Coming at the heparan sulfate problem from the outside

27 Aug 2021

We often talk about heparan sulfate (HS) being a problem in Sanfilippo due to its build up inside cells. But high levels of HS can also be found in the fluid that surrounds cells.

The build-up of HS both inside and outside of cells can affect cell function and sparks the many symptoms of the disease, which includes behavioural issues and cognitive decline.

New research has found that clearing the HS that accumulates outside of cells can help to restore some cell functions and reduce the internal cell defects in Sanfilippo. The study was performed by scientists at the University of Naples Federico II (Italy) and was funded by Cure Sanfilippo Foundation (USA).

In the lab, the team took immature nerve cells and turned off the NAGLU gene, effectively creating a cell model of Sanfilippo type B. They found HS accumulated inside and outside of these model cells. As expected, there were defects in the lysosomes, compartments inside the cell where HS accumulates in Sanfilippo. However, they also found that the immature neurons were unable to develop into mature brain cells when stimulated, further highlighting how HS can affect normal cell functions.

To test how the HS on the outside of cells might be contributing to this dysfunction, the team removed the HS that was built up outside these cells. To do this, they used a laboratory-modified version of a naturally occurring protein called NK1. Normally, NK1 is important in cell growth, development and communication. The modified NK1 can grab onto HS strongly, helping to remove it from around the cells.

They found that using this method to remove HS from outside the cells caused changes inside them. It restored the cells ability to mature into brain cells and also led to reduced levels of HS and lysosomal defects on the inside of the cells.

More research is needed to investigate this further, including whether it will work in animals rather than only cells grown in the dish. However, these findings indicate that removal of HS outside cells may be a potential therapeutic avenue for Sanfilippo. While a Sanfilippo type B model was used in this project, the results could be applied to all forms of Sanfilippo, and to other similar diseases like Hurler, Hunter and Sly Syndromes.