Stem Cell Therapy May Ease Neurological Symptoms of Sanfilippo Type A, Study Suggests

Treatment with blood stem cells genetically engineered to block interleukin-1 beta (IL-1b) signaling may be a promising approach for reducing brain inflammation and cognitive decline in Sanfilippo syndrome type A, a study in mice reports.

The study, “Haematopoietic stem cell gene therapy with IL ‐1Ra rescues cognitive loss in mucopolysaccharidosis IIIA,” was published in EMBO Molecular Medicine.

Mucopolysaccharidosis (MPS) disorders are identified by deficiencies in lysosomal enzymes involved in the degradation of large sugar molecules called glycosaminoglycans (GAGs).

The most common form of MPS, Sanfilippo syndrome type A, or MPS IIIA, is characterized by a deficiency in the enzyme sulfamidase, causing a buildup of GAG molecules called heparan sulfate.

Evidence suggests that accumulation of such molecules triggers widespread inflammatory responses, including extensive activation of immune cells in the brain, resulting in severe and rapid intellectual decline.

Broad spectrum anti‐inflammatory therapies have shown some promise in correcting the neurological features of Sanfilippo syndrome, but the exact inflammatory mechanisms leading to disease features are still unclear.

Researchers at the University of Manchester, in the U.K., investigated the role of the pro-inflammatory IL-1 signaling, which has been implicated in a series of neurological disorders, including Alzheimer’s, Parkinson’s, and multiple sclerosis, and also appears to have a role in MPS disorders.

The team used MPS-IIIA mice, which largely resemble humans in terms of disease mechanisms and behavioral problems. These animals had significantly greater levels of multiple inflammatory molecules — including IL-1b — in the brain, as well as extensive proliferation of astrocytes and glial cells, which play a key role in neurodegenerative diseases.

IL-1b has also been found at elevated levels in the blood and cerebrospinal fluid (CSF, the liquid surrounding the brain and spinal cord) of Sanfilippo patients, suggesting this inflammatory molecule plays a role in disease processes.

Researchers knew that heparan sulfate molecules could control inflammatory responses, but it was unclear if these molecules were triggering IL‐1‐dependent inflammation in MPSIII. They had found that heparan sulfate was essential to initiate an IL-1 inflammatory response, triggering IL-1b production inside cells. But it was not sufficient to activate and secrete this molecule into the extracellular space.

For that to happen, other secondary storage substrates, such as cholesterol, the energy molecule ATP, and amyloid‐beta, were also needed. These molecules were all at elevated levels in the brains of MPS-IIIA mice, and triggered the activation of NLRP3 inflammasome (a protein complex essential for the innate immune system to function), which drove the activation and secretion of IL-1b.

“Here, we show that neuroinflammation and cognitive decline in MPSIIIA are driven by a two‐step IL‐1‐dependent immune response mediated by the NLRP3 inflammasome,” the researchers wrote.

“Both pathogenic primary HS [heparan sulfate] substrates and secondary storage substrates are required to initiate the inflammasome and together mediate a robust pro‐inflammatory IL‐1 immune response,” they added.

Aiming to understand how IL-1b participated in disease symptoms, researchers created blood (hematopoietic) stem cells carrying a receptor, called IL-1 receptor antagonist (IL-1Ra), that blocks all IL-1 signaling. The genetic sequence for the receptor was introduced in cells’ genome through a harmless virus called a lentivirus, allowing them to pass on the receptor to future cells.

The goal was that, after being infused in mice, the stem cells would give rise to some immune cells, and these would have their IL-1b signaling blocked due to the presence of the IL-1Ra.

Between 75% and 86% of all immune cells — which derive from hematopoietic stem cells — were found to be producing this receptor, and some had reached the brain. Notably, transplanted animals showed significantly fewer behavioral problems than non-transplanted MPS-IIIA mice, including better working memory and less anxiety and hyperactivity.

Transplanted mice also had lower amounts of activated microglia and astrocytes, indicating that IL-1b signaling is a major driver of brain inflammation and damage.

Notably, these animals had no changes in lysosomal compartment size, meaning the approach’s benefits did not come by lowering the buildup of GAG molecules. The effects were also largely mimicked in animals lacking the receptor responsible for IL-1b signaling, again supporting the role of IL-1b in Sanfilippo syndromes.

“Blockade of IL‐1 prevents the development of the neurocognitive behavioural phenotype seen in MPSIIIA mice and ameliorates neuroinflammation without affecting lysosomal storage,” the researchers wrote.

Thus, “attenuation of IL‐1 signalling provides an attractive target for therapeutic intervention to ameliorate the consequences of neuroinflammation, in particular preventing cognitive decline,” they added.

The team suggests that both blood stem cell gene therapy and approved treatments that block IL-1b signaling may prove a therapeutic option for managing patients with Sanfilippo syndromes, and possibly those with other early-onset lysosomal diseases.