SMA treatment responses predicted by certain microRNAs in early study
MiR34 family of microRNAs linked to improved motor function after treatment
The MiR34 family of microRNAs represents a set of promising biomarkers to assess therapeutic response in spinal muscular atrophy (SMA), a study proposes.
MicroRNA levels in the cerebrospinal fluid (CSF), the liquid surrounding the brain and spinal cord, before and during therapy, predicted and correlated with improved motor function after treatment, researchers found.
The biomarker study, “MiR34 contributes to spinal muscular atrophy and AAV9-mediated delivery of MiR34a ameliorates the motor deficits in SMA mice,” was published in the journal Molecular Therapy Nucleic Acids.
SMN is a protein essential for the health of motor neurons, the specialized cells that control movement. In SMA, a lack of SMN causes motor neurons to deteriorate and die, resulting in muscle weakness and muscle atrophy (shrinkage).
miRNAs are tiny segments of RNA that modulate gene activity
MicroRNAs (miRNAs) are tiny segments of RNA that modulate gene expression, or gene activity (RNA stands for ribonucleic acid, which converts the genetic information of DNA into proteins). In diseases affecting motor neurons, such as SMA, a wide spectrum of miRNAs are abnormally regulated. As a result, they have potential as biomarkers for disease progression and treatment efficacy.
Researchers in Taiwan decided to systematically identify miRNA changes reflecting motor neuron disease to seek potential biomarkers that could predict SMA treatment efficacy.
miRNAs expressed in the spinal cords of mice were first identified. Among them, three miRNAs — MiR17a, MiR27a, and MiR34a — were produced at high levels in the spinal cord and were selected for further analysis.
In motor neurons derived from SMA patients, whose survival was markedly reduced compared to healthy cells, MiR34a was the only miRNA that was significantly reduced. MiR34a levels were also consistently lowered in the whole spinal cord of an SMN-deficient mouse model of SMA.
We propose that the MiR34 family represents a set of promising biomarkers to assess responses to SMN-restorative therapies.
Mice engineered to lack MiR34s
To investigate whether reduced MiR34a plays a role in motor neuron disease, mice were engineered to lack this miRNA and its related family members (MiR34b, MiR34c, and MiR449), all of which perform identical functions.
Besides reduced growth and a shortened lifespan, mice lacking MiR34 had an abnormal accumulation of neurofilament protein, a primary structural component of neurons, at the end of nerve fibers connecting with muscles.
Additionally, the connections between neurons and muscles, which receive nerve signals, were smaller, and muscle fibers had a reduced diameter, a sign of muscle atrophy.
Gene expression analysis in the spinal cord tissue of these mice found an altered activity of genes associated with several core neuronal pathways and an impaired formation of synapses, which are the connections between nerve cells.
Because MiR34 was consistently reduced in the SMA models and could regulate nerve-muscle connections, the team assessed whether increasing MiR34 could impact SMA symptoms in mice. After administering MiR34a via a modified harmless virus, miRNA levels were elevated in the spinal cord tissue.
Importantly, MiR34a treatment partially rescued the impaired motor function of SMA mice. This restoration was achieved by maintaining the connection between nerves and muscles.
“Together, these findings substantiate evidence for a mechanistic role of MiR34 in SMA pathology [disease], warranting further investigation regarding its predictive power in clinical settings,” the researchers wrote.
CSF collected from 7 children with SMA type 1 being treated with Spinraza
To assess MiR34’s potential as a biomarker to measure treatment response, the researchers tested the CSF collected from seven SMA type 1 children undergoing treatment with Spinraza (nusinersen), an approved SMA therapy.
The mean age of SMA onset was 2.9 months, and the mean age at the first Spinraza dose was 8.6 months. Patients received loading doses on days 0, 14, 28, and 64, followed by maintenance doses every four months.
Although no significant correlations were detected for the loading phase, changes in the MiR34 family, particularly MiR34b levels, correlated with improved motor function, as assessed by the Hammersmith Infant Neurological Examination (HINE-2). These changes occurred during the later treatment phases, on days 183 (six months) and 482 (nearly 16 months).
Furthermore, MiR34b levels in CSF before treatment (baseline) significantly correlated with the HINE-2 score after 16 months of treatment.
“MiR34b levels at baseline and during [Spinraza] therapy are predictive and are correlated with motor function after treatment,” the researchers concluded. “Therefore, we propose that the MiR34 family represents a set of promising biomarkers to assess responses to SMN-restorative therapies.”