Diverting heparan sulfate breakdown to help treat Sanfilippo

18 Sep 2023

Heparan sulfate (HS) is vital in the body. It is important for cells to communicate with other cells. It also helps cells to regulate themselves in response to their environment. 

However, HS needs to be recycled and replaced. This happens through a series of steps starting outside of the cell, when an enzyme called heparanase ‘cuts’ HS off the cell surface. HS is then transported into the cell, where it is fully broken down inside a cell compartment called the lysosome.

In Sanfilippo, one of four enzymes that help break down HS in the lysosome is either missing or does not work properly. This leads to the build-up of HS in the lysosome causing damage to cells throughout the brain and body. Researchers around the world are working on different approaches to reduce the HS build-up and develop treatments for people with Sanfilippo.

Dr Ariane de Agostini, based at the University of Geneva in Switzerland, and her team were funded by Fondation Sanfilippo Suisse to explore a new way to prevent HS building up in cells. The group’s approach is to try to divert HS into a different disposal pathway by blocking heparanase: if HS is not ‘cut’ from the cell surface, there may be less HS that builds up inside the lysosomes, and the cells would be forced to use another route to expel excess HS from the body.

The team recently published results of their study testing two compounds, called ‘A5_3’ and ‘A5_4’, known to block heparanase from working properly. Both compounds are derived from molecules made by microorganisms found in some of the harshest marine environments, such as hot springs on the ocean floor.

First, they tested A5_3 and A5_4 in a cell model of Sanfilippo type A, and saw that treated cells had less HS degradation in the lysosome as they had hoped. Based on their results, and because of the smaller size of the compound (which is easier to deliver to the brain), they selected A5_3 for use in a mouse model of Sanfilippo type A. 

They treated the mice from 4 weeks of age with A5_3 injected into the abdomen every week for 8 weeks. 

The team had previously measured markers of metabolism in the brain and demonstrated for the first time that mice with Sanfilippo show changes from as early as 4 weeks of age when compared to mice without Sanfilippo. Following the 8 weeks of treatment with A5_3, these metabolism markers were restored to healthy levels in the mice with Sanfilippo.

Brain imaging techniques were also used to investigate the structure of the brain tissue. Mice with Sanfilippo type A that received A5_3 displayed improvements in the white matter—the parts of the brain involved in communication between different parts of the brain—compared to mice with Sanfilippo that did not receive treatment. There were also reductions in the amount of inflammation in the brain in the mice with Sanfilippo that received the A5_3 injection compared to untreated mice.

Overall, their results indicate that A5_3 was well tolerated in the mice with Sanfilippo type A, and that A5_3 helped to improve aspects of metabolism and brain tissue structure and reduce inflammation in the brain.

The work also provides new evidence of how early the damage to cells starts in Sanfilippo, highlighting the importance of early access to treatment to potentially alter the disease course.

Further work is needed to optimise the delivery of these compounds to the brain and confirm if the approach has potential for treating Sanfilippo. Work is also needed to confirm the compounds can be safely used in humans before these could be tested in patients. If it is found to be a suitable therapy avenue, the approach would likely benefit all subtypes of Sanfilippo, and potentially other MPS disorders that lead to a build up of HS.