Treating a mouse model of Sanfilippo with a small molecule, called trehalose, may be a viable therapeutic approach for people with this syndrome, researchers suggest.
Their study, “Trehalose reduces retinal degeneration, neuroinflammation and storage burden caused by a lysosomal hydrolase deficiency” was published in the journal Autophagy.
Autophagy is a term used to describe the process by which cells isolate and degrade “unwanted” cellular components. Several parts of the cell participate in this process, including lysosomes, small vesicles that are disrupted in lysosomal storage disorders (LSDs).
Sanfilippo syndrome IIIB (also known as MPS IIIB) is a type of LSD that results from a deficiency in the lysosomal enzyme NAGLU. This leads to the accumulation of the enzyme’s substrate, heparin sulphate, in several tissues that, in turn, causes severe neurological symptoms, including progressive dementia, aggressive behavior, hyperactivity, seizures, deafness or loss of vision.
Using a mouse model of Sanfilippo syndrome IIIB, which lacks a functional NGLU enzyme, researchers explored the possibility of enhancing autophagic activity to help cells clear unwanted material.
Mice were given oral doses of a known activator of autophagy, known as trehalose, and were monitored to test the compound’s effect.
When as little as 2% of trehalose was added to the drinking water of the diseased mice, their median life-span increased significantly by 6.4 weeks, without causing any obvious adverse effects.
Trehalose treatment also improved several behavioral and neurological features, including lower brain inflammation and lesser retinal degeneration.
Upon microscopic examination, researchers found that trehalose enhanced debris-clearance in brain cells by specifically increasing a transcriptional network, called TFEB, that controls lysosomal formation and autophagic flux.
“[T]rehalose in fact exerts clearance effects and therefore opens completely unexplored avenues for the possible treatment of lysosomal storage disorders caused by the deficiency of lysosomal enzymes,” the researchers wrote.
“Because much of the quality of life of patients suffering from MPS IIIB is associated with loss of vision, our study finally introduces a possible avenue to mitigate this devastating clinical outcome,” they concluded.