Scientists investigate early life factors that may contribute to SMA

Spinal muscular atrophy (SMA) is a severe neurological disease for which there is currently no cure, although current treatments can alleviate symptoms. In the search for better treatments, scientists from DZNE and TU Dresden have focused on previously unnoticed abnormalities in embryo development. Their claims are based on the study of so-called organoids – laboratory-grown tissue cultures that can reproduce the disease process. The results of their research have been published in the journal. Cell Report Medicine.

In SMA, neurons in the spinal cord degenerate, leading to paralysis and muscle atrophy. The disease usually begins in childhood and affects an estimated 1,500 people in Germany. Defects in certain genes are thought to trigger SMA. These mutations lead to a deficiency of the so-called SMN protein (survival of motor neuron protein), which is important for neurons involved in movement control. For several years now, medical treatments have been available that address the protein deficiency through gene therapy. Interventions can be started within the first few days of life. However, although this approach can alleviate the symptoms of the disease, experience so far has shown that it does not lead to a cure.

A previously unknown omen

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

“Current understanding of SMA focuses on a postnatal disease, when the basic structures of the nervous system are largely formed. This view ignores that phenomena related to the disease may occur much earlier, when the nervous system is still developing. Indeed, our work suggests that SMA is associated with previously unknown abnormalities in fetal development. We therefore believe that the disease has previously unrecognized precursors and requires interventions beyond existing treatments.”

Dr. Natalia Rodríguez Muela, Research Group Leader, DZNE (German Center for Neurodegenerative Diseases)

Small tissue pieces

For their study, Rodriguez Muela and colleagues created “organoids” that replicate key features of both spinal cord and muscle tissue. These complex but artificially generated tiny samples of tissue, each about the size of a grain of rice, resemble the human Induced pluripotent stem cellsThese were obtained by reprogramming skin cells from people with SMA. “This is the first time such complex organoids have been generated to study SMA,” says Rodríguez Muela. “They are a model system with certain limitations, but they are quite close to the real situation, since they are composed of the diverse cell types and tissue structures that occur in the human body.” As the organoids mature over time, scientists can study different developmental stages. “The earliest stage that can be emulated with an organoid model corresponds to a human fetus a few weeks after birth. However, we can only reproduce the spinal cord and muscle tissue. We can start from early developmental stages and go up to the postnatal situation that is seen especially in SMA patients,” explains Rodríguez Muela.

Cellular abnormalities

When the scientists compared organoids with SMA pathology to healthy specimens, they found major differences. Specifically, stem cells in SMA organoids tended to develop immaturely into spinal cord neurons. Moreover, the cell population was skewed, with fewer neurons than normal, which were also very fragile, and more stem cell-derived muscle cells. Rodríguez-Muera and colleagues observed a similar effect in mouse embryos with SMA-like pathology, corroborating their findings in the organoids. These tissue cultures also yielded another important result: “When we corrected the gene defect associated with SMA, we still saw developmental abnormalities, although to a lesser extent,” says Rodríguez-Muera. “This suggests that simply repairing the gene, as current therapies do, is probably not enough to completely ameliorate SMA pathology. This is in line with the clinical experience so far. So, I believe that if we want to improve the treatment of SMA, we need to address the developmental abnormalities.”

Focus on regulations

Rodríguez Muela suspects that the cause of the observed developmental disorders may lie in impaired gene regulation. “It may not only be a question of whether the gene that produces the SMN protein is defective. It may also be that the lack of this protein affects other genes that are important for early fetal development. There may be a regulatory effect. The truth is, we don't know yet, but it's possible,” she says. “I think this idea should be explored further. In the long term, it may lead to improved treatments that combine existing approaches with drugs that target gene regulation. That is, we need to act on the so-called 'epigenetics'. It will most likely be necessary to apply such treatments early in pregnancy to minimize developmental abnormalities. This could be a treatment option if prenatal testing indicates SMA. “