Molecule from marine bacteria shows benefits in Sanfilippo type A
Findings in mice highlight therapeutic potential for all disease types
A carbohydrate molecule derived from marine bacteria was able to reduce inflammation in the brain, reverse metabolic dysfunction, and preserve brain tissue integrity in a mouse model of Sanfilippo syndrome type A, according to a new study.
These benefits corresponded to an easing of motor deficits in the mouse model of the rare genetic disorder.
Scientists believe the findings highlight a class of molecules that could have therapeutic potential to prevent neurodegeneration in all forms of Sanfilippo syndrome.
“We observed some behavioral benefits and protective effects over brain metabolism, microstructure and neuroinflammation,” the researchers wrote, calling their work “an innovative approach” for treating Sanfilippo syndrome type A.
Testing molecules derived from deep sea bacteria in mouse model
In Sanfilippo, genetic mutations lead to a lack of any of four enzymes necessary for the step-wise breakdown of heparan sulfate (HS), a complex sugar molecule. Mutations associated with each enzyme correspond with the four types of Sanfilippo syndrome — identified as type A, B, C or D. Type A is the most common and usually the most severe.
The toxic accumulation of HS fragments in various stages of breakdown inside cells is what ultimately drives the neurodegenerative symptoms in all Sanfilippo types.
Another enzyme, called heparanase, creates the first cut in HS that initiates its degradation by those four enzymes. Researchers believe that heparanase inhibitors could have therapeutic potential for Sanfilippo. By preventing the defective degradation process from being initiated at all, HS fragments wouldn’t accumulate inside cells.
Versions of heparin, a molecule that prevents blood clotting, are known to inhibit heparanase.
Compounds extracted from certain carbohydrate-secreting deep sea bacteria, called marine polysaccharides, share some characteristics with heparin, but without the associated effects on blood clotting. Thus, they could have potential as therapeutic molecules in Sanfilippo.
To learn more, the researchers examined the effects of these molecules in a cell model of Sanfilippo type A. Specifically, they compared the impact of two marine-derived polysaccharides and two heparin derivatives as a reference.
Data indicated that all evaluated molecules led to heparanase inhibition, resulting in reduced accumulation of smaller HS fragments inside cells. Marine molecules were slightly more efficient than the heparin derivatives at preventing HS degradation.
The team then tested one of the molecules — called A5_3 and derived from Vibrio diabolicus marine bacteria — in a mouse model of Sanfilippo type A. Some of the mice were injected with A5_3 three times weekly for eight weeks, whereas others were left untreated.
The scientists found significant metabolic alterations in the brains of the Sanfilippo mice compared with healthy mice as early as four weeks of age. This included reductions in markers of energy metabolism and healthy cellular function.
These metabolic differences between the Sanfilippo and healthy mice lessened with age, the scientists noted. This suggests that Sanfilippo mice might “produce more metabolites over time in order to ‘compensate’ the initial disequilibrium in the neurochemical profile,” the scientists hypothesized.
Treatment with A5_3 partially reversed this altered profile in the mouse model by normalizing the levels of some metabolites.
Treatment found to reverse nerve cell injury, inflammation in brain
Markers of neuroinflammation, cell death, and nerve cell injury all were increased in the brains of the Sanfilippo mice. A number of these markers, particularly those associated with neuroinflammation, were reversed with A5_3.
The benefits of A5_3 corresponded with partial restoration of tissue integrity. While the brain’s white matter — a portion that contains mostly nerve cell projections — showed signs of damage in the Sanfilippo mice, this was partially restored with treatment.
In turn, the motor deficits exhibited in the mouse model were partially reversed by A5_3.
Evidence of increased heparanase activity was observed in the brain, but was not reversed with treatment.
“Marine polysaccharides are able to exert pleiotropic effects [more than one effect] similarly to heparin, therefore we cannot exclude that their mechanism of action passes through other routes than [heparanase],” the scientists wrote.
The treatment was well-tolerated by the mice.
“Importantly, this study is the first to demonstrate that the repeated and prolonged administration of marine polysaccharides is a feasible approach in the context of [Sanfilippo type A],” the researchers wrote.
Future studies should further examine the best route of administration for these compounds to enable maximum brain entry and to “fully exploit the potential of A5_3 treatment in neurodegenerative conditions,” the team concluded.