Results from a study in fruit flies conducted by scientists in the Motor Neuron Center at Columbia University Medical Center in New York suggest that spinal muscular atrophy (SMA)— commonly thought to be a disease of muscle-controlling nerve cells called motor neurons— instead results from the dysfunction of motor circuits (networks made up of different types of specialized neurons that coordinate muscle movement).
A phase 2-3 clinical trial based on the findings is testing whether an existing drug called dalfampridine can improve walking ability and endurance in adults with type 3 SMA. (Dalfampridine is marketed under the name Ampyra for treatment of multiple sclerosis.)
In a second study, researchers identified the molecular pathway in SMA that leads to problems with motor function.
The findings could point the way to new therapeutic strategies for SMA.
In motor circuits, proprioceptive neurons pick up and relay information to the spinal cord and brain about the body’s position in space. Interneurons relay the signals to motor neurons, which are responsible for stimulating muscle movement.
In a study led by Brian McCabe, assistant professor of pathology and cell biology and of neuroscience at the Motor Neuron Center, researchers showed that SMA originates in proprioceptive neurons and interneurons, which then cause motor neurons to malfunction.
Mutations in the SMN1 gene are the underlying cause of SMA in humans. McCabe’s study was conducted in fruit flies that were genetically altered so that every cell had a defective copy of the SMN1 gene. The flawed SMN1 genes generated insufficient levels of SMN protein in the flies’ cells, resulting in reduced muscle size and motor function.
When the researchers put fully functional copies of the SMN1 gene into the flies’ motor neurons or muscle cells, there was no improvement. It was only when SMN1 was returned to proprioceptive neurons and interneurons that muscle size and motor function were restored.
In further experiments, McCabe’s team demonstrated that in fruit flies with defective SMN1, proprioceptive neurons and interneurons do not produce enough neurotransmitters. Blocking the flies’ potassium channels — either genetically or through the use of drugs — increased neurotransmitter activity, leading to improved muscle size and motor function. (Potassium channels play a crucial role in muscle contraction.)
Based on these findings, the SMA Clinical Research Center at CUMC launched a clinical trial of the potassium channel blocker Ampyra in people with SMA. The trial is designed to assess whether Ampyra improves walking ability and endurance in adults with type 3 SMA.
“This drug is unlikely to be a cure for SMA,” McCabe said in a press release. “But we hope it will benefit patient symptoms.”
For more information on the trial, see Short and Long Term Treatment With 4-AP in Ambulatory SMA Patients (ID number NCT01645787 at ClinicalTrials.gov).
Second study: Loss of SMN disrupts motor circuits
In a second study, led by MDA research grantee Livio Pellizzoni, assistant professor of pathology and cell biology at the Motor Neuron Center, and McCabe, scientists showed that the loss of SMN protein in cells disrupts RNA splicing, a fundamental cellular process required for translating genetic instructions into proteins. Among other effects, the altered splicing causes a reduction in the activity of a newly identified gene the researchers have named stasimon, which in turn disrupts motor circuits.
The researchers showed that increasing activity of the stasimon gene could correct some aspects of motor dysfunction in SMA disease models.
The findings provide a direct link from the loss of SMN1 gene activity, to defective splicing of the stasimon gene, to motor circuit dysfunction. In addition, they suggest that the stasimon gene and corresponding pathway potentially may serve as new therapeutic targets.
Full reports for both studies were published online Oct. 11, 2012, in Cell and are available for purchase. See SMN is Required for Sensory-Motor Circuit Function in Drosophila and SMN-Dependent U12 Splicing Event Essential for Motor Circuit Function.
For more about experimental treatments in development for SMA, see:
About Clinical Trials
A clinical trial is a test, in humans, of an experimental treatment. Although it's possible that benefit may be derived from participating in a clinical trial, it's also possible that no benefit, or even harm, may occur.
MDA has no ability to influence who is chosen to participate in a clinical trial.
To learn more, see Learn about Clinical Studies and Being a Co-Adventurer, which is about neuromuscular disease clinical trials. To see a continuously updated database of clinical trials, go to ClinicalTrials.gov.