A new therapeutic approach may one day delay neurodegeneration typical of a disease called mucopolysaccharidoses IIIB (MPS IIIB). Neurodegeneration in this condition results from the abnormal accumulation of essential cellular molecules called mucopolysaccharides. Looking to find alternative therapeutic strategies for this rare genetic disease, a team of researchers investigated whether enhancing the cells' ability to clear accumulation of cellular waste would help eliminate the abnormal storage of mucopolysaccharides.
The study was published in the journal Autophagy, that the sugar trehalose increases cellular waste disposal and improves the neurological symptoms in a mouse model of the disease. MPS IIIB is one of about 50 lysosomal storage disorders characterized by the accumulation of material inside tiny cellular sacs called lysosomes. In the case of MPS IIIB, a mutation on a gene that codes for a lysosomal enzyme that breaks down a cellular material called heparan sulfate renders the enzyme ineffective.
Consequently, the lysosome cannot do its work of degrading heparan sulfate to either discard it or recycle it, and the material accumulates. Over the years, accumulation of heparan sulfate in lysosomes leads to degeneration of brain tissue. Although infants appear healthy at first, they slowly begin to show behavioral problems, hyperactivity, aggressiveness, sleep disturbances and loss of vision and hearing.
Current strategies being tested for the treatment of this condition in animal models include attempting to correct the enzyme deficiency by providing a fully working enzyme. However, this approach faces challenges such as having limited ability to cross the blood-brain barrier and reaching the brain areas where the enzyme is needed.
A non-traditional approach
They explored a way to treat this condition with a nontraditional approach. They recently discovered that the small sugar trehalose promotes the recycling of cellular waste. This made us think of an indirect approach to try to solve the accumulation of heparan sulfate. Instead of correcting the enzyme deficiency, they would try to overcome it by enhancing the cells' natural ability to discard cellular waste.
The researchers tested their approach on a mouse model of MPS IIIB. These mice have a mutation that results in the recapitulation of most of the clinical symptoms observed in patients, including progressive neurodegeneration, loss of vision, brain inflammation and a shorter lifespan. Also, the researchers explored the molecular mechanism underlying the trehalose effect.
Previously, they had discovered that trehalose activates TFEB, a master regulator of the lysosomal system. As the activity of TFEB increases, the degradation and clearance of molecules in the lysosomes becomes more efficient.
Enzyme Replacement Therapy
The effect on the retina is important. Loss of vision is one of the most devastating aspects of some lysosomal diseases. In animal models, treatments based on enzyme replacement therapy do not reach the brain and do not counteract the loss of vision.
Our results encourage us to consider that trehalose also may be effective in other lysosomal storage diseases, such as Batten disease. Trehalose is a widely used food additive with no current restrictions for human use.