Scientists investigate factors influencing SMA in early childhood

Spinal muscular atrophy (SMA) is a sedate neurological disease for which there is currently no cure, although current therapies can alleviate symptoms. In their search for better treatment options, scientists from the DZNE and the Technical University of Dresden are focusing on previously unnoticed abnormalities in embryonic development. They base their argument on research into so-called organoids: laboratory-grown tissue cultures that can reconstruct disease processes. Their findings are published in the journal Cellular Reports Medicine.

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

A previously unknown prelude

Now, scientists from Dresden, Germany, propose to broaden the horizon in the search for better therapies.

The current view of SMA focuses on the disease after birth, when the basic skeleton of the nervous system is largely formed. This view ignores the fact that the phenomena relevant to the disease may occur much earlier, when the nervous system is still developing. In fact, our studies suggest that SMA is associated with anomalies in embryonic development that were previously unknown. Therefore, we believe that there is an as yet unrecognized prelude to this disease and that interventions beyond existing therapies are needed.

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

Minuscule pieces of tissue

For their study, Rodríguez-Muela and colleagues created “organoids” that replicate key features of both spinal cord and muscle tissue. These convoluted but diminutive samples of engineered tissue, each about the size of a grain of rice, were grown from human induced pluripotent stem cells, which were in turn obtained by reprogramming skin cells from people with SMA. “This is the first time that organoids of this complexity have been created for studying SMA,” says Rodríguez-Muela. “Although these are model systems that have some limitations, they are quite close to the real world, because they encompass the diversity of cell types and tissue structures found in the human body.” As the organoids matured, the researchers were able to study different stages of development. “The earliest phase that we can mimic with our organoid model is that of a human embryo at a few weeks of age. However, we are only replicating the spinal cord and muscle tissue. Starting from the early developmental phase, we can move on to the postnatal situation, in particular what is observed in SMA patients,” explains Rodríguez-Muela.

Cellular aberrations

When the researchers compared the SMA-affected organoids with vigorous specimens, they found significant differences: Specifically, the stem cells in the SMA organoids tended to develop prematurely into spinal cord neurons. In addition, there was a distortion in the cell population, i.e. fewer neurons than normal, which were also highly susceptible, and more muscle cells derived from the stem cells. Rodríguez-Muela and colleagues observed similar effects in mouse embryos with SMA-like pathology, confirming the results in the organoids. These tissue cultures also yielded another vital result. “When we corrected the genetic defect associated with SMA, we still observed developmental abnormalities, although to a lesser extent,” says Rodríguez-Muela. “This suggests that restoring the gene, as current therapies do, is most likely not enough to completely change the pathology of SMA. This is consistent with the clinical experience to date. Therefore, I believe that we need to address the developmental abnormalities if we want to improve the treatment of SMA.”

Regulation in the spotlight

Rodríguez-Muela suspects that impaired gene regulation may be the cause of the observed malformations. “It may not only be a question of whether the gene that produces the SMN protein is defective or not. It may also be vital whether the deficiency of this protein affects other genes that are critical for early embryonic development. There may be a regulatory effect. The fact is that we still don’t know, but it is a plausible possibility,” she says. “I think this idea should be explored further. In the long term, this could lead to improved therapies that combine existing approaches with drugs that target gene regulation. This means that they would have to act on what is called ‘epigenetics.’ To minimize developmental abnormalities, such treatments would most likely have to be administered early in pregnancy. If prenatal testing indicates SMA, this could be a therapeutic option.”