SMA may involve changes that occur before birth, study suggests
Addressing developmental abnormalities in utero may improve treatment
Spinal muscular atrophy (SMA) may involve changes that occur before birth, during an embryo’s development in the womb, and not just after an infant is born, a study in cell structures suggests.
This could mean that combining available disease-modifying treatments with medications that address early changes could help better treat the disease, according to researchers.
“We need to address the developmental abnormalities … if we want to improve treatment for SMA,” Natalia Rodríguez-Muela, PhD, a research group leader at the German Center for Neurodegenerative Diseases and Dresden University of Technology, in Germany, said in a center news story.
The study, “Isogenic patient-derived organoids reveal early neurodevelopmental defects in spinal muscular atrophy initiation,” was published in Cell Reports Medicine.
Investigating if problems before birth could contribute to SMA
SMA results from mutations in the SMN1 gene, which codes for a protein called SMN. Without enough SMN protein, motor neurons — the nerve cells involved in the body’s voluntary movements — degenerate, leading to muscle weakness.
“The current perception of SMA focuses on the disease after birth, when the basic framework of the nervous system is mostly formed,” Rodríguez-Muela said. “This view ignores that phenomena relevant to the disease could occur much before, when the nervous system is still developing.”
Instead of just looking at SMA after birth, the team looked at whether problems in early development — i.e., before birth — could contribute to the disease. To do this, the scientists grew organoids, or tiny structures made up of stem cells, derived from cells of patients with SMA and that mimicked the spinal cord and muscle tissue.
“Although these are model systems that have certain limitations, they come quite close to the real situation, because they comprise a diversity of cell types and tissue structures that occur in the human body,” Rodríguez-Muela said.
The current perception of SMA focuses on the disease after birth, when the basic framework of the nervous system is mostly formed. … This view ignores that phenomena relevant to the disease could occur much before, when the nervous system is still developing.
In SMA organoids, stem cells developed into spinal cord neurons too early when compared with healthy organoids, resulting in fewer neurons and more muscle cells. The neurons in SMA organoids also were more likely to be damaged.
These findings were confirmed in mouse embryos with SMA-like symptoms. Even when the genetic defect was corrected, some developmental problems remained, suggesting that current treatments might not fully address the underlying causes of SMA.
“When we corrected the genetic defect associated with SMA, we still observed developmental abnormalities, although to a lesser extent,” Rodríguez-Muela said. “This is in line with clinical experience to date.”
Given these findings, the scientist suggests that addressing these abnormalities is crucial for improving SMA treatment.
Rodríguez-Muela believes that these developmental problems may be due to changes in how genes are regulated, suggesting that treatment needs to start before birth if SMA can be detected through prenatal testing.
According to the researchers, their work suggests that “early neurodevelopmental defects may underlie later [motor neuron] degeneration.”
As such, “these insights constitute a foundation for future studies to uncover molecular events governing early developmental defects preceding SMA progression and selective [motor neuron] loss,” the researchers wrote.
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