Spinal muscular atrophy (SMA) is a serious neurological condition with no current cure, although available treatments can help manage symptoms. In their quest for improved treatment methods, researchers are focusing on previously overlooked issues in embryonic development. Their work is based on studies involving organoids, which are lab-grown tissue cultures that mimic disease processes.
SMA is a challenging neurological disorder without a cure, though existing therapies can reduce symptoms. Researchers at DZNE and the Dresden University of Technology aim to explore unnoticed irregularities in embryonic development to find better treatment solutions. Their research, highlighted in the journal Cell Reports Medicine, centers on organoids: laboratory-created tissues that replicate disease mechanisms.
In SMA, spinal cord neurons degenerate, leading to muscle weakness and paralysis. The condition typically presents during childhood and affects about 1,500 people in Germany. The onset of SMA is linked to mutations in a specific gene that causes a shortage of the SMN (Survival of Motor Neuron) protein, critical for motor function neurons. While gene therapy has been implemented in recent years to address this protein deficiency from a few days after birth, it alleviates symptoms but does not cure the disease.
A previously unknown prelude
Researchers in Dresden propose an expanded view for seeking more effective therapies. “The current focus on SMA primarily considers postnatal disease symptoms, overlooking developmental anomalies that could occur much earlier, during nervous system formation. Our research indicates that SMA may be linked to previously unidentified embryonic development abnormalities. Consequently, we believe that to understand this disease fully, we need interventions that extend beyond current therapies,” explains Dr. Natalia RodrÃguez-Muela, leader of a research group at DZNE’s Dresden branch and the Center for Regenerative Therapies Dresden (CRTD) at Dresden University of Technology.
Small tissue samples
RodrÃguez-Muela and her colleagues developed “organoids” that mirror significant characteristics of spinal cord and muscle tissues. These minuscule, intricate samples—approximately the size of a grain of rice—were created from human induced pluripotent stem cells, which were derived from the skin cells of SMA-affected individuals. “This marks the first instance of creating such complex organoids for SMA research,” says RodrÃguez-Muela. “Though model systems have limitations, they closely resemble real conditions due to their diverse cell types and tissue structures found in the human body.” As the organoids matured, the researchers investigated different developmental stages, from replicating a human embryo a few weeks old to postnatal similarities observed in SMA patients.
Cellular irregularities
When comparing SMA-affected organoids with healthy samples, researchers noticed significant distinctions: stem cells in SMA organoids often matured too quickly into spinal cord neurons. Furthermore, there were fewer neurons than normal, and those present were particularly fragile, alongside an increase in muscle cells. These patterns were echoed in mouse embryos with SMA-like characteristics, reinforcing the organoids’ findings. “Even after correcting the genetic defect linked to SMA, we still identified developmental irregularities, though they were less severe,” emphasizes RodrÃguez-Muela. “This indicates that simply restoring the gene, as current therapies do, might not fully resolve SMA’s issues. Based on our clinical findings, addressing these developmental shortcomings is crucial for enhancing SMA treatment.”
Focusing on regulation
RodrÃguez-Muela suspects that the identified developmental issues may stem from disrupted gene regulation. “It isn’t solely about whether the SMN protein’s gene is faulty. The impact of its deficiency on other essential genes involved in early embryonic development may also be significant, suggesting a possible regulatory role. We still need to investigate this further, but it’s a logical hypothesis,” she explains. “This concept should be pursued further, as it might lead to more effective treatments combining current methods with drugs that target gene regulation—essentially tackling the field of ‘epigenetics.’ Addressing developmental abnormalities would likely require intervention early in pregnancy. If prenatal tests reveal SMA, this could become a potential treatment strategy.”
