In Sanfilippo research, inflammation is often thought about in the context of the brain (known as neuroinflammation) brought on by the accumulation of heparan sulfate and the damage it causes in the brain. Now, researchers in the UK and France, led by Professor Brian Bigger, have found that an infection in other parts of the body may worsen neurodegeneration in a Sanfilippo type A mouse model.
In the study, they used a synthetic molecule called poly(I:C), which can mimic a molecule naturally found on some viruses. The researchers injected it into the bloodstream or abdominal cavity of the mice, and confirmed it stimulated effects in the body that are normally associated with an infection.
A high, sudden dose (e.g. mimicking an acute severe infection) and a low, chronic dose of poly(I:C) (e.g. mimicking a longer chronic illness) both led to weight loss in mice with and without Sanfilippo. Both doses also reduced overall activity in the Sanfilippo mouse model.
Before any poly(I:C) administration, many markers of inflammation and nerve cell damage were already significantly higher in the brain and blood of the mouse model of Sanfilippo compared to unaffected mice. However, these markers generally appeared to worsen in the Sanfilippo model following exposure to poly(I:C).
One important inflammatory molecule, IL-1ß, increased in the brain and blood of Sanfilippo and non-Sanfilippo mice following a high, sudden dose of poly(I:C) - but IL-1ß levels were higher in the Sanfilippo model than seen in the non-Sanfilippo mice in the hours after the poly(I:C) dose and remained higher for longer.
The researchers also measured a marker of nerve cell health in one part of the brain called the hippocampus, which is involved in memory and learning. Results indicate the health of these nerve cells in the Sanfilippo mice were significantly affected by both high, sudden and low, chronic doses of poly(I:C).
The ‘infection’ in the mouse model also impacted cognitive function. Twelve weeks of a chronic, high dose of poly(I:C) led to further reductions in working memory of the Sanfilippo mouse model compared to Sanfilippo mice that did not receive poly(I:C).
Overall, this study shows that a general infection outside of the brain in a Sanfilippo mouse model can lead to further neuroinflammation and impact the brain. This is important as recurrent infections, such as respiratory or urinary infections, are a common symptom of Sanfilippo syndrome.
Families can talk to their healthcare providers about the best ways to manage infections in their child or children affected by Sanfilippo. By diagnosing and treating infections early, and with guidance from the Sanfilippo syndrome consensus guidelines for clinical care, clinical teams can help to reduce the impact of general infections on neurodegeneration.
The study also highlights how treatments that might prevent or reduce the severity of infections in Sanfilippo may help to reduce their impact on cognitive decline. Further, treatments targeting the body’s immune system (for example see the recently published results of a clinical trial of the drug anakinra), may help to slow neurological symptoms in addition to addressing other important disease symptoms.
Funding for the study included a grant from the Orphan Disease Center at the University of Pennsylvania, USA.
