Neural Stem Cell Transplants May Delay Progression of SMARD1, Animal Study Suggests

Transplanting a subset of neural stem cells (NSCs) to the spinal canal may be a potential therapy to delay disease progression in children with spinal muscular atrophy with respiratory distress type 1 (SMARD1), according to a preclinical study.

The study, “CSF transplantation of a specific iPSC-derived neural stem cell subpopulation ameliorates the disease phenotype in a mouse model of spinal muscular atrophy with respiratory distress type 1,” was published in the journal Experimental Neurology.

SMARD1, a type of spinal muscular atrophy (SMA), is characterized by progressive weakness of the arms and chest muscles, leading to severe respiratory problems. Symptoms in these patients usually start to manifest between six weeks and six months of life.

While SMARD1 is known to be caused by mutations in the IGHMBP2 gene, the underlying mechanisms by which these mutations lead to motor nerve cell degeneration and muscular atrophy remain largely unclear.

Stem cell therapy has shown promise in the treatment of diseases associated with motor nerve cells due to stem cells’ potential to transform into virtually any functional cell type in the body, and to replicate rapidly. These stem cells have thus the potential to replace motor nerve cells that are lost, or to provide protective and survival signals to the remaining healthy motor cells.

Induced pluripotent stem cells (iPSCs), or stem cells derived from tissues of adult patients, have the advantage to allow researchers to generate iPSCs-derived cells from the patient and avoid the ethical concerns with using fetal or embryonic tissues.

In a previous study, an Italian research team showed that transplanting iPSC-derived neural stem cells improved motor function and prolonged the survival of a mouse model of SMARD1.

Researchers now evaluated the therapeutic potential of a specific subset of iPSC-derived neural stem cells with increased ability to be recruited to the central nervous system (brain and spinal cord) in SMARD1 mice.

This subset of neural stem cells — which produce important proteins for support cell migration and survival (like CD15, CXCR4 and beta 1 integrin) — previously were shown to have beneficial effects on models of amyotrophic lateral sclerosis, another disorder associated with motor nerve cell degeneration.

In addition to these intrinsic advantages, researchers placed the neural stem cells in contact with molecules known to enhance survival and allow them to maintain their nerve cell state, before their were transplanted.

The cells were injected directly into the spinal canal (intrathecal delivery) of mice resulting in significant improvements to their muscular function, weight gain, overall appearance, and survival, compared with those that received placebo injection.

The main cause of muscle atrophy in these mice is selective loss of motor nerve cells in an anterior region of the spinal cord (known as ventral horns), and subsequent degeneration of the neuromuscular junctions (the point of contact and communication between motor nerve cell and muscle cell). So, researchers next evaluated the effects of neural stem cell transplant in a mouse model of SMARD1.

Their experiments revealed that the neural stem cells could migrate to the ventral horns of the spinal cord. These mice also had significantly greater number and size of motor nerve cells compared to those who underwent a sham procedure, as well as showed partial recovery of NMJs and reduced muscle degeneration, with improved muscle fiber morphology and organization.

Researchers noted these findings suggest that transplanting this subset of stem cells promoted the protection of motor nerve cells, their ability to form new NMJs, and NMJs’ preservation. These effects likely were responsible for delaying onset of the disease and slowing its progression in SMARD1 mice.

“This minimally invasive stem cell approach can confer major advantages in the context of cell-mediated therapy for patients with neurodegenerative diseases [including SMARD1],” they wrote.