is the key
The underlying cause of chromosome 5-related SMA is the deficiency of a protein, crucial to the proper functioning of motor neurons, called SMN (for survival motor neuron).
Normally, cellular protein-building machinery constructs full-length, functional SMN protein using genetic instructions carried in the SMN1 gene — but in SMA this gene is flawed or missing. Instructions carried in a nearly identical neighboring gene, called SMN2, typically direct cells to produce the same SMN protein, but in much smaller amounts.
Generally, the more SMN protein that's produced, the milder the symptoms of the disease. This means that protein produced from the SMN2 genecan limit the impact of SMA; how much a person is helped depends on how many copies of the SMN2 gene are present.
Scientists understand why sufficient levels of SMN protein aren't usually produced with the SMN2 gene. The limited protein production is a result of the way SMN2 genetic instructions are processed.
"What we don't understand is how insufficient levels of the SMN protein in the period following development — i.e., adulthood — causes pathology [manifestations of disease] in different parts of the body," Krainer explains in a Sept. 9, 2013, CSHL press release. "That's why we set out to create a model in the adult mouse."
Adult-onset SMA mice showed key features of human disease
When SMN is diminished early in life, the motor nervous system does not develop normally.
Until now, the consequences of diminished SMN production at different time points have not been clear, but the newly developed adult-onset SMA mice are expected to help with understanding these consequences.
People with adult-onset SMA usually have at least four SMN2 gene copies and have normal or nearly normal motor function until adulthood. To replicate this situation in mice, the research team developed mice with four copies of the SMN2 gene but no copies of the mouse SMN gene; like people with adult-onset SMA, these mice showed minor abnormalities.
In humans with SMA, SMN protein production has been shown to diminish with age. To achieve this reduction in SMN production, the researchers used a drug to partially block the synthesis of normal-length SMN protein in the mice when they reached adulthood — 2 months of age.
These adult mice develop key features of adult-onset SMA, such as late-onset loss of motor function and strength.
A 'broad time window' for adult-onset SMA therapy
To test treatment avenues, the researchers treated the mice with an antisense oligonucleotide called ASO-10-27. This antisense compound also has been developed into an experimental SMA drug called ISIS-SMNRx.
ASO-10-27 (ISIS-SMNRx) increased SMN protein production and partially corrected the SMA-like defects in the mice. This same therapy also has been shown to ameliorate disease symptoms in several SMA mouse models that show earlier disease onset, and it currently is being tested in children and infants with SMA.
In comparison with untreated mice, the adult mice treated with ISIS-SMNRx had delayed onset of motor dysfunction, better strength, improved motor neuron survival and higher levels of a marker for the SMN protein. Although earlier treatment conferred more benefit, treatment administered later still had some effect.
The team says the study yielded encouraging findings that suggest:
Isis drug moving forward
ISIS-SMNRx is under development and testing by California-based biotechnology company Isis Pharmaceuticals. Its early-stage laboratory development was supported by MDA through a grant to Krainer, who says findings from the current study hold promise that the treatment also may work in adults with SMA.
"To the extent that our method models adult-onset SMA in mice, the fact that we can show therapeutic efficacy for ISIS-SMNRx implies that adult SMA patients might benefit from treatment with this drug," Krainer says, noting that in previous experiments conducted in other mouse models, the treatment was effective when the mice were treated soon after birth.
Currently, ISIS-SMNRx has been shown to be safe and well-tolerated in a phase 1 trial in which it was injected once into the spinal fluid of SMA-affected children. A trial to test the safety and tolerability of multiple doses of the drug in children with SMA is ongoing (but no longer recruiting participants), and a phase 2 clinical trial to test multiple doses of the drug in infants with SMA has opened in the United States and Canada.