Scientists are investigating early life factors that contribute to SMA

Spinal muscular atrophy (SMA) is a serious neurological disease for which there is currently no cure, although current treatments can relieve symptoms. In the search for better treatment options, scientists from the DZNE and the Dresden University of Technology are now drawing attention to previously unseen abnormalities in fetal development. They base their argument on studies of so-called organoids: Tissue cultures grown in the lab that can recreate disease processes. Their findings are published in the journal Cell Reports Medicine.

In SMA, neurons in the spinal cord degenerate, leading to paralysis and muscle wasting. The disease usually manifests itself in childhood and affects about 1,500 people in Germany. Defects in a specific gene are thought to cause SMA. These mutations lead to a deficiency of the so-called SMN protein (Survival of Motor Neuron protein), which is critical for neurons involved in motor control. For some years, medical treatments have been available to treat protein deficiency through gene therapy. Intervention can begin within days of birth. However, while this approach can alleviate the symptoms of the disease, experience so far shows that it does not provide a cure.

A hitherto unknown prelude

Now, scientists in Dresden, Germany are proposing to broaden the horizon in the search for better treatments.

Current understanding of SMA focuses on the disease after birth, when the basic framework of the nervous system is mostly formed. This view ignores that disease-related phenomena could occur much earlier, when the nervous system is still developing. In fact, our studies suggest that SMA is associated with abnormalities in fetal development that were not known until now. We therefore believe that there is a hitherto unrecognized precursor to this disease and that interventions beyond existing treatments are needed.

Dr. Natalia Rodríguez-Muela, Head of Research Group, DZNE – German Center for Neurodegenerative Diseases

Tiny pieces of tissue

For their studies, Rodríguez-Muela and colleagues created “organoids” that recapitulate key features of both spinal cord and muscle tissue. These complex yet tiny samples of artificially created tissue, each about the size of a grain of rice, were grown from human-induced pluripotent stem cells. These in turn had been obtained by reprogramming the skin cells of individuals affected by SMA. “This is the first time that organoids of this complexity have been created to study SMA,” says Rodríguez-Muela. “Although these are model systems that have certain limitations, they are quite close to the real situation because they include a variety of cell types and tissue structures that occur in the human body.” As the organoids matured over time, scientists were able to study various developmental stages. “The earliest phase we can mimic with our organoid model corresponds to that of a human embryo a few weeks old. However, we are only replicating the spinal cord and muscle tissue. Starting from the early developmental phase, we can proceed to the postnatal state , particularly as seen in SMA patients,” explains Rodríguez-Muela.

Cellular aberrations

When the scientists compared organoids with SMA pathology to healthy samples, they found significant differences: Specifically, stem cells in SMA organoids tended to develop prematurely into neurons in the spinal cord. In addition, there was a distortion in the cell population, meaning fewer neurons than normal, which were also highly vulnerable, and more muscle cells derived from the stem cells. Rodríguez-Muela and colleagues observed similar results in mouse fetuses with SMA-like pathology, supporting the findings in organoids. These tissue cultures also yielded another important result. “When we corrected the genetic defect associated with SMA, we still observed developmental abnormalities, albeit to a lesser extent,” says Rodríguez-Muela. “This suggests that restoring the gene, as current therapies do, is probably not enough to fully modify SMA pathology. This is consistent with clinical experience to date. So I think we need to address the developmental abnormalities if we want to improve treatment for SMA.”

Focus on setting

Rodríguez-Muela suspects that the reason for the observed developmental defects may lie in impaired gene regulation. “It may not only be a question of whether the gene that produces the SMN protein is defective or not. It may also be important if the deficiency of this protein affects other genes critical for early fetal development. There could be a regulatory effect. fact is that we still don’t know, but it’s a reasonable possibility,” he says. “I think this idea needs to be explored further. In the long term, this may lead to improved treatments that combine existing approaches with drugs that target gene regulation. That is, they should act on what is called “epigenetic”. To minimize developmental abnormalities, such treatment should probably be applied early in pregnancy, if prenatal screening indicates SMA, this could be a treatment option.