SMA effects on development of nervous system worse than thought: Study
Understanding abnormalities may be key to new, better treatments
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- A new study found that SMA more broadly impacts nervous system development than previously thought.
- Low SMN protein levels cause widespread developmental abnormalities and dysregulation in nerve cells.
- Early treatment, potentially prenatal, can correct these developmental defects, optimizing therapeutic outcomes for SMA, the researchers noted.
Spinal muscular atrophy (SMA) affects the nervous system — essentially, the body’s command center, where nerves transmit signals that coordinate actions, senses, and bodily functions — more profoundly than previously thought, a new study suggests.
Although it’s been established that SMA is marked by problems with motor neurons, the nerve cells that control movement, the new data suggest that the genetic disease also may cause more widespread problems with the development of other types of cells in the nervous system. Understanding these developmental abnormalities, the researchers say, may be key to developing optimal treatment strategies.
According to the team, “understanding early neurodevelopmental defects in SMA is crucial for optimizing therapeutic interventions.”
Their study, “Targeted antisense oligonucleotide treatment rescues developmental alterations in spinal muscular atrophy organoids,” was published in the journal Nature Communications.
A rare disorder, SMA is caused primarily by mutations in the SMN1 gene, which encodes a protein called SMN. It’s well-established that low levels of SMN protein in SMA lead to the dysfunction and death of motor neurons, which is what drives cardinal disease symptoms such as muscle weakness. However, the molecular mechanisms by which low SMN protein levels affect the nervous system remain poorly understood.
Lab models of nerve cells used to better understand development
Now, aiming to get a better understanding of this process, a research team from the U.S. and Italy conducted a series of tests using spinal cord organoids (SCOs), which are lab models of nerve cells and other nervous system cells. These cells are grown in a three-dimensional architecture designed to mimic how cells are arranged in the human spinal cord during early development.
The researchers used SCOs generated from cells derived from people with and without SMA to compare how the cells’ genetic activity was impacted by the presence of SMN protein.
The results showed that SCOs from people with SMA had abnormally low levels of motor neurons. Further, the motor neurons that were present showed profound dysregulation, with more than 2,000 genes expressed at abnormal levels.
Motor neurons were the cell type with the largest proportion of dysregulated genes, with progenitor cells, which are immature cells that grow into other types of cells, the next most affected cell type, according to the researchers.
“While the significant reduction in spinal [motor neurons] is a key hallmark of SMA, the altered abundance and [genetic activity] of progenitor cells reveal an equally critical aspect of the disease [biology] with a broader disruption in neural development,” the researchers wrote. The team also noted that the role of progenitor cells in SMA has not received much attention from scientists, writing that it’s “often disregarded in the investigation of this disease.”
Because progenitor cells help form new cells in the developing nervous system, the researchers conducted additional tests in which they tracked how SCOs developed over time. This revealed that the SMA models showed abnormalities in the development of not just motor neurons but also other nerve cell types.
Tests showed that SMA nerve cells had abnormalities in electrical activity, in SCOs, and also in models designed to mimic the brain, which was in line with the dysregulation of genes involved in nerve cell communication.
These data, the scientists say, suggest that “despite defects of spinal [motor neurons] function being the central feature of SMA [disease biology], the disease also has a broader impact.”
Findings suggest early treatment is key
Testing was then done in the SCO model to assess the effects of treatment designed to boost SMN protein levels. The specific type of therapy used, called an antisense oligonucleotide, is the same type of medicine used in the approved SMA therapy Spinraza (nusinersen).
The scientists found that the treatment corrected structural and functional abnormalities in the SMA models, while also preventing cell death, normalizing the proportions of different types of nerve cells, and restoring normal processing of RNA molecules in cells.
The finding that SMA causes problems with nervous system development — and that these problems can potentially be addressed with SMA treatments — could have important clinical implications, the researchers said.
This [research] not only opens new avenues of investigation to fully dissect the therapeutic mechanisms of action on the multifaceted aspects of SMA, but also confirms these models as suitable tools to improve the current therapeutic strategies in the clinic, and even expand to more personalized medicine in the future.
Specifically, the findings support the idea that SMA treatments will be most effective when given as early as possible — either immediately after birth, or even potentially starting treatment during pregnancy.
The scientists called for further studies to assess how SMA affects nervous system development and how this may be addressed with treatments.
“This [research] not only opens new avenues of investigation to fully dissect the therapeutic mechanisms of action on the multifaceted aspects of SMA, but also confirms these models as suitable tools to improve the current therapeutic strategies in the clinic, and even expand to more personalized medicine in the future,” the team concluded.
The researchers stressed the potential impact their work may have for patients.
“Our study suggests that SMN is a key molecule during prenatal spinal cord and brain development, meaning that SMA therapeutics will be most effective if delivered during the presymptomatic phase of the disorder, namely peri- [around the time of birth] or even prenatally,” the team noted.
