Kyle Loh, PhD, Associate Professor at Stanford Medicine, discusses research that could help scientists better understand spinal muscular atrophy (SMA) by generating new motor neurons from human hindbrain cells in the laboratory.
SMA is a genetic neuromuscular disorder characterized by the loss of motor neurons, causing progressive muscle weakness and loss of movement due to atrophy. SMA mainly affects the muscles involved in walking, sitting, arm movement, and head control. Breathing and swallowing may also become difficult as the disease progresses. SMA is caused by genetic mutations in the SMN1 gene. Extra copies of the nearby related gene, SMN2, modify the severity of SMA, with type 1 being the most severe and type 4 the least severe.
The study by Dr. Loh and his colleagues examined how different parts of the brain develop and use that knowledge to create new ways to generate new cells, including motor neurons. While the brain is often viewed as a single organ originating from one source, it is actually built from two distinct sources: one creating the forebrain/midbrain and another creating the hindbrain. As Dr. Loh explains, this distinction is critical for understanding the evolution of the brain and for developing human neurons in a laboratory setting.
Neurons in the hindbrain have received less attention than the well-studied spinal cord motor neurons. However, these hindbrain neurons are essential for life-sustaining functions, including eating, swallowing, speech, and facial movements. To study these neurons, specific genes that mark different progenitor cells were identified: OTX2 for forebrain/midbrain and GBX2 for the hindbrain. By directing stem cells toward these specific progenitor states, hindbrain motor neurons can be generated in a petri dish.
This study includes the creation of human induced pluripotent stem cell lines from patients with type 1 SMA to observe how the condition affects the growth of hindbrain motor neurons.
Dr. Loh is also interested in exploring the pathophysiology of SMA further. For example, the SMN1 gene is ubiquitously expressed in every cell in the body, its loss specifically impacts a small subset of motor neurons in patients with SMA. Further work is also needed to investigate why certain motor neurons, such as those innervating the diaphragm, appear resilient in patients with SMA while muscles nearby are impacted. Understanding this natural resilience could offer a new approach to therapy that moves beyond simply replacing the missing gene.
For more information, visit https://www.nature.com/articles/s41593-026-02433-7
To learn more about SMA and other rare neurological conditions, visit https://checkrare.com/diseases/neurology-nervous-system-diseases/
