In addition to muscle damage caused by the loss of motor neurons in the spinal cord, skeletal muscle degeneration inspinal muscular atrophy (SMA) also stems from low levels of the protein SMN in muscle fibers. Now a team of scientists from Germany and the United Kingdom reports that muscle damage caused by low SMN can be reversed with drugs.
The investigators showed that SMN protein levels are critical for the maintenance of skeletal muscle at a molecular level. This means that insufficient levels of the protein in people with SMA not only lead to muscle damage via motor-neuron death, but also through the disruption of regular muscle-cell maintenance activity.
Skeletal muscle damage due to disrupted maintenance is reversible via treatment with a class of drugs called HDAC inhibitors, the team found, noting that development of these drugs to specifically target SMN levels in skeletal muscle could lead to treatments for people with SMA.
Study data also showed changes in the activity levels of two proteins, VDAC2 and parvalbumin, in skeletal muscle in both mild and severe mouse models of SMA, as well as in people with the disease. This finding suggests that these proteins potentially may serve as biomarkers, biological markers of disease activity that are useful for assessing the effects of treatments in clinical trials.
The team published its findings online Aug. 12, 2011, in Human Molecular Genetics: Reversible molecular pathology of skeletal muscle in spinal muscular atrophy.
Impaired transport of the chemical signals that carry messages between motor neurons (nerve cells in the spinal cord) and the muscles they control appears to be at least one cause of the apparent muscle-nerve communication breakdown in SMA.
Axonal transport is a critical cellular process by which nerve cells send messages in the form of chemicals called neurotransmitters to other nerve cells or to muscle fibers.
In the motor system, neurotransmitters travel down long fibers called axons that extend from the motor neuron cell body to muscle fibers. Studies conducted in a mouse model of SMA showed that the delivery of nerve signals to muscles was disrupted before they could reach the nerve ending.
Investigators at the University of Missouri in Columbia published their results in the September issue of Acta Neuropathologica. (See: The spinal muscular atrophy mouse model, SMA delta7, displays altered axonal transport without global neurofilament alterations.)
Associate professor and study team member Michael Garcia suggested in a press release that the new findings might also advance understanding of other diseases involving motor neurons, such as amyotrophic lateral sclerosis (ALS).
Previous MDA-supported research has shown that in addition to the loss of motor neurons, abnormalities of nerve-to-muscle communication also are a feature of SMA and likely contribute to disease symptoms.
The identification of specific breaks in axonal transport may provide targets for the development of SMA therapies designed to prevent the breakdown of the nerve-muscle communication system.
The French pharmaceutical company Trophos announced Sept. 8, 2011, that it has completed patient enrollment for its 24-month, phase 2 efficacy trial of olesoxime (TRO19622) in SMA.
Efficacy results are expected in late 2013.
Trial participants are people with SMA, ages 3 years to 25 years, who have lost the ability to walk. Each will be randomly assigned to a treatment group or control group. Those in the treatment group will receive 10 milligrams per kilogram of body weight per day of olesoxime; those in the control group will receive a placebo.
The study is being conducted in approximately 20 centers in Belgium, France, Germany, Italy, the Netherlands, Poland and the United Kingdom.
In preclinical studies, olesoxime has been shown to promote the function and survival of neurons and other cell types via interaction with the cellular energy factories called mitochondria.
Trophos has been granted orphan drug designation for olesoxime for the treatment of SMA and ALS by the U.S. Food and Drug Administration (FDA). (Orphan drug status provides financial incentives for the development of drugs for rare diseases.)
For more information, see Safety and Efficacy of Olesoxime (TRO19622) in 3-25 Years SMA Patients.