MDA 2026: Study sheds light on how SMA affects spinal cord development
Mutations that cause spinal muscular atrophy (SMA) disrupt the development of spinal cord cells, leading to fewer nerve cells in early development, according to a new study in cell models.
The findings highlight potential new avenues for treating SMA in its earliest stages, researchers say.
Zeynep Dokuzluoglu, a graduate student at the German Center for Neurodegenerative Diseases, discussed the findings at the Muscular Dystrophy Association (MDA) Clinical & Scientific Conference 2026, in a talk titled “SMN deficiency disrupts lineage specification in neuromesodermal progenitors revealed by a neuromuscular organoid model of Spinal Muscular Atrophy.”
SMN deficiency may cause problems with nervous system development
SMA is chiefly caused by mutations in the SMN1 gene, which provides instructions for making the SMN protein. People with SMA produce little to no SMN protein, and as a result, motor neurons, the nerve cells that control movement, sicken and die.
Although it’s well-established that SMN protein deficiency drives motor neuron dysfunction in SMA, the exact molecular mechanism remains incompletely understood. Recent research suggests that SMN deficiency may cause problems with the development of the nervous system.
“SMN levels, if you look at when this protein is highly expressed and highly functional, it’s actually during the embryonic and fetal development,” Dokuzluoglu said. As such, she said researchers need to better understand how SMA affects early development to understand the disease fully.
Studying early human development is difficult — doing so in living participants presents a mountain of ethical issues. Instead, Dokuzluoglu and colleagues conducted a study using lab models called ventral neuromuscular organoids (vNMOs). Essentially, these models use human nerve and muscle cells arranged in a 3D architecture that mimics how motor neurons in the spinal cord connect with muscle cells to coordinate movement.
The researchers assessed how development differed in vNMO models derived from people with or without SMA. They also conducted experiments using cells derived from SMA patients that had been genetically edited to restore SMN protein production. This allowed them to evaluate the effect of SMN protein deficiency specifically.
SMA-deficient models had less nerve tissue
In early development, primordial spinal cord cells called neuromesodermal progenitors (NMPs) can develop into either nerve tissue or mesodermal tissue, which includes bone and muscle tissue. Normally, the balance between nerve and mesodermal tissue is carefully coordinated to ensure the spinal cord has all the right tissues in all the right places, including nerves and the surrounding bone and muscle.
Data from the vNMO models indicated that SMN protein deficiency led to a mesodermal fate bias – in other words, the SMN-deficient vNMOs had more mesodermal tissue and, consistently, less nerve tissue. As the cells developed, this skewing led to reduced numbers of motor neurons in the SMN-deficient vNMOs.
The researchers also analyzed embryos in a mouse model of SMA. Similar to the vNMO data, results indicated a reduction in the formation of nerve tissue in the spine during early development.
In further experiments, the researchers found that SMN deficiency led to decreased activity of the SOX2 pathway and increased activity of the WNT pathway. Both these molecular pathways play key roles in regulating whether NMPs develop into nerve or mesoderm tissue. The researchers found that they could restore motor neuron production in SMN-deficient vNMOs by engineering the cells to increase SOX2 pathway activity, highlighting a potential avenue for new treatment approaches.
“Taken together, we found a novel developmental role for SMN in NMP lineage specification and demonstrate how organoid models can uncover early cellular [misspecifications] underlying neuromuscular diseases. This approach provides novel therapeutic entry points for developmentally rooted disorders,” the scientists concluded in their abstract.
Note: The SMA News Today team is providing live coverage of the 2026 MDA Clinical & Scientific Conference March 8-11 in Orlando, Florida. Go here to see the latest stories from the conference.
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