Recent spinal muscular atrophy (SMA) research includes findings that shed additional light on the optimal "window of opportunity" for treatment and point toward a potential candidate for therapeutic development.
A research team based in the United States has shed light on the role of SMN protein in the development of motor neurons and on survival in zebrafish with a disease mimicking human SMA. (A deficiency of SMN protein is the underlying cause of most SMA.)
Christine E. Beattie at Ohio State University in Columbus, and colleagues, confirmed in a zebrafish model of SMA that low levels of SMN protein during embryonic development:
In studying the development of motor function, the investigators demonstrated that replacing SMN protein at the onset of motor neuron differentiation (maturation), before the development of axons, could normalize motor neuron development and fully rescue motor function in the fish. Replacement of the protein at later stages still had some effect, but to a lesser degree.
In studying survival time, the team similarly found that they could increase survival in the fish by adding SMN during embryonic development when the nervous system and other organ systems are developing.
Although the “window of opportunity” during which SMN impacted survival occurred later in embryonic development than the window for normalizing motor neuron growth, the researchers found that adding SMN during early embryonic stages had a more dramatic positive effect on survival than adding it at later stages.
Earlier treatment may be more effective, but later treatment isn’t without benefit. The researchers note that because the data demonstrate that optimal motor neuron development is not required for survival, the therapeutic window for treatment is widened.
The findings may inform scientists’ efforts to develop the most effective therapies for SMA.
The research team published its findings March 3, 2013, in Human Molecular Genetics. Read the full report, for a fee: Temporal Requirement for SMN in Motoneuron Development.
Treatment with an existing drug called celecoxib increased levels of SMN protein — the protein that’s deficient in SMA — improved motor function and increased survival time in a mouse model of SMA, reports a research team based at institutions in Canada and Spain.
Celecoxib (brand name Celebrex, or Celebra) is a prescription-strength nonsteroidal anti-inflammatory (NSAID) drug marketed by Pfizer.
Alex MacKenzie at the University of Ottowa (Canada), and colleagues, demonstrated that a low dose of celecoxib increased SMN protein levels in both human and mouse nerve cell cultures, as well as in fibroblasts taken from people with SMA.
In tests in mice with an SMA-like disease, those treated with celecoxib for five days, beginning at birth, showed a significant and sustained increase in SMN protein levels in the brain and spinal cord, compared to mice that received a placebo. A small increase in SMN protein levels was seen in the heart; none occurred in skeletal muscle.
In addition, mice treated with celecoxib showed a dramatic improvement in motor function and a significant extension of survival (an average of 18 days) when compared with placebo-treated SMA mice (an average of 13 days).
The investigators suggest that celecoxib works by activating the P38 pathway, which has been implicated in regulation of the gene for the SMN protein.
Celecoxib is approved by the U.S. Food and Drug Administration (FDA) to treat several conditions, including osteoarthritis and rheumatoid arthritis. Serious side effects associated with the drug include increased risk of heart attack and stroke, high blood pressure, stomach and intestine problems such as ulcers and bleeding, and allergic reactions.
Note: Although celecoxib is available by prescription in the United States, its effects on people with SMA are unknown. Individuals are strongly advised not to use celecoxib to treat SMA until it has been proven safe and effective in people with the disease.
The research team published its findings May 10, 2013, in Human Molecular Genetics. Read the full report, for a fee: Celecoxib Increases SMN and Survival in a Severe Spinal Muscular Atrophy Mouse Model Via P38 Pathway Activation.