Scientists are investigating aspects that contribute to SMA in formative years

Spinal muscular atrophy (SMA) is a serious neurological disease for which there may be currently no cure, but current therapies can alleviate the symptoms. Within the seek for higher treatment options, scientists from the DZNE and the TU Dresden at the moment are drawing attention to previously unnoticed anomalies in embryonic development. They base their argument on studies of so-called organoids: tissue cultures grown within the laboratory that may reconstruct disease processes. Their results have been published within the specialist journal.

In SMA, nerve cells within the spinal cord degenerate, resulting in paralysis and muscle atrophy. The disease normally manifests itself in childhood and affects an estimated 1,500 people in Germany. Defects in a particular gene are regarded as the trigger for SMA. These mutations result in a deficiency of the so-called SMN protein (Survival of Motor Neuron Protein), which is significant for motor nerve cells. For several years now, the protein deficiency has been in a position to be treated with medication using gene therapy. The intervention can begin just just a few days after birth. Although this approach can alleviate the symptoms of the disease, experience up to now has shown that a cure just isn’t possible.

A previously unknown start

Now Dresden scientists are proposing to broaden the attitude within the seek for higher therapies.

The present perception of SMA focuses on the disease after birth, when the essential framework of the nervous system is essentially formed. This view ignores that disease-relevant phenomena can occur much earlier, when the nervous system remains to be developing. Actually, our studies suggest that SMA is related to previously unknown abnormalities in embryonic development. We subsequently consider that there’s a previously unrecognized precursor to this disease and that interventions beyond existing therapies are needed.

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

Tiny pieces of tissue

For his or her studies, Rodríguez-Muela and colleagues created “organoids” that replicate essential features of each spinal cord and muscle tissue. These complex, albeit tiny, samples of engineered tissue, each concerning the size of a grain of rice, were created from human induced pluripotent stem cells. These, in turn, were obtained by reprogramming skin cells from individuals with SMA. “That is the primary time that organoids of this complexity have been created to check SMA,” says Rodríguez-Muela. “Although these are model systems with certain limitations, they’re quite near reality, as they include a wide range of cell types and tissue structures that occur within the human body.” Because the organoids matured over time, the scientists were in a position to study different stages of development. “The earliest phase that we are able to recreate with our organoid model corresponds to that of a human embryo just a few weeks old. Nonetheless, we’re only recreating the spinal cord and muscle tissue. Ranging from the early phase of development, we are able to advance to the situation after birth, as is observed particularly in patients with SMA,” explains Rodríguez-Muela.

Cellular aberrations

When the scientists compared organoids with SMA pathology with healthy samples, they found significant differences: Particularly, stem cells in SMA organoids tended to develop prematurely into spinal cord neurons. As well as, there was a cell population bias, meaning there have been fewer neurons than normal, which were also very vulnerable, and more muscle cells that arose from the stem cells. Rodríguez-Muela and his colleagues observed similar effects in mouse embryos with SMA-like pathology, supporting the findings in organoids. These tissue cultures also provided one other essential result. “Once we corrected the genetic defect related to SMA, we still observed developmental abnormalities, albeit to a lesser extent,” says Rodríguez-Muela. “This means that restoring the gene, as current therapies do, is almost definitely not enough to completely reverse SMA pathology. That is consistent with clinical experience up to now. Subsequently, I consider that if we wish to enhance the treatment of SMA, we’d like to handle the developmental disorders.”

Deal with regulation

Rodríguez-Muela suspects that the reason behind the observed developmental abnormalities may very well be as a result of impaired gene regulation. “It might not only be a matter of whether the gene that produces the SMN protein is flawed or not. Perhaps it is usually relevant whether the dearth of this protein has an impact on other genes which can be crucial for the early development of the embryo. There may very well be a regulatory effect. We do not know yet, nevertheless it is a plausible possibility,” she says. “I consider that this concept ought to be further investigated. In the long run, this could lead on to improved therapies that mix existing approaches with drugs that focus on gene regulation. That’s, they’d need to act on what’s generally known as ‘epigenetics.’ To attenuate developmental abnormalities, such a treatment would almost definitely need to be applied in early pregnancy. If prenatal tests indicate SMA, this may very well be a therapeutic option.”