The study, “AAV9-Mediated Delivery of miR-23a Reduces Disease Severity in Smn2B-/SMA Model Mice,” was published in Human Molecular Genetics.
SMA comprises a group of neurodegenerative disorders characterized by the gradual loss of motor neurons — the nerve cells responsible for controlling voluntary muscles — in the spinal cord, leading to muscle weakness. It is normally caused by mutations in the SMN1 gene, which provides instructions for making the SMN protein that is essential for motor neuron survival.
Despite recent advances in research, the molecular mechanisms involved in motor neuron degeneration in patients with SMA are still poorly understood, because “global cellular dysfunction obscures the identification and characterization of disease-relevant pathways and potential therapeutic targets,” the researchers wrote.
MicroRNAs (miRNAs) — tiny RNA molecules that control the expression of several genes (protein production) — have recently been implicated in a series of genetic disorders, including Duchenne muscular dystrophy, Alzheimer’s disease, amyotrophic lateral sclerosis (ALS), Parkinson’s disease and SMA.
A single miRNA can bind to several messenger RNAs (template sequence that encodes for a functional protein, mRNAs), preventing them from being translated into functional proteins. For this reason, miRNAs can be seen as central hubs that control entire gene networks by carefully fine-tuning their expression levels over time.
“Recent reports have suggested that miRNA dysregulation contributes to the pathogenic [disease] mechanism of SMA. Therefore, the identification and characterization of differentially expressed miRNAs in SMA should reveal gene populations that are improperly regulated in the disease state,” the investigators wrote.
To find out which miRNAs might be dysregulated in SMA, a group of researchers from the University of Missouri compared the levels of different miRNAs found in motor neurons derived from induced pluripotent stem cells (iPSCs) obtained from fibroblasts of patients with SMA and healthy individuals.
iPSCs are fully matured cells that are reprogrammed back to a stem cell state, where they are able to grow into any type of cell. Fibroblasts are cells from the connective tissue.
This experiment revealed that motor neurons derived from SMA patients contained very low levels of miR-23a, a miRNA that is thought to inhibit skeletal muscle atrophy (muscle wasting) and protect neurons from degeneration.
To explore the potential role of miR-23a in SMA, researchers then placed an artificial form of miR-23a inside motor neurons derived from SMA patients. They found that increasing the levels of miR-23a inside motor neurons significantly reduced their degeneration and death, indicating that miR-23a may act as a disease modifier in SMA.
To examine the potential therapeutic effects of miR-23a in SMA, investigators used a specialized viral vector to deliver miR-23a to a mouse model of SMA. Administration of miR-23a significantly reduced disease severity, prolonged animals’ lifespan, increased motor neurons’ size and the area of muscle fibers.
“These results demonstrate that modulation of differentially regulated miRNA can significantly lessen the severity of SMA and confirm miR-23a as a novel protective modifier of SMA,” the researchers wrote.
“Further experimentation is warranted to identify additional disease-modifying miRNAs to better understand the pathways involved in SMA pathogenesis [disease development] as well as potentially opening the door to new molecular therapeutic targets,” they added.