Changes Seen in Brains of Sanfilippo D Mice May Advance Therapy Work

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by Steve Bryson, PhD |

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An examination of brain tissue from a mouse model of Sanfilippo syndrome type D revealed several progressive disease-related features, including the altered degradation of energy-producing mitochondria and the abnormal activation of immune cells associated with inflammation and brain cell death, a study reported.

Findings show key underlying processes associated with the disorder that may help the design of preclinical models to test potential treatments, the researchers said.

The study, “Neuropathology of murine Sanfilippo D syndrome,” was published in the journal Molecular Genetics and Metabolism.

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Extremely rare, Sanfilippo syndrome type D is caused by mutations in the GNS gene, which carries instructions for an enzyme that helps degrade the complex sugar molecule called heparan sulfate in lysosomes, the cell’s recycling center.

GNS is one of four Sanfilippo-related genes that, when defective, result in the toxic buildup of heparan sulfate within lysosomes, triggering cellular damage, especially in brain tissue, and leading to symptoms in children resembling Alzheimer’s disease.

Understanding how excess heparan sulfate leads to disease-causing tissue damage in animals can inform the design of preclinical studies and spotlight potential targets that may give rise to the development of new therapies.

Sanfilippo D has “no available effective therapies, and until recently, there were no mouse model[s] … for preclinical use,” the study noted.

Researchers at the Washington University in St. Louis, Missouri, and Children’s Hospital Orange County Research Institute in California examined the brain tissue of mice that lacked the GNS gene, compared to unaffected mice, at 12, 24, 36, and 48 weeks (one year) of age.

As expected, levels of LAMP-1, a membrane protein in lysosomes that is a biomarker for lysosomal enzyme deficiency, were higher in Sanfilippo mice than control animals. LAMP-1 was more pronounced at 12 and 24 weeks of age than at 36 and 48 weeks, because control mice also had higher age-related LAMP-1 levels.

In specific regions of the brain, by 24 weeks of age, there was the lysosomal accumulation of misfolded SCMAS, a protein within mitochondria. This buildup, which increased with age, is considered an indicator of abnormal mitophagy — the degradation of mitochondria when they are defective due to damage or stress.

Sanfilippo type D mice starting at 12 weeks of age and onward had progressively higher levels of markers associated with activation of microglia, cells found throughout the brain and spinal cord that are the first and main form of active immune defense.

At the same time, there was a progressive increase in markers showing the abnormal activation of astrocytes, star-shaped cells in the brain with many supportive functions.

Activation of both microglia and astrocytes is a typical response to injury or disease in the brain. Abnormal astrocyte activation, called astrogliosis, suggested inflammation and the death of brain cells in the area.

The researchers noted these findings were consistent with a separate Sanfilippo type D mouse model as well as an examination of post-mortem brain tissue from two type D patients.

“Cataloging the regional neuropathology of Sanfilippo D mice may aid in understanding the disease [development] and designing preclinical studies to test brain-directed treatments,” the scientists wrote.

Creation of this Sanfilippo D mouse model was funded in part by a Rare Disease Science Challenge 2012 prize to the Jonah’s Just Begun Foundation and the study by grants from the National Institutes of Health (NIH), mostly to the biotech company Phoenix Nest.

This company is developing enzyme replacement therapies for Sanfilippo syndrome types C and D, aiming to treat the condition by providing the missing lysosomal enzymes. Recently, Phoenix Nest received a $3.4 million NIH grant to fund a natural history study — an observational study following a group of Sanfilippo syndrome type D patients over time.